© 2024 Journal of Pharmacy & Pharmacognosy Research, 12 (1), 39-49, 2024

ISSN 0719-4250
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DOI: https://doi.org/10.56499/jppres23.1726_12.1.39

Original Article

Mesenchymal stem cell secretome therapy on inflammation:

A systematic review
[Terapia con secretoma de células madre mesenquimales sobre la inflamación: Una revisión sistemática]
Mutiara I. Sari1*, Nelva K. Jusuf2, Delfitri Munir3, Agung Putra4, Imam B. Putra2, Tatang Bisri5, Farhat Farhat3,
Syafruddin Ilyas6, Adi M. Muhar7
1Departmentof Biochemistry, Faculty of Medicine, Universitas Sumatera Utara, Medan 20155, Indonesia.
2Departmentof Dermatology & Venereology, Faculty of Medicine, Universitas Sumatera Utara, Medan 20155, Indonesia.
3Department of Ear, Nose & Throat, Head & Neck, Faculty of Medicine, Universitas Sumatera Utara, Medan 20155, Indonesia.
4Stem Cell and Cancer Research, Faculty of Medicine, Universitas Islam Sultan Agung, Semarang 50112, Indonesia.
5Department of Anesthesiology and Intensive Care, Faculty of Medicine, Universitas Jenderal Achmad Yani, Bandung 40513, Indonesia.
6Department of Biology, Faculty of Mathematics and Natural Sciences, Universitas Sumatera Utara, Medan 20155, Indonesia.
7Department of Surgery, Faculty of Medicine, Universitas Sumatera Utara, Medan 20155, Indonesia.

*E-mail: [email protected]

Abstract
Context: With recent biochemical studies, inflammation has been considered a therapeutic target. Mesenchymal stem cells are considered a therapeutic
option because of the immunomodulatory effects of their bioactive factors, the secretome.
Aims: To systematically review the potential of mesenchymal stem cell secretome therapy on inflammation through its effects on biomarker characteristics,
organ damage, and survival rate.
Methods: This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement. A
literature search was performed in PubMed, ScienceDirect, and ProQuest, and through citation searching for records published in the last ten years. The
eligibility criteria of the identified study as follows: Population (P): Human, animal, or in vitro models with inflammatory disease; Intervention (I): Stem cell
secretome administration; (C): Healthy human, animal, or in vitro models; and Outcome (O): Inflammatory biomarker statistics, organ injury, or survival rate.
AXIS tool was used to assess the quality of the records.
Results: 3,258 records were found. The duplicates and undesired articles were excluded with automation tools. 38 relevant records were further identified
through citation searching. The screening and exclusion of records based on the inclusion and exclusion criteria left 24 eligible studies. The studies show that
secretome improves the biomarker characteristics by reducing proinflammatory cytokines levels while increasing anti-inflammatory cytokines levels. Many
studies show that secretome also improved organ injury and survival rate.
Conclusions: Secretome alleviates inflammation with its immunomodulatory effects, which may be associated with improvements in organ injury and overall
outcome.
Keywords: disease; inflammation; mesenchymal stem cells; secretome; therapeutics.

Resumen
Contexto: Con los recientes estudios bioquímicos, la inflamación se ha considerado una diana terapéutica. Las células madre mesenquimales se consideran
una opción terapéutica debido a los efectos inmunomoduladores de sus factores bioactivos, el secretoma.
Objetivos: Revisar sistemáticamente el potencial de la terapia con secretoma de células madre mesenquimales sobre la inflamación a través de sus efectos
sobre las características de los biomarcadores, el daño orgánico y la tasa de supervivencia.
Métodos: Este estudio se realizó de acuerdo con la declaración Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020. Se realizó
una búsqueda bibliográfica en PubMed, ScienceDirect y ProQuest, y mediante la búsqueda de citas de registros publicados en los últimos diez años. Los
criterios de elegibilidad del estudio identificado fueron los siguientes: Población (P): Modelos humanos, animales o in vitro con enfermedad inflamatoria;
Intervención (I): Administración de secretoma de células madre; (C): Modelos humanos sanos, animales o in vitro; y Resultado (O): Estadísticas de
biomarcadores inflamatorios, lesión de órganos o tasa de supervivencia. Se utilizó la herramienta AXIS para evaluar la calidad de los registros.
Resultados: Se encontraron 3.258 registros. Los duplicados y los artículos no deseados se excluyeron con herramientas de automatización. Además, se
identificaron 38 registros relevantes mediante la búsqueda de citas. El cribado y la exclusión de registros en función de los criterios de inclusión y exclusión
dejaron 24 estudios elegibles. Los estudios muestran que el secretoma mejora las características de los biomarcadores al reducir los niveles de citocinas
proinflamatorias y aumentar los niveles de citocinas anti-inflamatorias. Muchos estudios muestran que el secretoma también mejoró la lesión de órganos y la
tasa de supervivencia.
Conclusiones: El secretome alivia la inflamación con sus efectos inmunomoduladores, lo que puede estar asociado con mejoras en la lesión de órganos y el
resultado global.
Palabras Clave: células madre mesenquimales; enfermedad; inflamación; secretoma; terapéutica.

