8 rEPROGRAMMING

Biomedicine & Pharmacotherapy 176 (2024) 116806
Contents lists available at ScienceDirect
Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha
Review
Reprogramming of astrocytes and glioma cells into neurons for central

nervous system repair and glioblastoma therapy
Junyuan Wei a, Miaomiao Wang a, Shilin Li b, Rui Han c, Wenhong Xu a, Anqi Zhao a, Qi Yu a,
Haokun Li a, Meiying Li a, *, Guangfan Chi a, *
a
The Key Laboratory of Pathobiology, Ministry of Education, and College of Basic Medical Sciences, Jilin University, Changchun 130021, China
b
School of Public Health, Jilin University, Changchun 130021, China
c
Department of Neurovascular Surgery, First Hospital of Jilin University, 1xinmin Avenue, Changchun, Jilin Province 130021, China
A R T I C L E I N F O A B S T R A C T
Keywords: Central nervous system (CNS) damage is usually irreversible owing to the limited regenerative capability of
Neuron neurons. Following CNS injury, astrocytes are reactively activated and are the key cells involved in post-injury
Astrocyte repair mechanisms. Consequently, research on the reprogramming of reactive astrocytes into neurons could
Reprogramming
provide new directions for the restoration of neural function after CNS injury and in the promotion of recovery in
Glioblastoma
various neurodegenerative diseases. This review aims to provide an overview of the means through which
reactive astrocytes around lesions can be reprogrammed into neurons, to elucidate the intrinsic connection
between the two cell types from a neurogenesis perspective, and to summarize what is known about the neu
rotranscription factors, small-molecule compounds and MicroRNA that play major roles in astrocyte
Abbreviations: AAV, adeno-associated virus; AD, Alzheimer’s disease; ALC5, Activin-like receptor kinase 5; AP-1, activator protein 1; APC, adenomatous polyposis
coli; Ascl1, achaete-scute family bHLH transcription factor 1; BFGF, basic fibroblast growth factor; BMP, bone morphogenetic protein; BBB, blood-brain barrier; BEV,
bevacizumab; BRD8, bromodomain containing 8; Brn2, POU class 3 homeobox 2; CAR, chimeric antigen receptor; CDKN2A, cyclin dependent kinase inhibitor 2A;
CEND1, cell cycle exit and neuronal differentiation 1; CHAT, choline acetyltransferase; Chd7, Chromodomain helicase DNA-binding protein 7; CK1, Casein Kinase 1;
NS, Central nervous system; CSPGs, chondroitin sulfate proteoglycans; CTIP2, COUP-TF interacting protein 2; Ctip2, chicken ovalbumin upstream promoter tran
scription factor-interacting protein 2; DAPT, 24-diamino-5-phenylthiazole; DCX, doublecortin; DLX2, distal-less homeobox 2; DNMT1, DNA methyltransferase 1;
DLL1, delta-like 1; DRG, dorsal root ganglion; EphrinB3, ephrin B3; FOXG1, forkhead box G1; GABA, gamma-aminobutyric acid; GAD67, glutamate decarboxylase
67; GBM, glioblastoma; GFAP, glial fibrillary acidic protein; GSK3, glycogen synthase kinase 3; GSK3β, glycogen synthase kinase 3 beta; HESC, shuman embryonic
stem cells; HMG, high mobility group; HiPSCs, human-induced pluripotent stem cells; Id1-3, inhibitor of DNA-binding 1–3; IL-1, interleukin one; IL-6, interleukin-6;
INs, induced neurons; Insm1, insulinoma-associated protein 1; JAK, Janus kinase; JAK-STAT, Janus kinase signal transducer and activator of transcription; JNK, c-
Jun N-terminal kinase; Klf10, Krüppel-like factor 10; LCMV, lymphocytic choriomeningitis virus; LIF, leukemia inhibitory factor; LMX1A, LIM homeobox tran
scription factor 1 alpha; MAGs, myelin-associated glycoproteins; MAP2, microtubule-associated protein 2; MAPK, mitogen-activated protein kinase; MMR, mismatch
repair; MTOR, mechanistic target of rapamycin kinase; Myt1, Myelin Transcription Factor 1; NANOG, Nanog Homeobox; Myt1l, myelin transcription factor 1 like;
NC, neuroblastoma cells; NF200, neurofilament 200; ICD, Notch intracellular domain; NKX6.1, NK6 homeobox 1; NPC, neural progenitor cell; NSC, neural stem cell;
NSPC, neural stem/progenitor cell; NeuN, neuronal nuclear antigen; NeuroD1, Neurogenic differentiation 1; NeuroD4, neurogenic differentiation 4; Neurog2,
neurogenin 2; NGN2, neurogenin-2; Nurr1, nuclear receptor related 1 protein; Oct4, octamer-binding transcription factor 4; OMgp, oligodendrocyte myelin
glycoprotein; OPCs, Oligodendrocyte precursor cells; Par3, protease-activated receptor 3; Pax6, paired box protein 6; PCNA, proliferating cell nuclear antigen; PD-1,
programmed cell death protein 1; PD-L1, programmed death-ligand 1; PTBP1, Polypyrimidine tract-binding protein 1; PVALB, parvalbumin; RAC1, Ras-related C3
botulinum toxin substrate 1; RACs, Reactive astrocytes; REST, RE-1 silencing transcription factor; RG, radial glial; ROCK, Rho-associated protein kinase; R-Smad,
receptor activated SMAD; SAG, Smoothened agonist; SEM4D, sema domain, immunoglobulin domain Ig, transmembrane domain TM and short cytoplasmic domain,
semaphorin 4D); Smad, homolog of mothers against decapentaplegic; Sema3A, semaphorin 3A; Sema4D, semaphorin 4D; SGL, subgranular layer; SOX2, sex
determining region Y-box 2; SOX11, Sex Determining Region Y-Box 11; STAT, signal transducer and activator of transcription; STAT3, signal transducer and activator
of transcription 3; SV2, synaptic vesicle protein 2; SVZ, subventricular zone; SYN1, synapsin 1; TAAs, tumor-associated antigens; TCF, transcription factors; TGF-β,
Transforming growth factor beta; TH, tyrosine hydroxylase; TMZ, temozolomide; TNF-α, tumor necrosis factor alpha; TUJ1, Taurine upregulated 1; VPA, Valproic
acid; VGLUT1, vesicular glutamate transporter 1; VGLUT2, vesicular glutamate transporter 2; β-Trcp, bcta-transducin repeats-containing proteins.
* Corresponding authors.
E-mail addresses: [email protected] (J. Wei), [email protected] (M. Wang), [email protected] (S. Li), [email protected]
(R. Han), [email protected] (W. Xu), [email protected] (A. Zhao), [email protected] (Q. Yu), [email protected] (H. Li), limeiying@jlu.
edu.cn (M. Li), [email protected] (G. Chi).
https://doi.org/10.1016/j.biopha.2024.116806
Received 9 February 2024; Received in revised form 18 May 2024; Accepted 20 May 2024
Available online 25 May 2024
0753-3322/© 2024 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC license
(http://creativecommons.org/licenses/by-nc/4.0/).
J. Wei et al. Biomedicine & Pharmacotherapy 176 (2024) 116806
reprogramming. As the malignant proliferation of astrocytes promotes the development of glioblastoma multi
forme (GBM), this review also examines the research advances on and the theoretical basis for the reprogram
ming of GBM cells into neurons and discusses the advantages of such approaches over traditional treatment
modalities. This comprehensive review provides new insights into the field of GBM therapy and theoretical in
sights into the mechanisms of neurological recovery following neurological injury and in GBM treatment.
1. Introduction caused by CNS injury. Stroke is the most common CNS injury disease
[2]. Studies have found that inducing reprogramming of reactive as
During neurogenesis in the CNS, neural stem cells (NSCs) differen trocytes into neurons after stroke can help promote neurological re
tiate into neurons and glial cells (Fig. 1); moreover, neurons are termi covery after injury [3]. However, except for stroke, neurodegenerative
nally differentiated cells that gradually lose their regenerative capacity diseases, including Alzheimer’s disease and Parkinson’s disease, are also
during development and maturation as a result of transcriptomic major causes of CNS damage. The lesions are mostly characterized by
changes and chromatin remodeling processes [1]. Although astrocytes abnormal aggregation of proteins, triggering inflammatory reactions,
reactively proliferate, the capacity for neuronal regeneration is further neuronal damage and death, and destruction of neuronal networks, ul
impaired following CNS injury, during which the formation of a glial timately leading to neurometabolic dysfunction [4]. In this process, the
scar is promoted through communications with microglia, and large abnormal proliferation of glial cells, including astrocytes, plays an
amounts of neurotransmitters are secreted, further impeding neuronal important pathogenic role [5], and the reactive activation of astrocytes
regeneration (Fig. 1). Therefore, the induction of neural recovery has is a major pathological change in AD tissues, reactive astrocytes
become a primary therapeutic challenge following neuronal death contribute to the neuroinflammatory changes in AD through the release
Fig. 1. The processes of neurogenesis under physiological conditions and in repair following CNS injury. During normal neurogenesis, neural stem cells differentiate
into astrocytes and neural progenitor cells, the latter of which differentiate further into primary neurons after 3 days. These primary neurons subsequently migrate to
their designated locations at 1 week where they gradually undergo maturation into immature neurons after 3 weeks and into mature neurons after 4 weeks. However,
when the CNS is injured, such as during a stroke, astrocytes proliferate in large numbers and undergo a phenotypic switch to “activated” GFAP-positive reactive
astrocytes, which are hyperproliferative; such astrocytes communicate with and drive the activation of microglia, leading to the formation of a glial scar that prevents
the injury from expanding further. During glial scar formation, neuroinhibitory factors produced by reactive astrocytes, such as CSPG, MAG, OMgp, EphrinB3, and
Sema4D, impede neuronal regeneration and axon formation as well as neurological functional repair after CNS injury. The key genes that have been shown to induce
astrocyte-to-neuron differentiation after CNS injury are listed on the right. The reprogramming of glial cells into neurons can be induced by the downregulation of
PTBP1 (Polypyrimidine tract-binding protein 1) and p53 or the upregulation of Sox2, Ascl1, Pax6, NeuroD1, Neurog2, NeuroD4, CEND1, DXL2, and Oct4 expression.
