Pre-Clinical Cell-Based Therapy for Limbal Stem Cell Deficiency
Abstract
:1. Cornea and Limbal Stem Cells
2. Limbal Stem Cell Deficiency
3. Treatment Approaches for Limbal Stem Cell Deficiency
Author, Year, (Reference) | Cell Source | Methods | LSCD Model | Follow-up Time | Evaluation | Results |
---|---|---|---|---|---|---|
Ma et al. 2006 [35] | Bone Marrow-Derived MSCs; Human | Cultured on AM carrier; Transplanted (n = 16); Control groups: 1) transplanted with fibroblast cells on AM (n = 8) and 2) transplanted with only AM (n = 7) | Rats; Disc paper saturated with 1 N NaOH onto cornea | 4 weeks | Slit lamp evaluation; Histology; IH | Reconstruction in 100% (16/16) of animals; Cornea completely transparent in 56.3% (9/16) of animals; Neovascularization detected within 2 mm and over 2 mm in 37.5% (6/16) and 12.5% (2/16) of animals, respectively; No complications |
Ye et al. 2006 [39] | Bone Marrow-Derived MSCs; Rabbit | Cultured in α-MEM; IV injection; Four groups:
| Rabbits; Filter paper saturated with 1 N NaOH onto cornea | 1 month | Slit lamp evaluation; IH | Reconstruction in 100% (15/15) of animals in Group 2; Cornea more clear in group 2 compared with other groups; Neovascularization appeared on day 14 in Group 2; No complications |
Gu et al. 2009 [33] | Bone Marrow-Derived MSCs; Rabbit | Cultured on fibrin carrier; Transplanted (n = 10); Control: eyes transplanted with only fibrin graft gel (n = 10) | Rabbits; Cornea treated with n-heptanol | 4 weeks | Slit lamp evaluation; Histology; FC; IF | Reconstruction in 100% (10/10) of animals; Iris partially clear in 30% (3/10) and completely obscure in 70% (7/10) of animals; Neovascularization detected over 3 mm from the limbus in 80% (8/10) of animals; No complications |
Omoto et al. 2009 [36] | Bone Marrow-Derived MSCs; Human | Cultured in α-MEM; Carrier-free sheets transplanted; Control: no transplantation; Number of animals not reported | Rabbits; Cornea treated with n-heptanol | 4 weeks | Slit lamp evaluation; Histology; IH; RT-PCR | Reconstruction of corneal epithelium successful; Corneal clarity: no data; Neovascularization: no data; No complications |
Jiang et al. 2010 [34] | Bone Marrow-Derived MSCs; Rat | Cultured on AM carrier; Three groups:
| Rats; Filter paper saturated with 1 N NaOH onto cornea | 10 weeks | Slit lamp evaluation; Histology; CLCM; SEM; FC; IF; IH | Reconstruction in 75% (9/12) of animals in group 3; Cornea completely transparent in 75% (9/12) of animals; Neovascularization limited within 2 mm of the limbus; No complications |
Zajicova et al. 2010 [40] | Bone Marrow-Derived MSCs; Mouse | Cultured on nanofiber scaffold carrier; Co-transplantation of LSC and MSCs; Control: normal eyes; Number of animals not reported | Mice; Epithelial debridement with a needle | 2 weeks | Slit lamp evaluation; CLCM; FC; RT-PCR | Significantly inhibited local inflammatory reactions and supported healing process; Corneal clarity: no data; Neovascularization: no data; No complications |
Reinshagen et al. 2011 [37] | Bone Marrow-Derived MSCs; Rabbit | Cultured in DMEM; Three groups:
| Rabbits; Cornea treated with n-heptanol | 6 months | Slit lamp evaluation; Histology; IH | Reconstruction in 100% (6/6) of animals in Group 1; Improved corneal clarity; Neovascularization of the entire cornea in all animals; No complications |
Rohaina et al. 2014 [38] | Bone Marrow-Derived MSCs; Human | Cultured on AM carrier; Transplanted (n = 4); Control groups:
| Rats; Disc paper saturated with 1 N NaOH onto cornea | 8 weeks | Slit lamp evaluation; Histology; IH; OCT; RT-PCR | Reconstruction in 100% (4/4) of animals; Moderate corneal clarity; Minimal vascularization; No complications |
Author, Year, (Reference) | Cell Source | Methods | LSCD Model | Follow-up Time | Evaluation | Results |