ARTICLE INFO AUTHOR INFO

Received: June 21, 2023. ORCID: 0000-0001-6510-2196 (MIS) 0000-0002-9822-3119 (AP)
Accepted: October 8, 2023. 0000-0002-9798-3941 (NKJ) 0000-0003-1805-7278 (IBP)
Available Online: November 13, 2023. 0000-0002-8526-6398 (DM) 0000-0003-1204-5321 (FF)
Sari et al. Secretome therapy on inflammation

INTRODUCTION yet to be a systematic review detailing the effects of

secretome on various inflammatory conditions, while
Inflammation is one of the protective adaptive re- secretome application on inflammation has been
sponses against cell injury, microbial infection, trau- widely studied (Jayaramayya et al., 2020; Műzes and
ma, or toxin in vascularized tissue that involves an Sipos, 2022). Therefore, this systematic review aims to
influx of immune cells and the release of various me- assess the potential of secretome therapy on inflam-
diators to the affected site (Ansar and Ghosh, 2016). In mation through its effects on biomarker characteris-
acute response, cellular and molecular interaction tics, organ damage, and survival rate.
minimizes injury and contributes towards the resolu-
tion of inflammation. However, uncontrolled and MATERIAL AND METHODS
untreated acute inflammation will develop into
chronic inflammation and cytokine storm, leading to
Literature search
organ failure and even death. Chronic inflammatory
disease has been known as a significant cause of This study was conducted in accordance with the
death worldwide, contributing to more than 50% of Preferred Reporting Items for Systematic Reviews
deaths (Chen et al., 2017; Furman et al., 2019; Hirano, and Meta-Analyses (PRISMA) 2020 statement (Page et
2021; Zhou et al., 2021). With the development of bio- al., 2021). The relevance of the study is determined
chemical studies on the potential inflammatory medi- with the inclusion criteria formulated using Popula-
ators and biomarkers, inflammation has been consid- tion, Intervention, Comparison and Outcomes (PICO).
ered a therapeutic target (Ansar and Ghosh, 2016). The PICO for this review is as follows: Population (P):
Human, animal, or in vitro models with inflammatory
Mesenchymal stem cell (MSC) therapy has been
disease; Intervention (I): Stem cell secretome admin-
considered an option for treating inflammatory dis-
istration; (C): Healthy human, animal, or in vitro
eases. These cells are capable of producing bioactive
models; and Outcome (O): Inflammatory biomarker
factors to exert immunomodulatory effects. This se-
statistics, organ injury, or survival rate. Case-control,
ries of bioactive factors, secretome, has been shown to
cohort, clinical trials, randomized controlled trials,
modulate the immune response in inflammatory dis-
cross-sectional, retrospective, prospective, pilot, and
ease by modulating the innate and adaptive immune
observational studies were included as well. Case
cells. The immunomodulatory processes include the
reports, review articles, books, comments, abstracts,
upregulation of anti-inflammatory cytokines such as
correspondence, encyclopedias, editorials, and non-
IL-4 and IL-10, the downregulation of proinflammato-
English articles were excluded.
ry cytokines such as IL-1 and TNF-α, and inducing
macrophages polarization to the anti-inflammatory A literature search was conducted in PubMed, Sci-
M2 macrophages (Munoz-Perez et al., 2021; Regmi et enceDirect, and ProQuest with the keywords “(Stem
al., 2019; Zhao et al., 2021). Cell OR Mesenchymal Stem Cell OR Mesenchymal
Stromal Cell) AND (Secretome OR Exosome OR Ex-
Secretome consists of cytokines, growth factors,
tracellular Vesicles OR Soluble Factors) AND (In-
and extracellular vesicles (EVs), including microvesi-
flammation OR Inflammatory Disease)” to find stud-
cles (MVs) and exosomes (Fathi-Kazerooni et al.,
ies published in the last ten years (2013-2023). Record
2022). The main advantage of secretome is its ability
identification was also performed through citation
to yield similar effects to MSC without the risk of
searching. After the initial selection through screen-
tumorigenicity and immunogenicity. Aside from be-
ing, potentially relevant articles were retrieved for
ing easier to mass-produce, the safety, effectiveness,
full-text analysis. Eligible articles were chosen in ac-
and dose of secretome can be monitored like conven-
cordance with the inclusion and exclusion criteria of
tional drugs. Another benefit of secretome is the lack
this study.
of concern regarding cell survival after transplanta-
tion (Daneshmandi et al., 2020; González-González et The articles were screened and reviewed by four
al., 2020; Vizoso et al., 2017). Secretome offers thera- independent reviewers (T.B., F.F., S.I., A.M.M.). The
peutic effects such as tissue regeneration and anti- quality of the study and the risk of bias were assessed
inflammatory response (Jahandideh et al., 2018). with AXIS tool (Downes et al. 2016). Any disagree-
ments will be resolved by reevaluating the articles
Possessing immunomodulatory and regenerative
using the checklist and discussion with other investi-
effects, secretome is potentially more effective than
gators (M.I.S., N.K.J., D.M., A.P., I.B.P.). The final
anti-inflammatory agents. These biological activities
decision was taken based on the agreement of all re-
help maintain immune homeostasis and increase the
viewers.
regeneration of damaged tissue. However, there has