(CNS, Central nervous system; GFAP, glial fibrillary acidic protein; CSPG, chondroitin sulfate proteoglycans; MAG, myelin-associated glycoprotein; OMgp,
oligodendrocyte-myelin glycoprotein; EphrinB3, ephedrineB3; Sema4D, Transmembrane semaphorin4D; Sox2, SRY-box transcription factor 2; Ascl1, Achaete-scute
complex-like 1; Pax6, Paired box protein 6; NeuroD1, Neurogenic differentiation 1; Neurog2, Neurogenin2; NeuroD4, neuronal differentiation 4; CEND1, cell-cycle
exit and neuronal differentiation 1; DLX2, distal-less homeobox 2; Oct4, octamer (ATGCAAAT)-binding transcriptional factor 4).
2
of cytokines, inflammatory factors, and inducing an imbalance of the administration of a single neurotranscription factor has a limited influ
redox state [6]. Studies have suggested that cell therapy may be a new ence on the conversion of astrocytes into neurons; therefore, subsequent
treatment for neurodegenerative diseases [7]，reprogramming human induction protocols were developed to augment the efficacy of the
pluripotent stem cells, fibroblasts, and astrocytes into neurons may hold transformation through the concurrent administration of multiple neu
great promise as a potential strategy for treating Parkinson’s disease [8]. rotranscription factors. Based on the functions of the various neuro
Therefore, inducing reactive astrocytes around the lesion instead of the transcription factors involved in neurogenesis, distinct combinations
normal astrocytes prevalent in the brain to reprogram neurons can can be selected to facilitate the preservation of neuronal morphology
promote neuronal regeneration and reconstruct the neural function and function to effectively enhance the astrocyte-to-neuron differenti
network on the one hand, and maintain the normal function of astro ation process. In practice, however, the selection of multiple neuro
cytes on the other hand, provide a microenvironment suitable for transcription factors poses a technical obstacle, as numerous
neuronal survival, and maintain brain homeostasis [9]. Reactive astro transfections impede cellular survival. Furthermore, there is some con
cytes are ideal cells for reprogramming into neurons because they retain troversy regarding the safety of utilizing retroviruses or adeno-
the original morphology of the radial glia (RG) that neurons can be associated viruses (AAVs) that carry multiple transcription factors in
generated from [10]. In addition to reactive astrocytes, we note that in vivo experiments. Thus, a third induction approach was developed to
NG2-positive glial cells also have the potential to be induced into neu enhance conversion efficiency while simultaneously maintaining safety;
rons. NG2-positive cells, also known as oligodendrocyte precursor cells this approach involves combining neurogenic transcription factors with
(OPCs), under in vitro conditions, NG2 cells exhibit pluripotent stem cell small molecules to synergistically promote the differentiation of astro
properties. They can differentiate into oligodendrocytes, astrocytes, and cytes into neurons. Several studies have confirmed that such an
even neurons when stimulated by specific factors [11]. The study found approach using a combination of small-molecule compounds can induce
that reactive astrocytes derived from NG2 cells could be detected in the direct reprogramming of astrocytes into neurons [19], creating new
CNS-injured transgenic mice [12,13], and after spinal cord injury, NG2 opportunities to improve the efficiency and safety of such conversions
cells are involved in scar formation [14]. Therefore, the induced while also reducing the oncogenic potential.
reprogramming technique is also suitable for transforming NG2 cells Initially, small-molecule compounds were predominantly used as
into neurons to promote the recovery of neurological function after CNS molecularly targeted drugs to induce therapeutic effects by inhibiting
injury. The feasibility of this idea has been demonstrated by the ability the proliferation and metastasis of malignant tumors [20–22], including
of NG2 cells to produce neurons [15,16], and by utilizing the neurogenic those in the CNS. The clinical treatment of glioblastomas (GBMs), which
potential of NG2 cells to produce neurons after spinal cord injury, can be triggered by the malignant proliferation of astrocytes [23], has
contributing to the recovery of neurological function after injury [17]. remained challenging owing to the high levels of proliferation and the
In addition, various studies have demonstrated that protocols tar ease of recurrence of the disease [24], and immunotherapies such as
geting specific neural transcription factors such as SRY-box transcription those involving programmed cell death protein 1 (PD-1)/programmed
factor 2 (Sox2), achaete-scute complex-like 1 (Ascl1), and paired box death-ligand 1 (PD-L1) as well as chimeric antigen receptor (CAR) T-cell
protein 6 (Pax6) are likely to be the main means through which neuronal therapy remain unoptimized due to the limited specificity and incom
reprogramming is induced (Fig. 1). plete clearance of tumor cells [25]. Existing studies have shown that
The reprogramming of reactive astrocytes into neurons primarily inducing the differentiation of tumor cells into normal cells, thereby
involves two approaches. The first approach is cellular dedifferentiation, inhibiting their proliferation and reducing their number, is likely to be a
in which astrocytes are induced to form neurospheres; subsequently, novel means of inhibiting tumor progression. Therefore, inducing
differentiation into neurons that exhibit typical neuronal properties astrocyte reprogramming into neurons may provide a new theoretical
[18]. The second approach is “transdifferentiation,” also known as basis for GBM treatment.
“direct cellular reprogramming,” which involves the transformation of The purpose of this review was to explore the feasibility of ap
cells of one lineage into those of another through the reprogramming of proaches for reprogramming astrocytes into neurons from a molecular
somatic cells in response to specific factors; this process occurs more biological perspective using several possible induction strategies. This
quickly and efficiently than does indirect reprogramming, as it does not review summarizes the small-molecule compounds that can be used to
require intermediate transition states. In principle, such reprogramming induce this type of cellular reprogramming. Additionally, it describes
is more suitable for in vivo tissue repair than indirect reprogramming the superiority of combining the administration of neurotranscription
because it can occur ex vivo and in situ within the target tissue. In factors with small-molecule drugs as new therapeutic strategies for
addition, direct reprogramming exhibits a greater capacity for preser promoting neural regeneration and the recovery of neurological func
ving the epigenetic characteristics of the original (primitive) cells than tion after CNS injury or for the reprogramming of GBM cells into neu
indirect reprogramming [17], making it particularly suitable for rons to compensate for the shortcomings and side effects of existing
reprogramming reactive astrocytes into neurons. Therefore, a great treatments.
focus is placed on the process of direct reprogramming and its induction
schemes. 2. The role of astrocytes and neurons in the CNS
Both astrocytes and neurons are derived from the neuroectoderm;
however, the direction of differentiation is determined by the signaling Astrocytes and neurons are the primary cellular components of the
pathways that are predominantly activated during the redifferentiation CNS, playing important and complementary roles in maintaining brain
process. Therefore, the key to successfully inducing the reprogramming function and performing tasks related to the regulation of energy sup
of astrocytes into neurons lies in activating the neuron differentiation- plies and cell signaling. Astrocytes are the most abundant type of glial
related signaling pathways while simultaneously inhibiting those asso cells in the brain, predominantly exerting trophic and support functions
ciated with astrocyte differentiation; this can be achieved through the under normal physiological conditions [26]. Astrocytes control the up
application of protocols that reduce neuronal apoptosis or other types of take of glucose from blood vessels and store large quantities of glycogen,
cell death after induction while maintaining their functional activity. and the lactic acid broken down by astrocytes provides a source of en
Currently, three main methods have been identified for inducing the ergy for neurons during states of hypoglycemia or high neuronal activ
direct reprogramming of reactive astrocytes into neurons. The first ity. Astrocytes also regulate ion transport [27], including the movement
method involves the selection of transcription factors that promote of Ca2+, K+, Cl-, HCO-3, and I-, which helps in the maintenance of energy
neuronal differentiation during neurogenesis; the overexpression of sources by regulating the extra-neuronal ionic environment. Astrocytes
such factors in astrocytes will alter their phenotype and function, can increase their buffering capacity to maintain the intra- and extra
facilitating their differentiation into neurons. However, the cellular pH balance and normal neuronal activity while participating in
3
complex signaling and pathological processes in the CNS. When lesions reprogramming technology to induce astrocyte reprogramming into
occur in the CNS as a result of stroke, trauma, tumor growth, or neurons could become an important therapeutic strategy for restoring
neurodegenerative diseases [28] or owing to inflammatory conditions neurological function after CNS injury.