---|---|---|---|---|---|---|
Homma et al. 2004 [41] | Embryonic SCs; Mouse | Cultured on collagen IV-coated plates; Carrier-free sheets transplanted (n = 10); Control: no transplantation (n = 10) | Mice; Cornea treated with n-heptanol | 24 h | FC; Histology; RT-PCR; WB | Reconstruction in 100% (10/10) of animals; Corneal clarity: no data; Neovascularization: no data; No complications |
Ueno et al. 2007 [44] | Embryonic SCs; Mouse | Cultured on gelatin-coated plates; Transfected with Pax6; Carrier-free sheets transplanted (n = 5); Control groups:
| Mice; Cornea treated with n-heptanol | 24 h | Histology; IF; RT-PCR | Reconstruction in 100% (5/5) of animals 12 h after transplantation; Corneal clarity: no data; Neovascularization: no data; No complications |
Kumagai et al. 2010 [42] | Embryonic SCs; Monkey | Cultured on collagen IV-coated plates; Carrier-free sheets transplanted (n = 10); Control groups:
| Mice; Cornea treated with n-heptanol | 6 h | CLCM; IF; RT-PCR | Transplanted cells adhered to the corneal stroma and formed multiple cell layers in 100% (10/10) of animals; Corneal clarity: no data; Neovascularization: no data; No complications |
Notara et al. 2013 [43] | Embryonic SCs; Mouse | Cultured on collagen IV-coated plates; Carrier-free sheets transplanted; Control: no transplantation; Number of animals not reported | Pigs; Epithelial debridement with a blade | 5 weeks | Histology; IH; RT-PCR; WB | Reconstruction after 1 week; Corneal clarity: no data; Neovascularization: no data; Mild immune reaction |
Author, Year, (Reference) | Cell Source | Methods | LSCD Model | Follow-up Time | Evaluation | Results |
---|---|---|---|---|---|---|
Yang et al. 2007 [47] | Epidermal SCs; Goat | Cultured on AM carrier; Transplanted (n = 7); Control groups:
| Goats; Excision of the cornea and limbus | 24 months | IH; SEM; TEM | Reconstruction in 100% (7/7) of animals; Two or three quadrants of clear cornea in 71.4% (5/7) of animals at follow-up time to 24 months; Minimal neovascularization; Perforation through the pupil during operation in one eye |
Yang et al. 2008 [46] | Epidermal SCs; Goat | Cultured on AM carrier; Transplanted (n = 10); Control groups:
| Goats; Excision of the cornea and limbus; Burned with 1 N NaOH | 30 months | Digital camera; Histology; IH | Reconstruction in 100% (10/10) of animals; Three or four quadrants of clear cornea in 80% (8/100) of animals at follow-up time to 30 months; Minimal neovascularization; No complications |
Ouyang et al. 2014 [45] | Epidermal SCs; Human | Cultured on fibrin carrier; Transduction of Pax6 converted these cells into LSC-like cells; Transplanted and covered with AM (n = 5); Control: transplanted with only AM (n = 4) | Rabbits; Excision of the cornea and limbus | 3 months | CLCM; IF; Microarrays; Quantitative PCR; RNA-sequencing; WB | Reconstruction in 100% (5/5) of animals; Transparent cornea in 100% (5/5) of animals for over 3 months; Minimal neovascularization; No complications |
Author, Year, (Reference) | Cell Source | Methods | LSCD Model | Follow-up Time | Evaluation | Results |
---|---|---|---|---|---|---|
Monteiro et al. 2009 [50] | IDPSCs; Human | Cultured on AM carrier; Transplanted (n = 5); Control: transplanted with only AM (n = 5) | Rabbits; Chemical burn of the cornea | 3 months | Slit lamp evaluation; CLCM; IF; RT-PCR | Reconstruction in 100% (5/5) of animals; Gradual improvement in corneal transparency in 100% (5/5) of animals during follow-up time of 3 months; Neovascularization: no data; No complications |
Gomes et al. 2010 [49] | IDPSCs; Human | Cultured on AM carrier; MCB (n = 5), SCB (n = 4); Transplanted and covered with AM; Control: transplanted with only AM (n = 6) | Rabbits; Filter paper saturated with 0.5 M NaOH for 25 s (MCB), and for 45 s (SCB) | 3 months | Slit lamp evaluation; EM; Histology; IH | Reconstruction in 100% (5/5) of animals; Less organized and loose corneal epithelium in 75% (3/4) of SCB animals; Improved corneal clarity in 100% (5/5) of MCB animals; Superficial neovascularization in one animal No complications |