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Sari et al. Secretome therapy on inflammation

Figure 1. Study selection flowchart.

Data analysis 5 human studies (Fig. 1). The quality assessment of

the records is presented in Fig. 2.
Articles were retrieved from the PubMed, Sci-
enceDirect, and ProQuest databases for studies on Tables 1 and 2 summarize the analysis of the stud-
secretome administration in inflammatory conditions. ies. Clinical studies on the use of secretomes in in-
For preclinical studies, all articles were reviewed for flammation have been conducted on COVID-19, but
the animal model and the inflammation induction many clinical trials are still ongoing.
process, the type of secretome, biomarker characteris-
tics, organ injury, and survival. For clinical studies, DISCUSSION
the articles were reviewed for the condition, the study
phase, the type of secretome, biomarker characteris- Main finding
tics, organ injury, and survival. Articles that did not
clearly indicate the exposure and outcome variables Mice are mainly used in preclinical studies of se-
were excluded. The selected studies were compiled cretome effects on inflammation. Genomic studies
using Mendeley Citation Manager. The findings were have highlighted the genetic homology between mice
presented in a table and described with a narrative and humans. These studies, together with the devel-
synthesis approach. opment of methods for creating transgenic, knock-
out, and knock-in mice, have resulted in powerful
research tools and led to a dramatic increase in the
RESULTS
use of mice as research models. Studies in mice have
A total of 3,258 mesenchymal stem cell secretome made many contributions to human biology, particu-
and inflammation records was found in PubMed, larly the immune system. This research has led to the
ScienceDirect, and ProQuest, with 2,989 records ex- discovery of major histocompatibility complex (MHC)
cluded by automation tools and 3 duplicates exclud- genes and T cell receptors, as well as the regulation of
ed. Next, we screened the titles and abstracts and antibody synthesis and many other features of the
excluded 235 records, all of which were available for immune system. In addition, the small size makes
full-text retrieval. Then, a full-text screening was per- mice cost-effective models and facilitates large-scale
formed on the remaining studies, and 21 records were studies. However, the use of mice in research is not to
further excluded as they had no data of interest. Rec- perfectly replicate diseases or disease mechanisms,
ord identification was also performed through cita- but rather to obtain specific functional information
tion searching, and there were 38 relevant records, all (Perlman, 2016; Vandamme, 2014).
of which were available for retrieval. Then, a full-text Many preclinical studies focused on the effect of
screening was performed on the remaining studies, secretome on colitis. Colitis is a form of inflammatory
and 24 records were excluded as they had no data of bowel disease (IBD), a chronic and recurrent inflam-
interest. Lastly, the 24 eligible studies were analyzed, matory disease of the bowel. In colitis, NF-κB path-
which consisted of 19 animal and in vitro studies and way is activated, causing the production of various