[29], pro-inflammatory cytokines such as tumor necrosis factor-alpha
(TNF-α) and interleukin one (IL-1) stimulate the proliferation and po 3. Neurogenesis of astrocytes and neurons
larization of quiescent astrocytes into a reactive phenotype (A1 astro
cytes). An increase in A1 astrocytes predominantly occurs during the 3.1. Neurogenic processes
early stages of injury [30]; these reactive astrocytes secrete inflamma
tory factors and neurotoxic mediators, which further aggravate CNS Neurogenesis begins with the proliferation of NSCs and the balanced
injury. However, astrocytes may also hinder axonal regeneration in the and unbalanced divisions that lead to the formation of directed pro
late stages of injury owing to glial scarring [31]. genitor cells that gradually migrate toward functional regions where
In contrast, the main functions of neurons are to receive, integrate, they undergo continuous plastic changes and establish synaptic con
and conduct signals to transmit information[32]. In terms of subcellular nections with other neurons to generate neural functionality. The pro
components, the cytosol and dendrites are mainly responsible for cess begins with RG cells in the subgranular region of the embryo [33],
receiving and integrating information, whereas the axon is mainly which have a high capacity for expansion. These expanded cells are
responsible for generating action potentials and integrating information, called progenitor cells, which will eventually divide asymmetrically to
which is transmitted neurochemically across synaptic terminals to produce adult neurons; more specifically, they gradually migrate toward
effector cells or other neurons. However, neurodegenerative diseases or the granule cell layer and develop into immature granule neurons, after
neuroinflammation can impair the ability of neurons to regenerate, which they migrate toward the molecular layer to form mature granule
resulting in a deterioration of function and ultimately leading to neurons, which can then be integrated into the hippocampal circuitry to
neuronal death. influence behavior. After birth, NSCs are present in the developing brain
The limited ability for neurons to regenerate makes it difficult to and continue to lead to the production of neurons, primarily in the
restore neural function once the CNS has been damaged and a large subependymal ventricular zone (SVZ) in the lateral ventricular wall.
number of neurons have died, which can have a severely negative These neurons migrate to the olfactory bulb, where they continuously
impact on normal human life. Therefore, the application of cell replace localized interneurons. Neurogenesis also continues to occur in
Fig. 2. The key signaling pathways and mechanisms that regulate the differentiation of NSCs into astrocytes. A: In the JAK-STAT signaling pathway, cytokines bind
to receptors expressed on the cell membrane and mediate receptor dimerization. JAK binds to cytokine receptors on the cell membrane, exposing tyrosine binding
sites and promoting their phosphorylation. The phosphorylated cytokine receptors recruit STAT, which binds to tyrosine residues on the receptor, allowing JAK to
further mediate the phosphorylation of STAT. Phosphorylated STAT promotes dimerization and entry of the dimer into the nucleus. Intranuclear STAT binds to target
gene promoters and promotes the transcription of target genes such as GFAP and DLL1. B: The Notch signaling receptor is transferred to the cell membrane after being
sheared by Furin protease on the Golgi apparatus through a process known as S1 cleavage. DLL1 binds to Notch1/3/4, inducing binding between the Notch ligand
and Notch receptor; this activates the Notch signaling pathway, causing the entry of the Notch protein into the cell. In which, the S2 and S3 cleavages are performed
under the action of metalloproteinases and Γ-secretase, respectively, ultimately forming a Notch intracellular domain (NICD), which enters the nucleus and binds to
the promoter region of the target gene. This results in the dissociation of DNMT1 from a target gene such as GFAP, thereby promoting its transcription; these changes
are accompanied by the demethylation of the promoter region of a target gene such as S100ß and recruitment of the transcription factor STAT to promote its
transcription. C: When an ischemic injury occurs, fibrous protein blood vessels become exposed, initiating a signaling cascade involving the activation of type II and
type I serine-threonine kinase receptors, mediating receptor-activated R-Smad phosphorylation. R-Smad binds to Smad4 and enters the nucleus as an aggregator,
binding to the promoter of a target gene such as GFAP and promoting its expression. (JAK, Janus kinase; STAT, signal transducer and activator of transcription; DLL1,
Delta-like ligand 1; DNMT1, DNA methyltransferase 1).
4
the adult hippocampus, particularly in the subgranular layer (SGL) of hippocampal region, promoting their differentiation into astrocytes in
the dentate gyrus [34]. Accordingly, both astrocytes and neurons are vitro.
derived from the neuroectoderm; however, the direction of differentia
tion depends on the signaling pathways that predominate during the 3.3. Signaling pathways involved in the differentiation of NSCs into
redifferentiation process. By understanding the signaling pathways that neurons
exert a regulatory role in the process of neurogenesis, the balance be
tween astrocytes and neurons can be controlled by activating or inhib Recently, several studies have focused on the neurogenic effects of
iting the function of one or more pathways. Wnt family proteins, such as Wnt4, Wnt5a, and Wnt11. Non-classical
Wnt signaling pathways, including the Wnt/Ryk, Wnt/Ca2+, and Wnt/
3.2. Signaling pathways involved in the differentiation of NSCs into c-Jun N-terminal kinase (JNK) pathways, have been reported to play
astrocytes key roles in neural differentiation, with Wnt4 having been identified as a
key effector molecule that promotes NSC-to-neuron differentiation
Various signaling pathways that play important roles in the differ during neurogenesis. Wnt4 promotes neuronal differentiation through
entiation of NSCs into astrocytes have been identified to date and are the Wnt/β-linker protein and mitogen-activated protein kinase (MAPK)/
summarized in Fig. 2[35–40]. From late gestation to the perinatal JNK signaling, and Wnt4 inhibits the negative effects of Notch signaling
period, NSCs give rise to astrocytes, and Janus kinase/signal transducer in neuronal differentiation by suppressing Hes1 and Hes5 in vitro [44].
and activator of transcription (JAK-STAT) signaling plays a critical role Additionally, the activation of the Wnt4 pathway significantly increases
in various developmental pathways, particularly in those that promote the expression of various neuronal markers, including β3-microtubulin,
the generation of astrocytes [38]. During late gestation, a period that is microtubule-associated protein 2 (MAP2), and neurofilament 200
associated with a decrease in basic helix-loop-helix (bHLH) expression (NF200) (Fig. 3), without altering the expression levels of the astrocyte
levels, this signaling pathway is strongly activated and plays an marker GFAP.
important role in the generation of astrocytes [39]. This pathway can be In addition, Transforming growth factor beta (TGF-β) also promotes
activated by various proteins, including leukemia inhibitory factor (LIF), the development of dopaminergic neurons [45] and is involved in cell
basic fibroblast growth factor (bFGF) [36], and members of the inter cycle exit and the initiation of neuronal differentiation, among other
leukin 6 (IL-6) family of cytokines. Upon receptor binding, JAK becomes processes. Furthermore, endogenous TGF-β signaling may be active in
autophosphorylated, resulting in its activation. Activated JAK, in turn, both post-mitotic immature neurons and in mature neurons in the
phosphorylates tyrosine residues on the intracellular structural domains dentate gyrus [46]. Smad2/3 is an intracellular molecule that partici
of these receptors, where the signal transducer and activator of tran pates in the TGF-β signaling cascade, and several studies have shown
scription 3 (STAT3) is recruited and phosphorylated by JAK; subse that Smad2/3 is expressed in neuroblasts as well as immature and
quently, phosphorylated STAT3 homodimerizes and translocates into mature granule neurons, controlling the survival of intermediate pro
the nucleus to induce the expression of astrocytic genes, such as glial genitors and the rate of denovo neuron production in the adult dentate
fibrillary acidic protein (GFAP), thereby promoting astrocyte differen gyrus [47]. Deficiency of the TGF-β type I receptor, ALK5, results in a
tiation (Fig. 2A). reduction in the number of doublecortin (DCX)+ neurons, whereas
Notch signaling controls the direction of NSC differentiation in favor activation of ALK5 promotes neuronal maturation (Fig. 3). Thus, TGF-β
of astrocytes over neurons. To verify the mechanism of action of Notch, exerts neuroprotective effects and promotes neurogenesis in adults.
Tanigaki et al. [40] overexpressed Notch in pluripotent neural progen Glycogen synthase kinase 3 (GSK3), a key regulator of neuro
itor cells (NPCs) and found that activated Notch1 and Notch3 promoted development, is widely expressed in the CNS, with particularly high
astrocyte development by inhibiting neuronal and oligodendrocyte dif expression levels in the hippocampus in all stages from embryonic
ferentiation; they also observed that disrupting the binding of STAT3 to development to adulthood. During the proliferative phase of neuro
GFAP did not affect Notch-induced activation of GFAP transcription, development, the upstream signal protease-activated receptor 3 (Par3),
suggesting that the Notch pathway regulates astrocyte differentiation in as well as Wnt and Notch signaling, can inhibit GSK3, promote NPC
a matter that is independent of STAT3. Another study conducted by proliferation, and impede neuronal differentiation. A previous study
Kanski et al. [37] also demonstrated that the Notch signaling pathway [46] demonstrated that during the late developmental phase, GSK3
regulates astrocyte differentiation in concert with the JAK/STAT phosphorylation degrades c-Myc/β-linker proteins, thereby inhibiting
pathway. In terms of the molecular mechanism, the interaction is NPC proliferation and promoting neuronal differentiation. In a clinical
mediated by STAT3, which induces Notch delta-like ligand 1 (DLL1); study involving preterm infants [48], intraventricular hemorrhage led to
this results in the activation of Notch signaling in adjacent cells. Notch damage of the cerebral cortex and detrimental effects on neuro
drives the differentiation of NSCs into astrocytes through the deme development, whereas GSK3β inhibition restored the process of neuro
thylation of astrocyte-specific genes. More specifically, the expression of genesis and the number of neurons in the suprachiasmatic cortical layer.
the Notch intracellular domain (NICD) induces transcription of the Collectively, the results from the studies that have investigated
GFAP promoter as well as the S100β demethylation of STAT3 binding related signaling pathways have led the authors to hypothesize that the
sites within the promoter [35], and Notch activation leads to dissocia inhibition of signaling pathways that promote astrocyte differentiation
tion of DNA methyltransferase I (DNMT1) from the GFAP promoter, (e.g., those involving JAK/STAT, Notch, and BMP), as well as the acti
leading to its transcription (Fig. 2B). vation of signaling pathways that promote the differentiation of NSCs
Bone morphogenetic proteins (BMPs) are well-studied cytokines that into neurons (e.g., Wnt signaling), are key steps in optimizing the in
induce the generation of astrocytes in neural stem/progenitor cells duction of neuronal reprogramming. This can be achieved through the
(NSPCs) during the late gestational period [41]. Numerous studies have application of specific small-molecule drugs, such as SP600125, which is
demonstrated that BMP signaling promotes the differentiation of NPCs a selective JNK pathway inhibitor, and the artificial overexpression of
into astrocytes. Fibrinogen activates BMP type I receptors through neuron-related neurotranscription factors could also be an effective
binding to the αC structural domain, resulting in the activation of BMP means of inducing such reprogramming.
signaling. Fibrinogen treatment of NSPCs induces the expression of BMP
target genes, such as inhibitors of DNA-binding 1–3 (Id1–3), resulting in
the activation of signal transducer Smad1/5 and the regulation of GFAP
expression [42] (Fig. 2C). Circulating blood-derived fibrinogen induces
the generation of astrocytes in ectopic brain stem cells [43] and inhibits
the neuronal differentiation of primary NSPCs from the SVZ or
5
Fig. 3. The key signaling pathways and mechanisms involved in regulating of the differentiation of NSCs into neurons. A: Wnt4 binds to transmembrane proteins
with a cysteine-rich domain before binding to the receptor through the extracellular N-terminal structural domain to activate the Wnt signaling pathway. When Wnt
signaling is not activated, β-catenin exists within the cytoplasm in a phosphorylated form where it forms a complex with Axin, GSK3β, CK1, βTrCP, and APC. When
Wnt signaling is activated, however, Dishevelled in the cytoplasm inhibits the formation of the complex, allowing β-catenin to exist in a free, dephosphorylated form.
This form of β-catenin enters into the nucleus from the cytoplasm and binds to TCF (transcription factors) to induce the expression of downstream neuronal marker-
related genes. (e.g., β3-tubulin, MAP2, and NF200). Dishevelled can also activate RAC1, which can, in turn, phosphorylate and activate JNK, which enters the nucleus
where it can synergize with a variety of transcription factors (e.g., c-JUN, AP1), ultimately affecting the transcription of genes and resulting in the upregulated
expression of β3-tubulin, MAP2, and NF200. B: Different activation modes of the TGF-β signaling pathway induce different directions of differentiation of neural stem
cells. The TGF-β family cytokines induce serine/threonine kinase-type receptors on the cell membrane to form ALK5, a functional complex involving two type II
receptors (RII) and two type I receptors (RI). RII receptors phosphorylate the GS region in the intracellular structural domain of RI, activating the kinase activity of RI;
the phosphorylation of RI activates downstream Smad2/3, which subsequently polymerizes with Smad4 to induce the formation of the Smad complex, which enters
the nucleus and binds to the promoter regions of target genes, regulating the expression of neuron-related genes such as DCX and PCNA. (LPR5/6, Low-density
lipoprotein receptor-related protein 5/6; APC, Adenomatous polyposis coli protein; GSK3β, Glycogen synthase kinase-3β; MAP2, Microtubule-associated protein2;
NF200, Neurofilament 200; DCX, Doublecortin; PCNA, proliferating cell nuclear antigen; RAC1, Ras-related C3 botulinum toxin substrate; JNK, c-Jun N-terminal
kinase; TCF, Transcription factor; AP-1, activating protein-1; ALK5, TGF-β receptor type-1; TGF-β, Transforming growth factor beta; Smad, Signal trans
duction factor).
4. Cell reprogramming techniques for inducing astrocyte-to- neurotranscription factors is critical for achieving astrocyte reprog
neuron differentiation ramming to neurons. This section will focus on existing neuronal
reprogramming induction schemes, beginning with somatic cell
4.1. Ectopic expression of transcription factors promotes the reprogramming, with an emphasis on the neural transcription factors
reprogramming of astrocytes to neurons that play a prominent role in such processes.
Since the first demonstration that the ectopic expression of tran 4.1.1. Sox2
scription factors could alter the fate of somatic cells via cell lineage Sox2, a transcription factor containing a high-mobility group (HMG)
switching, an increasing number of studies have focused on the role of box, belongs to the SOXB1 subset of Sox genes [52]. It plays a critical
transcription factors in cellular reprogramming. Today, it was found role in nervous system development after embryogenesis. Increased
that targeted inhibition of Notch1 signaling after spinal cord injury Sox2 expression is often observed in undifferentiated NPCs, making it a
promotes the reprogramming of reactive astrocytes to neurons by useful marker of NSC characteristics [53]. Sox2 controls the develop
upregulating neuro transcription factors such as NeuroD1, Neurog2, and ment of different brain regions at the NSPC level, thereby influencing the
Pax6 [49]， overexpression of NeuroD1 induces reprogramming of as development of specific differentiated neuronal and glial cell types [54].
trocytes into neurons in the brains of AD model mice [50], targeting In addition, Sox2 is associated with glial cell reprogramming, and it
specific transcription factors and miRNAs can induce the reprogram can promote reparative neurogenesis in Müller/RG cells after retinal
ming of astrocytes into neurons in Parkinson’s disease and play a ther injury in zebrafish [55]. Besides that, following spinal cord injury, Sox2
apeutic role [51]. This suggests that targeting specific induces the reprogramming of Oligodendrocyte precursor cells (OPCs,
6
NG2 glial cells) into early neurons and can promote neurological re differentiate into gamma-aminobutyric acid (GABA) neurons that ex
covery [17]. After brain injury, retroviruses carrying Sox2 have also press high levels of the neurotrophin receptor p75NTR and ultimately
been shown to induce the transformation of NG2 cells into neurons [56]. undergo rapid cell death [76].
Similarly, the ectopic expression of reprogramming factors such as Oct4, As a transcription factor expressed during neurogenesis in the
Sox2, and Nanog Homeobox (NANOG) in astrocytes activates genetic developing cortex, Pax6 is a critical driver of telencephalon formation
programming in NSCs and induces the generation of cells expressing [77]. Pax6 is also of interest for research focusing on the mechanisms of
NSPC markers. CD44+ mature astrocytes also undergo this lineage astrocyte neurogenesis, as experiments have shown that it is localized in
switching, giving rise to cells that express NSPC markers and subse RG cells. It influences the neurogenesis of embryonic cortical precursors
quently undergo differentiation into neurons, astrocytes, and oligoden during the neurogenic deficit period, while its overexpression in
drocytes without passing through a pluripotent state [57]. Research Pax6-negative cortical astrocytes induces their differentiation into
suggests that a single transcription factor, Sox2, can reprogram astro neurons [77].
cytes into proliferating neuroblasts. When neurotrophic factors or his
tone deacetylase inhibitors are applied in combination, neuroblasts 4.1.4. NeuroD1
transdifferentiated from astrocytes can further differentiate into mature The neurotranscription factor NeuroD1 is a member of the bHLH
neurons and functionally integrate into local neural networks [58]. The family. NeuroD protein has been confirmed to be involved in the dif
application of combination treatments that involve the neuro ferentiation of neuroectoderm cells into neurons during neurogenesis,
transcription factor Sox2 and small-molecule drugs has also been shown and it becomes transiently overexpressed when a subset of neurons ul
to be effective in regulating reprogramming efficiency and progression. timately differentiate into their mature form [78]. Studies have found
that the ectopic overexpression of NeuroD1 in Xenopus embryos pro
4.1.2. Ascl1 motes neurogenesis and induces the premature differentiation of NPCs, a
In nervous system development, the generation and differentiation of process that is essential for the maturation of cerebellar and hippo
neurons are dependent on a class of bHLH transcription factors known as campal granule neurons [78–81].
proneural genes [59], which were initially discovered in Drosophila and The earliest studies on somatic reprogramming into neurons found
named for their ability to regulate the differentiation of immature that the overexpression of NeuroD1 could induce the reprogramming of
neuroectodermal cells into NSCs [60]. Subsequently, the proneural gene fetal fibroblasts into neuron-like cells that exhibited typical neuronal
achaete-scute homolog 1 (Ascl1) was identified in mice [60–63], and its morphology and marker expression [69]. Subsequently, some re
expression was later confirmed in NPCs in vertebrate species, as was its searchers who focused on inducing the transformation of glial cells into
ability to induce neuronal differentiation, leading to further neuronal neurons have demonstrated that astrocytes located in the cerebral cortex
subtype characterization [64,65]. Ascl1 was found to be critical for the of mice with a brain injury or Alzheimer’s disease (AD) models could be
generation of glutamatergic neurons in the hypothalamus during em directly reprogrammed into functional neurons when NeuroD1 was
bryonic development [66]. overexpressed, and such cells were capable of integrating into the local
Investigations into the role of Ascl1 have revealed its ability to induce neural circuitry. In addition to mouse models, NeuroD1 can reprogram
trans-lineage reprogramming [67]. For example, in studies investigating human cortical astrocytes into functional neurons [50]. Another study
its role in somatic cell reprogramming, cells treated with Ascl1 in com found that three transcription factors, NeuroD1, Ascl1, and LIM ho
bination with doxycycline induced the transformation of fibroblasts into meobox transcription factor 1 alpha (LMX1A), in combination with
neurons in vitro. [68,69], and the ectopic expression of Ascl1 in neuro microRNA 218, could reprogram astrocytes into induced dopaminergic
blastomas inhibited the expression of key transcriptional regulators that neurons both in vitro and in vivo [82]. In addition, NeuroD1-mediated in
are known to be necessary for neuroblastoma proliferation, while situ conversion of astrocytes into neurons can induce the regeneration of
simultaneously promoting the differentiation of neuroblastoma cells, a large number of new functional neurons following ischemic injury, and
inducing a shift from a proliferative neuroblast state to a state conducive AAV-based gene therapy involving NeuroD1 was shown to induce
to neuronal differentiation [70]. neuronal regeneration and promote the recovery of injured neurons,
The role of Ascl1 has also been investigated in mediating the significantly contributing to the restoration of neuronal function [83].