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Sari et al. Secretome therapy on inflammation

Figure 2. Quality assessment of studies

Two preclinical studies observed the effects of se-

proinflammatory cytokines (Cai et al., 2021; Chen et
cretome on neuroinflammation. In neuroinflamma-
al., 2017; Maghfiroh et al., 2021). In our systematic
tion, the binding of toll-like receptor (TLR)-4 to lipo-
review, we found that secretome administration does
polysaccharide (LPS) will activate microglia, which
not only reduce the levels and expression of proin-
will lead to the release of various proinflammatory
flammatory cytokines such as TNF-α, IL-6, and IL-1β,
cytokines, free radicals, and neurotoxic compounds
but also increases the levels and expression of anti-
(Chen et al., 2017; Kaur et al., 2020). Similar to the
inflammatory cytokines such as IL-10 in the serum
previously discussed studies on colitis, secretome
and colonic tissue. Histopathological examination of
administration also reduced levels of proinflammato-
the colon in colitis mice given secretome therapy
ry cytokines and increased levels of anti-
showed improved tissue integrity and increased colon
inflammatory cytokines (Jaimes et al., 2017; Zhou et
length (An et al., 2020; Cao et al., 2019; Duan et al.,
al., 2022). Histopathological examination of the brains
2020; Legaki et al., 2016; Liao et al., 2016; Liu et al.,
of mice given secretome showed improvements in the
2019; Sun et al., 2021).
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Sari et al. Secretome therapy on inflammation

Table 1. Summary of the preclinical studies on the usage of secretome in various inflammatory diseases.

Reference Animal model Disease Type of secretome Biomarker Organ injury Survival
or condition characteristics

(An et al., Mouse, dextran Colitis Canine adipose (AD)-MSC Decreased mRNA Improved integrity Not
2020) sodium sulfate EV preconditioned with relative expression of of colonic tissues determin
(DSS) TNF-α and IFN-γ TNF-α, IL-1β, IFN-γ ed (ND)
Increased mRNA relative
expression of IL-10

(Cao et al., Mouse, DSS Colitis Mouse bone marrow (BM)- Decreased serum IFN-γ Milder structural ND
2019) MSC EV and TNF-α levels damage in colonic
Increased serum IL-10 lesions
levels
Increased M2
polarization

(Duan et al., Mouse, 2,4,6- Colitis Human placenta MSC EV Decreased expression Increased colon Improved
2020) trinitrobenzene level of IL-1β, TNF-α, length
sulfonic acid IFN-γ, IL-6 in colon
(TNBS) tissues
Increased expression
level of IL-10 and TGF-β
in colon tissues
Reduced oxidative stress
(Harrell et al., Mouse, Chronic Human placenta MSC Decreased serum TNF-α, Significantly lower ND
2020) cigarette airway exosome IL-1β, and IFN-γ levels number of lung-
smoke inflammation infiltrated
leucocytes
Preserved alveolar
and blood vessel
structures in the
lungs
Improved
pulmonary function
(Jahandideh Mouse, LPS Acute Human embryonic- Increased serum IL-10 Reduced Improved
et al., 2018) systemic derived stem cell (ESC)- levels inflammatory
inflammation MSC unconditioned, No significant changes in infiltrate in lungs
trimetazidine (TMZ)-, serum TNF-α, IFN-γ, IL-6 Decreased
diazoxide (DZ)-, and and IL-1β levels necroinflammatory
MG132-preconditioned score of kidneys
secretome
Decreased
necroinflammatory
score of liver in
TMZ- and DZ-
preconditioned
secretome
treatment

(Jaimes et Mouse BV2 Microglia Mouse BM-MSC MV Decreased TNF-α, IL-6, ND ND

al., 2017) cells, LPS inflammation and IL-1β levels in the
cell culture
(Kearney et Horse, LPS Radiocarpal Equine BM-MSC Decreased synovial fluid Decreased ND
al., 2022) joint synovial secretome TNF-α radiocarpal joint
inflammation preconditioned with circumference
equine IFN-γ and TNF-α

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Sari et al. Secretome therapy on inflammation

Table 1. Summary of the preclinical studies on the usage of secretome in various inflammatory diseases (continued...)