reprogramming of astrocytes into neurons. As a proneural transcription
factor, Ascl1 can induce the reprogramming of early postnatal cortical 4.1.5. Neurogenin 2 (Neurog2)
astrocytes into actively conducting neurons capable of generating action Neurog2, which is expressed in hypothalamic tubercular progenitor
potentials, which are characteristics of authentic neurons [71,72]. These cells, is another member of the proneural gene family [60]. It plays a key
effects of Ascl1 may be related to the actions of Krüppel-like factor 10 role in the neurogenesis of early-born neurons within the embryonic
(Klf10) and Myelin Transcription Factor 1 (Myt1), as neuronal differ tubercular hypothalamus, with the process being arrested in its absence
entiation 4 (Neurod4) and Chromodomain helicase DNA-binding protein [84]. In contrast, the overexpression of NEUROG2 in human embryonic
7 (Chd7) have been identified as key genes required for the efficient stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs)
transformation of astrocytes into neurons [73]. Another study further results in the rapid and efficient generation of excitatory neurons, and
investigated the role of Ascl1 in mediating the transformation of adult induces the formation of a network of inhibitory GABAergic neurons in
astrocytes into neurons in vivo, showing greater neuronal transformation hESCs. [85].
efficiency when six serine phosphorylation receptor sites in Ascl1 were Further studies have explored the role of Neurog2 in the trans
mutated to alanine (Ascl1SA6); thus, Ascl1SA6 may be a key transcrip formation of astrocytes into neurons in greater detail. For example,
tion factor for use in future studies [74]. experimental models that have employed AAV-mediated delivery sys
tems to induce the single-factor overexpression of Neurog2 in astrocytes
4.1.3. Pax6 have demonstrated that the majority of astrocytes could be successfully
Pax6 plays an important role in cellular reprogramming. For converted into neurons in multiple brain regions, as well as in the
example, the overexpression of Pax6 in mouse embryonic stem cells midbrain and spinal cord. In the midbrain, Neurog2-induced neuronal
induces their differentiation into retinal NPCs [75]. Pax6 also plays a cells exhibit a neuron-like morphology, with similar electrophysiolog
key role in regulating the neuronal subtypes involved in neurogenesis ical characteristics, glutamatergic properties (approximately 60 %
and in determining their ultimate fate. In addition, Pax6-positive RG similarity), and the ability to form local circuits of synapse-like struc
cells in the cerebral cortex serve as progenitors of most glutamatergic tures. In the spinal cord, studies have shown that both normal and
neurons, and the absence of Pax6 expression in embryonic stem cells lesion-derived astrocytes can be transformed into functional neurons via
results in the generation of Mash1-positive RG cells, which tend to the ectopic expression of Neurog2 alone, and healthy spinal cord-derived
7
Neurog2-induced neuronal cells respond to different afferent signals nor the genetic knockout of PTBP1 could induce the transdifferentiation
transmitted from the dorsal root ganglia (DRG), indicating that induced of astrocytes into neurons, with one study suggesting that the neurons
neurons are fully functional [86]. Another study reported that adult thought to have been generated as a result of trans-differentiation were
human cortical astrocytes can be directly reprogrammed by exposure to endogenous neurons that were already present in the body [96]. Sub
either cell-cycle exit and neuronal differentiation 1 (CEND1) or Neurog2 sequently, controversial questions arose about the effect of PTBP1 in
into cells with the morphology of differentiated neurons, with long neuronal reprogramming, with several studies published in 2023
axons and dendritic branching. In that study, the neuronal marker genes reporting a failure of PTBP1 to induce astrocyte-to-neuron trans
were significantly upregulated, whereas astrocytic marker genes were formation and suggesting that the previous findings were false positives
downregulated, with the differentiation-induced neurons exhibiting arising from carrier leakage [97–100]. Accordingly, a subsequent study
GABAergic and glutamatergic/dopaminergic properties upon CEND1 argued that the knockout of PTBP1 did indeed produce different phe
and Neurog2 overexpression, respectively [87]. notypes and that positive induction results required the simultaneous
downregulation of PTBP2 expression [101]. To verify the authenticity of
4.1.6. NeuroD4 the experimental results, different control groups should be established,
NeuroD4 is another protein that plays an important role in neuronal and the source of the induced neurons should be traced more precisely.
differentiation. The continuous expression of NeuroD4 in adult and Such controversies surrounding the induction methods further highlight
mouse cerebellar and hippocampal cells may be related to neuronal the limitations of strategies that are solely based on the regulated
cellular regeneration [88,89]. In a study in which the overexpression of expression of individual genes. Strategies that modulate the expression
NeuroD4 was induced in NSCs via a pseudotype retroviral vector with a levels of two or more genes are increasingly being recognized as a
neurotropic lymphocytic choriomeningitis virus (LCMV) envelope, NSCs critical approach for the reprogramming of astrocytes into neurons, such
were successfully transformed into neurons that exhibited the capacity as protocols involving the overexpression of Oct4 coupled with p53
for axonal regeneration. Additionally, such overexpression facilitated silencing. Furthermore, such strategies combined with the
the differentiation of NSCs into both excitatory and inhibitory neurons co-application of small molecules can significantly enhance the effi
while concurrently suppressing glial lineage-mediated scar formation, ciency of neuronal reprogramming and can even induce the formation of
and the authors verified that the induced neurons were capable of organ-like structures [102].
forming functional synapses with neighboring cells [90].
As previously mentioned, NeuroD4 can be used as a downstream 4.2. The role of small-molecule compounds and microRNA in the
target gene of Ascl1 to induce the transformation of astrocytes into reprogramming of astrocytes into neurons
neurons capable of generating functional action potentials, and the
reprogramming efficiency was shown to be stronger than that associated 4.2.1. Small-molecule compounds
with the modulation of other genes downstream of Ascl1 [73]. The integration of small molecules has long been explored in cell
Another study reported that the regulation of NeuroD4 itself was reprogramming, especially in the conversion of somatic cells to induced
sufficient for the induction of neuronal reprogramming in astrocytes pluripotent stem cells. In those studies, the addition of small molecules
from both mice and humans, even without modulating upstream Ascl1, not only improved the induction efficiency but also further reduced the
and co-expression with insulinoma-associated protein 1 (Insm1) further potentially negative outcomes related to the c-Myc oncogene as well as
induced the formation of mature glutamatergic neurons; however, as the carcinogenicity of the induction protocol [103–105]. Subsequently,
trocytes gradually became resistant to such reprogramming. Although studies confirmed the ability of small-molecule compounds to induce the
the mechanism responsible for such resistance was unclear, it was reprogramming of astrocytes into neurons [19]. More recently, a study
speculated to be partly attributed to the prevention of Neurog2 binding found that the combined application of four small-molecule compounds
to the NeuroD4 promoter by the transcription repressor RE-1 silencing (SB431542, RepSox, CHIR99021, and Y-27632) in an induction protocol
transcription factor (REST), thereby inhibiting NeuroD4 expression [72]. resulted in the successful reprogramming of human cortical astrocytes
In addition to the aforementioned transcription factors, many other into neurons through the overexpression of Oct4 and the silencing of
genes play important roles in the reprogramming of astrocytes into p53, a strategy that was also capable of further inducing the generation
neurons. For example, nuclear receptor-related 1 protein (Nurr1) and of organoid tissues [102]. The criteria for the selection of small-molecule
Neurog2 efficiently target astrocytes to facilitate their reprogramming compounds for reprogramming protocols are predominantly based on
into neurons [10], and CEND1 can induce the reprogramming of astro the inhibition of signaling pathways that favor glial cell differentiation
cytes into GABAergic neurons [87]. Downstream of Ascl1, Klf10, Myt1, and the activation of neuron-related signaling pathways [106].
and myelin transcription factor 1 like (Myt1l) are all also capable of Small-molecule compounds that have been reported to be involved
inducing neuronal generation [73], and the ectopic expression of in cellular reprogramming include SB431542, LDN193189, CHIR99021,
distal-less homeobox 2 (Dlx2) can induce the conversion of astrocytes RepSox, Y-27632, forskolin, 24-diamino-5-phenylthiazole (DAPT),
into GABAergic neurons [91]. In addition, the splicing factor Poly SB203580, TTNPB, Kenpaullone, Valproic acid (VPA), Smoothened
pyrimidine tract-binding protein 1 (PTBP1) has been confirmed to play a agonist (SAG), purmorphamine, SP600125, GO6983, bromodomain and
critical role in neuronal reprogramming. For example, genetic deletion extra terminal inhibitor 151 (I-BET151), isoxazole 9 (ISX9), dibutyryl
of PTBP1 in a Parkinson’s disease model induced the differentiation of cyclic adenosine monophosphate (DBcAMP), and dorsomorphin
astrocytes into neurons, consistent with previous findings, confirming [106–111]. Small-molecule compounds involved in the neuronal
the important targeting role of PTBP1 in neuronal reprogramming [92, reprogramming process and their ability to induce the generation of
93]. positively expressed neuronal markers are listed in Table 1.