Reference Animal model or Disease Type of secretome Biomarker Organ injury Survival
condition characteristics

(Kim et al., Human epidermal Atopic Human umbilical Decreased IL-6 and ND ND
2020) keratinocytes dermatitis cord (UC)-MSC TNF-α production in
(HaCaT) cells, secretome HaCaT cells
TNF-α/IFN-γ
stimulated

(Lai et al., 2018) Mouse, bone Chronic graft Human BM-MSC Increased IL-10- Less epidermal Improved
marrow and versus host exosome expressing Treg cells fibrosis with a
spleen cells disease decreased thickness
injection (GvHD) of the dermis and
less loss of hair
follicles
Less lung fibrosis
Alleviated liver
fibrosis
(Legaki et al., Mouse, DSS Colitis Human spindle Decreased mRNA Significantly ND
2016) shaped amniotic relative expression of decreased extension
fluid (SS-AF)-MSC TNF-α and IL-1β in and severity of the
secretome colon tissues colon inflammation
Increased mRNA
relative expression of
IL-10 in colon tissues
(Liao et al., Mouse, TNBS Colitis Mouse BM-MSC Decreased mRNA Increased colon Improved
2016) soluble factor expression of TNF-α, IL- length
IGFBP7 6, and IL-1β
Increased mRNA
expression of IL-10
(Liu et al., 2019) Mouse, oral DSS Colitis Human BM-MSC Decreased expression of Increased colon Improved
and intrarectal exosome IFN-γ, IL-1β, IL-6, and length
TNBS infusion TNF-α Maintained
Increased expression of intestinal structural
IL-10 integrity
Significantly
reduced disruptions
of the architecture,
crypt loss, and
infiltration of
inflammatory cells

(Liu et al., 2020) Mouse, CLP Sepsis Mouse BM-MSC TGF- Decreased plasma IL-1β Decreased injury ND
β1 and IL-6 levels scores in lung, liver,
Increased plasma IL-10 and spleen
levels
(Shi et al., 2021) Mouse, P. Pneumonia Human AD-MSC EV Decreased BALF levels Less inflammatory Improved
aeruginosa of IL-6 and TNF-α cells infiltrating
intratracheal Increased BALF levels of interalveolar septa
instillation IL-10 and respecting
alveolar space and
lung architecture
Reduced
histological severity
of lung injury
(Shologu et al., Rat alveolar Lung Human BM-MSC and Decreased IL-6 levels ND ND
2018) epithelial cells, ischemia- AD-MSC secretome Increased TNF-α and IL-
hypoxia reperfusion 10 levels
injury

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Sari et al. Secretome therapy on inflammation

Table 1. Summary of the preclinical studies on the usage of secretome in various inflammatory diseases (continued...)

Reference Animal model or Disease Type of Biomarker Organ injury Survival

condition secretome characteristics

(Sun et al., 2021) Mouse, CLP Sepsis Mouse BM- Decreased serum TNF- Improved kidney, Improved
MSC α, IL-1β, IL-6 liver, and lung
exosome Increased serum IL-10 damage

(Wang et al., 2016) Mouse, allogeneic Acute GvHD Human UC- Decreased serum TNF-α Attenuated Improved
hematopoietic MSC EV and IFN-γ levels histological
stem cell Increased serum IL-10 changes in large
transplantation levels intestine, liver and
(allo-HSCT) skin

(Yang et al., 2022) Mouse, imiquimod Psoriasis Human Decreased relative Decreased ND
(IMQ) amniotic mRNA levels of TNF-α, neutrophil
epithelial IL-1β, IL-6 in the lesion infiltration in the
cells (AEC)- lesion
SC
secretome
(Zhou et al., 2022) Mouse and mouse Neuroinflammation Human NSC Decreased mRNA Significantly ND
BV2 cells, LPS secretome expressions of TNF-α, abolished gliosis in
IL-1β, and IL-6 in the the brain
cortex and Reduced shrunken
hippocampus neurons in the
Increased mRNA cortex and
expressions of IL-10 in hippocampus
the cortex and
hippocampus
Decreased TNF-α, IL-1β,
and IL-6 levels in BV2
cells
Increased IL-10 levels in
BV2 cells

Table 2. Summary of the clinical studies that use secretome in inflammatory diseases.