Despite these positive findings, the methods used to induce neuronal BMP2/4 as well as TGF-β1, which are involved in the TGF-β signaling
reprogramming through the modulated expression of single genes are pathway, are strong inducers of NPCs into astrocytes [115], whereas
controversial. A study published in 2019 suggested that NeuroD1 regu SB431542, LDN193189, and RepSox are inhibitors of the TGF-β
lates epigenetic remodeling and induces the conversion of small glial signaling pathway that mainly target different processes in TGF-β
cells into neurons, with potential implications for neuronal regeneration signaling cascades. For example. LDN193189 and RepSox are both
in the therapeutic management of degenerative diseases such as AD specific BMP1 receptor inhibitors that are capable of inhibiting TGF
[94]; however, that study’s findings were later challenged in 2022, with signaling pathway-mediated maturation at an early stage, whereas
some scientists suggesting that the observed effects of NeuroD1 were SB431542 mainly inhibits the TGF-β receptor, which, in turn, inhibits
instead a result of the leakage of retroviruses [95]. As early as 2021, the phosphorylation and activation of downstream genes, preventing
some laboratories believed that neither the overexpression of NeuroD1 the signaling from occurring [116]. Activation of the p38/MAPK
8
Table 1 miRNA also plays an important role in the reprogramming process.

Small-molecule compounds for neuronal reprogramming. MicroRNAs (miRNAs) are a class of non-coding single-stranded RNA
Name Function Positive indicators Cited molecules of approximately 22 nt in length, which are involved in
post-transcriptional regulation of gene expression [121]. Several miR
SB431542 ALK4\5\7 activity MAP2, TUJ1, PAX6, [102]
inhibitor Nkx6.1, Olig 2, GAD67, NAs have also been shown to play a role in the transformation of as
VGLUT1, FOXG1 trocytes into neurons, including miR-302/367, miR-365, miR-124, and
Y-27632 ALK5 inhibitor MAP2, TUJ1, PAX6, [102] miR-21, among others. For example, in 2015 it was first demonstrated
Nkx6.1, Olig 2, GAD67, that microRNAs can transform astrocytes into neuroblasts.
VGLUT1, FOXG1
CHIR99021 GSK-3α/β inhibitor MAP2, TUJ1, PAX6, [102]
miR-302/367 co-administered with valproic acid (VPA), a histone
Nkx6.1, Olig 2, GAD67, deacetylation inhibitor, resulted in a high conversion of astrocytes into
VGLUT1, FOXG1 neuroblasts. This method transforms astrocytes into neurons without
RepSox ALK5 inhibitor MAP2, TUJ1, PAX6, [102] reprogramming to the pluripotent stage [122]. In an animal model of
Nkx6.1, Olig 2, GAD67,
transient MCAO, increased levels of miR-365 inhibited the conversion of
VGLUT1, FOXG1
LDN193189 ALK2\3 activity NeuN, TUJ1, MAP2, SV2, [106] astrocytes to neurons. This was achieved by targeting Pax6. On the other
inhibitor FoxG1, Ctip2, Prox1, hand, overexpression of Pax6 negated the miR-365-mediated reduction
VGLUT1, DCX of astrocyte-to-neuron conversion in the rat brain after MCAO.
DAPT γ-secretase inhibitor NeuN, TBR1, PVALB, [106] Furthermore, the knockdown of miR-365 enhanced Pax6-mediated
CTIP2, VGLUT2
Forskolin ALK5 inhibitor MAP2, TUJ1，DCX, NeuN, [3]
astrocyte neurogenesis and reduced neuronal damage in the brain after
SYN1, CHAT, VGLUT1, TH ischemic stroke [90]. miR-124 not only regulates physiological and
SB203580 P38/MAPK inhibitor MAP2, TUJ1，DCX, NeuN, [3] pathological neuronal differentiation in NSC but is also a potent driver
SYN1, CHAT, VGLUT1, TH of astrocyte to immature neuronal fate reprogramming transition. It can
Ruxolitinib JAK1/2 inhibitor MAP2, TUJ1，DCX, NeuN, [3]
directly target the RNA-binding protein Zfp36L1 and inhibit Zfp36L1
SYN1, CHAT, VGLUT1, TH
TTNPB RAR agonist NeuN, Tuj1, MAP2, SV2, [106] neurogenic interactions, and in vivo experiments have demonstrated
FoxG1, Ctip2, Prox1, that miR-124 induces the direct conversion of responsive astrocytes into
VGLUT1, DCX immature induced neurons (iN) [123]; miR-124 also interacts with the
SAG Smo receptor agonist NeuN, TUJ1, MAP2, SV2, [106] small molecules ruxolitinib, SB203580 and trichostatin to inhibit HES1
FoxG1, Ctip2, Prox1,
expression by targeting the Sox9-NFIA-HES1 axis to promote the con
VGLUT1, DCX
VPA HDAC1 inhibitor NeuN, TUJ1, MAP2, SV2, [106] version of reactive astrocytes to neurons and to maintain neuronal
FoxG1, Ctip2, Prox1, stemness and inhibit the transition to a differentiated state [3]. miR-21,
VGLUT1, DCX a switch that regulates the polarization of reactive astrocytes, can pro
Kenpaullonec GSK-3βinhibitor Tuj1, MAP2, HB9, ISL1, [107]
mote the transformation of astrocytes to ASCs after acute ischemic spinal
CHAT, NeuN, SYN, VAChT
purmorphamine Smo receptor agonist TUJ1, MAP2, HB9, ISL1, [107] cord injury (iN). It can promote astrocyte polarization toward type A2,
CHAT, NeuN, SYN, VAChT targeting glycoprotein precursor (Gpc6) and glial cell line-derived
SP600125 JNK inhibitor NeuN [112] neurotrophic factor (GDNF) through the STAT3 signaling pathway to
GO6983 PKC inhibitor TUJ1, DCX, NeuN, MAP2, [113] promote synapse formation and synapse growth [124]. These studies
GABA, VGLUT1
suggest that microRNAs are not only involved in neuronal maturation,
I-BET151 BET bromodomain NeuN, TBR1, PVALB, [109]
inhibitor CTIP2, VGLUT2 growth, and synapse generation but also play an important role in
ISX9 neural stem cell NeuN, TBR1, PVALB, [109] promoting the transformation of astrocytes into neurons.
differentiation inducer CTIP2, VGLUT2
DBcAMP PKA activator NeuN, TBR1, PVALB, [109]
5. Prospects for reprogramming techniques for the treatment of
CTIP2, VGLUT2
dorsomorphin AMPK inhibitor Neurite-bearing cell [114] CNS injury and GBM
5.1. Neurological recovery following CNS injury

signaling pathway promotes astrocyte survival [117]. Therefore, some
studies have used the p38/MAPK inhibitors SB203580 and RepSox as CNS injury leads to primary or secondary neuronal damage or death,
neuronal inducers, which effectively trigger the reprogramming of as as well as axonal degeneration [125], resulting in both structural and
trocytes into neurons [3]. functional damage to the nervous system. Owing to the production of
In addition to small molecules that target specific components of factors that inhibit neuronal growth near the site of injury, the local
signaling pathways, other effective small-molecule agents that function pathological microenvironment is not conducive to nerve regeneration,
by maintaining cell survival are usually co-applied, thereby improving and it is difficult to generate new neurons and axons after a CNS insult.
reprogramming efficiency; one such example is the GSK3 inhibitor The growth of axons of central neurons is typically limited to protrusions
CHIR99021, which is mainly used to maintain the homeostasis of NPCs following injury, after which a retractile bulb is formed at their ex
and induce subsequent neural differentiation [118]. Other small mole tremities, which prevents the axon from traversing the injury site and
cules include the Rho-associated kinase (ROCK) inhibitor Y27632, ultimately leads to regeneration failure. In addition, astrocytes located
which is used to promote cell survival and enhance reprogramming ef around the lesion are stimulated and transform into Reactive astrocytes
ficiency [119] and the γ-secretase inhibitor DAPT, which helps promote (RACs) [126], forming a hard gelatinous scar that hinders axonal
neural differentiation [120]. growth. Furthermore, cytokines produced at the site of injury, such as
The co-application of small-molecule compounds greatly improves CNS myelin [127], chondroitin sulfate proteoglycans (CSPGs) released
the efficiency of regimes intended for the reprogramming of astrocytes by RACs from the formation of a glial scar [128], myelin-associated
into neurons, and unique combinations could be used for further opti glycoproteins (MAGs) derived from oligodendrocytes and myelin
mizing such protocols. debris [129], Nogo proteins [130], oligodendrocyte myelin glycoprotein
(OMgp) [130], EphrinB3, and semaphorin 4D (Sema4D) [131] have all
4.2.2. MicroRNA been identified as factors that inhibit axonal regeneration.
In the previous introduction, we noticed that transcription factors Advances in cellular reprogramming technology are expected to
combined with miRNA can induce the reprogramming of astrocytes into provide fundamental solutions to overcome these unfavorable factors. In
neurons under in vivo and in vitro conditions [82], indicating that addition to directly inducing the transdifferentiation of astrocytes into
9
neurons, the process not only provides a means of generating newly born However, there is evidence of hypermutation, malignant trans
neurons and solving the problems associated with neuronal regenera formation, and DNA mismatch repair (MMR) defects following treat
tion, but the application of reprogramming technology also further re ment with chemotherapeutic agents [137], and there is still controversy
duces the generation of glial scarring and the secretion of inhibitory regarding whether progression-free survival can be prolonged with such
cytokines that occurs in the later stages following CNS injury, facili treatment [138]. In addition, a long-standing problem in the treatment
tating the formation of a local microenvironment that provides favor of brain diseases that are reliant on systemic therapy is the presence of
able conditions for nerve regeneration and axon reconstruction, the blood–brain barrier (BBB), which limits the passage of chemother
promoting functional recovery after injury. apeutic agents into target tissues, reducing the efficacy of treatment
[139] and isolating the CNS from the peripheral immune system [140].
5.2. Current and emerging therapeutic strategies for gliomas Prolonged chemotherapeutic regimens lead to chemoresistance as well
as the incomplete obliteration of tumor cells, increasing the likelihood of
Gliomas are the most common type of CNS tumors requiring tumor recurrence. Although radiotherapy is another important treat
neurosurgery and are the most frequently encountered cranial tumors in ment option for some individuals with gliomas, the rapid growth of such
terms of their incidence. Gliomas can occur in all regions of the brain, tumors can decrease the sensitivity to radiotherapy; thus, large doses of
including in the cerebellum or brainstem, although they primarily occur radiotherapy are needed to achieve the desired effect, which can also
at the junction of the cortex and white matter, and they can be classified increase undesirable side effects and result in greater brain damage
as astrocytomas (including GBMs), oligodendrogliomas, and mixed gli (Fig. 4A). Therefore, the identification of novel therapeutic strategies is
omas, among several other types, including gliomas of the optic nerve urgently needed, in addition to the traditional surgical and chemo
and brainstem [132]. Most gliomas originate from the malignant pro radiotherapeutic approaches to overcome the current challenge associ
liferation of astrocytes, especially GBMs, the most malignant form ated with glioma treatment.
[133–135]. Therefore, starting from the characteristics of astrocytes to The aforementioned limitations have led to the development of
find treatment options for glioma provides a new perspective for immunotherapeutic approaches to glioma treatment becoming a hot
improving patient prognosis. topic in current medical research, some of which have been successfully
Currently, there are three main treatment options for individuals applied in clinical settings, such as the application of PD1/PD-L1,
with gliomas (surgical resection, chemotherapy, and radiotherapy); lysovirus therapy, and CAR T-cell therapy. However, it is still difficult
however, most treatment regimens involve a combination of these to eliminate all tumor cells to prevent recurrence, as such approaches
methods. The preferred treatment remains radical surgical resection; induce the activation of inflammatory signaling in vivo, which can
however, surgery for the removal of brain tumors is the most difficult negatively impact the function of other organs while attempting to
surgical procedure, and it can be further complicated by the fact that promote CNS repair, and the highly tumor-immunosuppressive micro
gliomas do not have distinct boundaries and not all tumor cells can be environment and the evasion mechanisms tumors adopt to avoid im
completely removed. Therefore, chemotherapy is one of the most mune system detection can negatively affect the therapeutic efficacy
important treatment options for gliomas, which can include the use of [141] (Fig. 4A). Therefore, new therapeutic approaches are required to
agents such as temozolomide (TMZ) and bevacizumab (BEV) [136]. further improve the treatment of gliomas.
Fig. 4. Current and emerging therapeutic strategies for gliomas. A: Current treatment options for gliomas include surgery, chemotherapy, radiotherapy, and
immunotherapy. Surgery is the most basic treatment strategy; however, it does not eliminate all tumor cells. TMZ and BEV are commonly used chemotherapeutic
agents; however, their administration can cause genetic mutations and promote the development of chemoresistance. Radiotherapy can lead to off-target damage to
normal cells, and the sensitivity of gliomas to radiation remains questionable. Immunotherapies based on PD1/PD-L1, oncolytic viruses, and CAR T-cell therapy are
limited by immune escape. Although some personalized treatments are available, they are mostly palliative. B: The emerging treatment strategies for gliomas mainly
involve gene therapy, including those that promote tumor cell apoptosis by inducing the ectopic expression of Neurog2 and those that induce the transformation of
tumor cells into functional neurons by regulating the expression of Ascl1, Brn2, Neurog2, SOX11, NeuroD1, and PTBP1. Alternatively, Pax6, Ascl1, Brn2, Neurog2,
and Sox11 can be used to inhibit tumor cell proliferation. (Ascl1, achaete-scute family bHLH transcription factor 1; BEV: bevacizumab; Brn2, POU class 3 homeobox
2; CAR, chimeric antigen receptor; NeuroD1, Neurogenic differentiation 1; Neurog2, neurogenin 2; Pax6, paired box protein 6; PD-1, programmed cell death protein
1; PD-L1, programmed death-ligand 1; PTBP1, Polypyrimidine tract-binding protein 1; SOX11, Sex Determining Region Y-Box 11; TMZ: temozolomide).
10
Recent studies have shown that promoting the differentiation of upregulated expression of the neuronal markers DCX and NeuroD1
tumor cells into normal non-tumor cells, thereby inhibiting their pro expression and the ability to generate action potentials [148]. Another
liferation and reducing their number, could be a new and unique group showed that the synergistic effects of Neurog2 and Sox11 effec
treatment method with the potential to halt tumor progression. Inducing tively transformed human glioma cells into terminally differentiated
astrocyte-derived glioma cells to differentiate into normal astrocytes or neuron-like cells with a typical neuronal morphology that was accom
directly into neurons seem to be viable options, as existing studies have panied by the expression of neuronal markers and the presence of
proven that GBM cells can be induced into neurons. However, astrocytes electrophysiological properties, and the proliferation and development
appear to be pro-carcinogenic, and not an ideal choice; therefore, an of GBM was inhibited [149]. The previous section mentioned that the
increasing number of studies have focused on inducing the differentia ectopic expression of Ascl1 in neuroblastoma cells was shown to induce
tion of glioma cells into neurons [142,143]. their trans-differentiation into neuronal cells, and the same effect has
been confirmed in terms of the shift from GBM cells. The single
5.3. Theoretical feasibility of reprogramming glioma cells into neurons neuro-transcription factor Ascl1 promotes the reprogramming of GBM
cells into terminally differentiated neurons that exhibit typical neuronal
Based on the etiology of glioma cells, the first step in reprogramming morphology and expressed neuronal markers, a process that was medi
strategies is to induce glioma cells to restore their astrocytic properties. ated through the inhibition of Notch signaling; similarly, this process
However, GBM cells produce receptor activator of nuclear factor kappa induces cell cycle exit in GBM cells and inhibits their proliferation [143,
B (NF-κB) ligand (RANKL), which activates the NF-κB signaling 150]. Therefore, the combination of NeuroD1, Neurog2, and Ascl1 further
pathway, thereby promoting the proliferation and activation of astro improved the efficiency of this conversion to neurons, and neurons
cytes into tumor-associated astrocytes (TAAs), which subsequently produced in response to the administration of NeuroD1 and Neurog2
produce pro-tumorigenic factors, such as TGF-β, that are known to behaved as excitatory glutamatergic neurons, whereas those produced
enhance the invasive ability of GBM cells [142,144,145]. Meanwhile, it through the administration of Ascl1 behaved as inhibitory GABAergic
has been reported that TAAs induce an anti-inflammatory response that neurons [151]. In addition, the knockdown of the shear factor PTBP1
triggers an immunosuppressive environment and impedes the efficacy of induces a similar differentiation of GBM cells into neurons [152]
immunotherapy, while glioma and microglia synergize to further pro (Fig. 4B). Besides, it is worth exploring that AAV-NeuroD1 induced
mote astrocyte activation, creating a vicious circle [145]. Due to the neural reprogramming was reported to be the first AAV treatment for
interaction between TAAs and GBM, it is relatively difficult to convert GBM in humans very recently, completed by NeuExcell Therapeutics, a
GBM cells into normal astrocytes. On the one hand, under in vivo con study that took transcription factor-based gene therapy from theory to
ditions, the transformation of GBM cells into astrocytes may be pre reality. However, the available data are still insufficient to support the
vented due to the presence of TAAs. In addition, it is difficult to use of AAV-NeuroD1 as a clinical treatment. There is still a lack of
determine whether the astrocytes transformed by GBM cells are normal enough evidence on primates to treat GBM, and extensive phase III
cells, resulting in that the transformed astrocytes may not have normal clinical trials are still needed to assess the safety of the AAV-NeuroD1
physiological functions. Finally, the abnormal astrocytes transformed by treatment and the stability of its efficacy. In addition, the controversy
GBM cells may also be transformed into TAAs under the stimulation of over AAV-NeuroD1 persists, and the safety and immune rejection of the
the local tumor microenvironment, which further promotes the prolif AAV virus itself, the authenticity of the positive results, and the side
eration and immune resistance of GBMs, and the formation of a positive effects of this kind of drug therapy still require continued attention. In
feedback communication between TAAs and GBM cells in the tumor the above studies, the cell lines selected were all astrocyte-derived gli
local area aggravates the progression of the tumor. oma cell lines, such as U87, U251, and KNS-89. And the target factors
To address these issues, some researchers have proposed strategies used to reprogram GBM cells into neurons largely overlap with those
that promote the direct differentiation of GBM cells into neurons rather used to reprogram astrocytes into neurons. It is speculated that the in
than relying on the intermediate generation of astrocytes that must duction protocol targeting the transformation of astrocytes into neurons
undergo further reprogramming. Neurons, which are terminally differ is also effective in reprogramming astrocyte-derived glioma cells into
entiated, non-proliferating cells, are better targets for transformation neurons. Subsequent research can further develop safer induction stra
than proliferating astrocytes and inducing the direct differentiation of tegies on this basis, such as combining neural transcription factors with
GBM cells into neurons can greatly preserve neurological function in the small molecule compounds. In this process, it has been found that the
brain, facilitating the recovery from the neurological dysfunction caused combination of small molecule compounds, cAMP inhibitors and HDAC
by tumor invasion during tumor treatment. inhibitors, can induce the transformation of glioma cells into neurons
via the histone post-translational modification pathway, which effec
5.4. Research progress on the reprogramming of GBM cells into neurons tively inhibits tumor proliferation and has a higher safety profile [153].