Biomarker
Reference Condition Phase Type of secretome Organ injury Survival
characteristics

(Fathi-Kazerooni COVID-19 I/II Human menstrual Reduced C- Significant Improved

et al., 2022) stem cell (MenSC) reactive improvement in lung
secretome protein (CRP) lesions
levels

(Harrell et al., Chronic ND Human placenta ND Improved pulmonary ND

2020) obstructive MSC exosome status
pulmonary Significantly alleviated
disease (COPD) emphysematous
changes in the lungs

(Kim et al., 2020) Atopic dermatitis ND Human UC-MSC ND Improved skin stratum ND
secretome corneum and
strengthened skin
barrier in lesion and
non-lesion

(Sengupta et al., COVID-19 ND Human BM-MSC Reduced CRP ND 83% survival

2020) exosome levels rate
(Zhu et al., 2022) COVID-19 IIa Human AD-MSC Reduced CRP Different degrees of ND
exosome and IL-6 levels resolution of
pulmonary lesions

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Sari et al. Secretome therapy on inflammation

form of decreased gliosis and areas of shrinking neu- lowered CRP and IL-6 levels but also improved lung
rons in the cortex and hippocampus (Zhou et al., lesions in COVID-19 patients (Fathi-Kazerooni et al.,
2022). 2022; Sengupta et al., 2020; Zhu et al., 2022). Secre-
tome administration also improved lung injury in
There are also preclinical studies on the effect of
preclinical studies of mice with pneumonia and
secretome on systemic inflammation, such as sepsis
chronic airway inflammation (Harrell et al., 2020; Shi
and GvHD. In systemic inflammation, the most com-
et al., 2021).
mon cause of mortality is organ dysfunction due to
cytokine storm. This systemic inflammatory syn- Lastly, a preclinical study observed the effect of
drome involves immune response dysregulation in secretome on radiocarpal joint synovial inflammation.
the form of increased levels of circulating cytokines In the study, administering secretome was found to
(Fajgenbaum and June, 2020). Secretome administra- reduce the synovial fluid TNF-α (Kearney et al., 2022).
tion can improve this condition by reducing proin- The main pathogenesis of joint inflammation involves
flammatory cytokines and increasing anti- an increase in cytokines that cause articular cartilage
inflammatory cytokines in serum. In addition, the degradation and a decrease in chondrogenesis-
administration of secretome was also found to repair inducing factors. For instance, in the pathogenesis of
damage to various organs such as the lungs, liver, rheumatoid arthritis (RA), IL-1 is a major inflammato-
spleen, kidneys, and colon (Jahandideh et al., 2018; ry factor. Activation of IL-1 causes migration of in-
Lai et al., 2018; Liu et al., 2020; Sun et al., 2021; Wang flammatory cells into the joint and synovium and also
et al., 2016). The survival of mice with secretome induces other proinflammatory cytokines, such as
treatment was also found to increase compared to TNF-α and IL-6, that aggravate the damage (Chow
mice without secretome treatment (Jahandideh et al., and Chin, 2020; Kim et al., 2017; Zhang, 2021).
2018; Lai et al., 2018; Sun et al., 2021; Wang et al.,
Secretome is a cell-secreted substance consisting of
2016).
soluble and vesicular fractions of MSCs with various
Preclinical studies of secretome treatment on therapeutic properties. The soluble fraction of MSCs
GvHD found that secretome improved skin injury contains many immunomodulatory molecules, cyto-
and fibrosis (Lai et al., 2018; Wang et al., 2016). Two kines, chemokines, and growth factors. Meanwhile,
studies observed the effect of secretome on inflamma- the vesicular fraction consists of extracellular vesicles
tory skin diseases such as atopic dermatitis and psori- (EV) that can decrease IL-6 and IL-12p70 production
asis (Kim et al., 2020; Yang et al., 2022). Among the with the expression of IL-10 and transforming growth
many types of skin inflammation, psoriasis and atopic factor (TGF)-β (González-González et al., 2020;
dermatitis are the more common chronic inflammato- Jeppesen et al., 2019; Műzes and Sipos, 2022).
ry skin diseases. Psoriasis and atopic dermatitis share
IL-10 is a potent immunoregulatory molecule tar-
several features, such as infiltration of immune cells
geting almost all types of leukocytes. IL-10 binds to
in the skin, changes in the expression of several proin-
IL-10R, triggering the JAK-STAT signaling pathway
flammatory cytokines, and changes in the barrier
that culminates in the activation of STAT1, STAT3,
(Bozek et al., 2020; Song et al., 2022). As shown in the
and STAT5 (Rojas et al., 2017; Senousy et al., 2022).
studies, secretome can reduce the expression of proin-
STAT3 plays a vital role in the effect of IL-10 on im-
flammatory cytokines in skin cells and neutrophil
mune cells. While IL-6 also activates STAT3, the acti-
infiltration in the lesions (Kim et al., 2020; Yang et al.,
vation by IL-10 leads to different effects. This is due to
2022).
the induction of the suppressor of cytokine signaling
The term cytokine storm was first used by Ferrara 3 (SOCS3), which regulates the kinetics of STAT3
to describe cytokine dysregulation in GvHD. Since the activation. Because SOCS3 does not block STAT3 acti-
COVID-19 pandemic, cytokine storm has returned to vation by IL-10, STAT3 activation is maintained and
the spotlight because of its association with the severi- will provide an anti-inflammatory effect (Cevey et al.,
ty and mortality of COVID-19 (Hu et al., 2021; Tang et 2019; Hillmer et al., 2016).
al., 2021). It is triggered by immune and inflammatory
Several growth factors within secretome offer im-
responses induced by the infection and associated
munoregulatory effects. For instance, together with
with elevated CRP levels, which play a role in endo-
hepatocyte growth factor (HGF), TGF-β will suppress
thelial cell dysfunction, thrombus formation, and
T-cell proliferation. HGF also polarizes macrophages
coagulation cascade activation, eventually leading to
to M2 phenotype, increasing the production of IL-10
organ failure (Luan et al., 2021; Valle et al., 2023;
and TGF-β. These factors will alleviate ongoing in-
Wahyuni et al., 2022). Therefore, clinical studies often
flammation and promote repair and regeneration
study the effect of secretome administration on the
(Han et al., 2022; Yuan et al., 2019).
inflammation that occurs in COVID-19. As shown by
the studies above, secretome administration not only