In addition, the study has found that the use of GSK3β inhibitors com
Gene therapy studies for the treatment of gliomas are increasingly bined with TMZ can effectively inhibit GBM proliferation [154].
being conducted to address the existing therapeutic bottlenecks. Given Therefore, to address the issues of viral vectors as well as transformation
that astrocytes are capable of reprogramming into neurons, most studies efficiency, and in conjunction with existing studies, this review suggests
have focused on exploring protocols that induce this type of trans- that transcription factors in combination with small molecule drugs are
differentiation. alternative induction regimens.
For example, the neuro-transcription factor Pax6, which is capable of Small molecules and chemotherapeutic agents can also play an
inducing the reprogramming of astrocytes into neurons, could also important role in promoting the conversion of GBM cells into neurons.
inhibit the growth of GBM cells [146], and a subsequent study based on For example, the administration of a combination of fasudil, Tranilast,
this finding reported that a combination of three transcription factors, and TMZ induces the reprogramming of human GBM cells into neuron-
Ascl1, POU class 3 homeobox 2(Brn2), and Neurog2, could efficiently like cells that express neuronal marker genes and possess electrophysi
transform human glioma cells into functional neurons while inhibiting ological properties [155], and a small molecule cocktail consisting of
the proliferation of glioma cells [147]. Neuron formation is regulated by forskolin, ISX9, CHIR99021, I-BET 151, and DAPT can successfully
neurogenic transcription factors such as Neurog1/2 and NeuroD1, which reprogram U87 cells into neurons [156], further confirming the
another study demonstrated were barely expressed in GBM cells; importance of small molecules in cellular reprogramming. Interestingly,
therefore, after constructing GBM cells that did express Neurog2, the we found that the small molecule drugs and their combinations that
authors found that there was an increase in GBM cell death, and the induced the reprogramming of GBM cells into neurons were highly
surviving cells exhibited evidence of neuronal morphology, with similar to those used during the reprogramming of astrocytes into
11
neurons. This suggests that fully exploring the induction strategies of and the neglect of the connections between other biological processes.
astrocyte-to-neuron reprogramming could help develop more effective At the same time, linking cellular reprogramming with metabolic
protocols for the transformation of GBM cells into neurons. reprogramming and epigenetic reprogramming is expected to further
improve reprogramming efficiency and patient survival rates, as well as
6. Forecast delay the progression of cancer.
Although astrocytes can proliferate in the CNS, their regeneration
The emergence of cellular reprogramming technologies has enabled occurs slowly, and converting a large number of astrocytes into neurons
the development of novel treatments for various diseases, and the could potentially deplete their populations in the CNS, which could have
reprogramming of astrocytes into neurons offers a promising approach a detrimental effect on neural system function and raise concerns about
for promoting regeneration following CNS injuries and for restoring the resultant potential harm to humans. Therefore, determining the
neural function in various neurodegenerative conditions. Despite this, optimal transformation multiplicity while simultaneously enhancing the
the outcomes of these induction strategies have remained controversial, transformation efficiency and controlling the impact of any residual
regarding whether inadvertent contamination from the extraction pro drugs on the transformation procedure following discontinuation of the
cess was responsible for the presence of the neuron-like cells that were induction scheme are technical obstacles that must be resolved. To
transdifferentiated from astrocytes. In addition, some experimental enhance the conversion efficiency, most researchers have focused on
findings have led researchers to challenge the presumed role of certain inducing combinations of genes and using small molecules that target
transcription factors in these processes, with some suggesting that specific signaling pathways involved in neurogenesis. Therefore, the
leakage of the viral vector me be responsible for inducing neuronal neural reprogramming technique mentioned in this review aims to
production. To address these issues, tracing the exact origins of the specifically induce the transformation of RAs into neurons by focal in
apparently induced neurons without interference from viral vectors is an situ injection of inducing reagents in the injured or lesion area, rather
essential priority. In addition, the field remains limited by the challenges than inducing the neural differentiation of normal astrocytes in the
associated with explicitly targeting gene regulation, screening specific whole brain through blood administration of inducing reagents, for
drug combinations, enhancing the production or delivery of viral vec example. Although the reprogramming techniques of RAs for neural
tors, and validating positive results. differentiation need to be further improved, through this method we
Moreover, based on previous studies that have suggested that GBM could precisely manipulate neural regeneration and remodeling in the
cells can originate from astrocytes, research should focus on methods lesion area, which is eventually beneficial to reducing glial scar and
that facilitate the direct reprogramming of GBM cells into neurons to enhancing neural functional recovery.
alter the characteristics of tumor cells, induce their cell death, suppress Following CNS injury, neurons are damaged and their ability to
their proliferation, and restore neural functions. Although such ap regenerate is limited, whereas a large number of astrocytes undergo
proaches could lead to new therapeutic options for the treatment of proliferation, which is the main factor hindering nervous system re
GBM, several primary challenges must be overcome to optimize the covery. Therefore, reprogramming astrocytes into neurons may help
reprogramming of astrocytes or GBM cells into neurons in terms of replenish damaged populations and restore neural functions. This re
conversion efficiency and safety. It remains a possibility that some view discussed the feasibility of strategies for reprogramming astrocytes
fraction of GBM cells cannot undergo effective reprogramming into into neurons from the perspective of neurogenesis, with a focus on the
neurons, meaning that some residual tumor cells could remain after key pathways, transcription factors, and small-molecule compounds
treatment. Therefore, it will be important to further enhance the con involved in neuronal reprogramming and the associated mechanisms of
version efficiency and guarantee the complete elimination of tumor cells action. In doing so, it provides an up-to-date reference that summarizes
to minimize the likelihood of recurrence and optimize clinical outcomes the existing research on nervous system repair post-injury. The discus
while minimizing the impact of treatment on non-tumor cells. To cope sion of the feasibility and research progress on the reprogramming of
with this problem, combined with the existing studies, we believe that GBM cells into neurons will highlight the shortcomings of existing gli
choosing a suitable carrier to carry the drug is the best optimization oma treatment methods and provide new ideas for the treatment of GBM
solution. Exosomes are a class of extracellular vesicles with a diameter of that will improve clinical outcomes.
about 100 nm. It has been found that exosomes can deliver siRNAs,
microRNAs, and chemotherapeutic agents, and are considered to be the Ethics approval statement
leading candidates for cancer therapeutic delivery vehicles [157]. It is
hypothesized that small molecule compounds delivered via exosomes Not applicable.
may be able to target tumor tissues, practice precise neuronal reprog
ramming, and greatly improve the efficiency of neural reprogramming. Consent for publication
Combining cell reprogramming techniques with existing clinical treat
ments (such as radiotherapy), can help to further improve patient sur Not applicable.
vival and prognosis. Cell reprogramming technology provides new
treatment options for GBM patients. Funding
It is well known that tumor cells undergo glycolysis function, which
produces a large amount of lactic acid, putting the tumor cells in a high- This work was supported by the National Natural Science Foundation
lactic acid microenvironment [158]. The tumor microenvironment is of China [grant number 82271425]; the Outstanding Youth Fund project
closely related to tumor properties, and glioma is no exception. How of Jilin Provincial Department of Education [grant number
ever, most of the current studies targeting the reprogramming of glioma JJKH20241324KJ]; and the Technology Development Plan Project of
cells into neurons have not taken into account the effects of lactate. In Jilin Province [grant number 20220101278JC].
addition to cellular reprogramming, cyclin-dependent kinase inhibitor
2 A (CDKN2A) mediated lipid reprogramming, mechanistic target of CRediT authorship contribution statement
rapamycin kinase (mTOR)-mediated metabolic reprogramming, and
bromodomain containing 8 (BRD8)-mediated epigenetic reprogram Meiying Li: Funding acquisition, Conceptualization. Guangfan Chi:
ming can induce tumor cells to enter a non-proliferative state, which in Writing – review & editing, Funding acquisition, Conceptualization. Qi
turn inhibits tumor proliferation and invasion [159–161]. Problems in Yu: Investigation. Haokun Li: Writing – review & editing. Junyuan
transformation efficiency and multiple aspects of existing induction Wei: Writing – original draft, Software. Shilin Li: Formal analysis.
protocols may be due to the neglect of the role of the microenvironment Miaomiao Wang: Visualization. Wenhong Xu: Writing – review &
12
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Biomedicine & Pharmacotherapy 176 (2024) 116806

Contents lists available at ScienceDirect

Biomedicine & Pharmacotherapy

Reprogramming of astrocytes and glioma cells into neurons for central

Table 1 miRNA also plays an important role in the reprogramming process.

5.1. Neurological recovery following CNS injury

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