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Sari et al. Secretome therapy on inflammation

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Cevey ÁC, Penas FN, Alba Soto CD, Mirkin GA, Goren NB (2019)
inflammatory condition. A narrower focus on the IL-10/STAT3/SOCS3 axis is involved in the anti-
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The use of secretome in experimental animal mod-
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CONFLICT OF INTEREST blood stromal cells secretome to treat severe COVID-19
patients: clinical trial phase I & II. Stem Cell Res Ther 13(1): 96.
The authors declare no conflicts of interest. https://doi.org/10.1186/s13287-022-02771-w
Furman D, Campisi J, Verdin E, Carrera-Bastos P, Targ S,
Franceschi C, Ferrucci L, Gilroy DW, Fasano A, Miller GW,
ACKNOWLEDGMENTS Miller AH, Mantovani A, Weyand CM, Barzilai N, Goronzy JJ,
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The authors would like to thank the Universitas Su-
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matera Utara Research Institution and the dean of Universi-
the life span. Nat Med 25(12): 1822–1832.
tas Sumatera Utara Faculty of Medicine. This research did https://doi.org/10.1038/s41591-019-0675-0
not receive any specific grant from funding agencies in the
González-González A, García-Sánchez D, Dotta M, Rodríguez-Rey
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Contribution Sari MI Jusuf NK Munir D Putra A Putra IB Bisri T Farhat F Ilyas S Muhar AM

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Citation Format: Sari MI, Jusuf NK, Munir D, Putra A, Putra IB, Bisri T, Farhat F, Ilyas S, Muhar AM (2024) Mesenchymal stem cell secretome therapy
on inflammation: A systematic review. J Pharm Pharmacogn Res 12(1): 39–49. https://doi.org/10.56499/jppres23.1726_12.1.39

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