Meyer-Blazejewska et al. 2011 [48] | HFSCs; Mouse | Cultured on fibrin carrier; Transplanted (n = 31); Control: no transplantation (n = 31) | Mice; Cornea and limbus removed | 5 weeks | Slit lamp evaluation; Histology; IF | Reconstruction in 87.5% (7/8) of animals after two weeks Improved corneal clarity; Neovascularization in 12.5% (1/8) of animals; No complications |
Reza et al. 2011 [52] | UCSCs; Human | Cultured on AM carrier; Three groups:
| Rabbits; Cornea and limbus removed | 4 weeks | Slit lamp evaluation; Histology; IC; IH; RT-PCR | Reconstruction in 66.7% (4/6) of animals; Corneal clarity: no data; Severe neovascularization in one eye; Mild superficial inflammation in one other |
Lin et al. 2013 [51] | OFSCs; Human | Cultured in MesenPro medium; Topical application of cells (n = 9), Intra-limbal injection of cells (n = 3); Control: Topical application of PBS (n = 6), Injection of PBS (n = 3), no treatment (n = 3) | Mice; Filter paper saturated with 0.5 N NaOH onto cornea | 1 week | Digital camera; Histology; IH; IF; WB | Reconstruction of corneal epithelium after 1 week; Improved corneal clarity; No neovascularization; No complications |
Methods | Materials | References |
---|---|---|
Transplantation | Carrier-free cell sheets | [36,41,42,43,44] |
Transplantation | Amniotic membrane | [34,38,46,47,49,50,52,53] |
Intravenous injection | – | [39] |
Transplantation | Fibrin scaffold | [33,45,48] |
Transplantation | Nanofiber scaffold | [40] |
Injection under amniotic membrane | – | [37] |
Topical application/Intra-limbal injection | – | [51] |
4. Substrates for Corneal Reconstruction
Biological/Biosynthetic | Synthetic |
---|---|
Amniotic membrane [57] | Contact lenses [58] |
Chemically cross-linked hyaluronic acid-based hydrogels [59] | Mebiol Gel (thermo-reversible polymer gel) [53] |
Chitosan matrix/silver matrix/gold matrix [60] | Nanofiber scaffolds [40] |
Collagen IV-coated plates [61] | Petrolatum gauze [24] |
Collagen membranes [62] | Plastic [25] |
Corneal stroma [63] | Poly(lactide-co-glycolide) electrospun scaffolds [64] |
Fibrin [65] | Poly-ε-caprolactone electrospun scaffolds [66] |
Human keratoplasty lenticules [67] | |
Laminin-coated compressed collagen gel [68] | |
Matrigel (reconstituted basement membrane extract) [69] | |
Plastic compressed collagen [70] | |
Recombinant human cross-linked collagen scaffold [71] | |
Silk fibroin [72] | |
Silk fibroin mixed with polyethylene glycol [72] |
Carriers/Methods | Transparency | Mechanical Strength | Elasticity | Advantages | Disadvantages |
---|---|---|---|---|---|
AM | + | ++ | +++ | Stimulates cell growth, anti-inflammation, anti-angiogenesis, proper elasticity | Limited transparency, variable quality, risk of disease transmission, limited mechanical strength, poor standardization |
Carrier-free method | N/A | N/A | N/A | Rapid adhesion, does not require preparation and standardization of membranes, does not require sutures | Possibility for detachment from the ocular surface in the early period after surgery |
Fibrin gel | ++ | +++ | +++ | Proper transparency, good bioadsorbence, easy manipulation, good mechanical strength, elasticity, degradable | Possibility for immune response, risk for disease transmission |
Nanofiber | ++ | ++++ | ++ | Good transparency, high mechanical strength, highly flexible, proper biocompatibility, easy to use, controlled shape and pore size, low cost | Limited elasticity, high cost |
5. Cultured Bone Marrow-Derived Mesenchymal Stem Cells
6. Cultured Embryonic Stem Cells
7. Cultured Epidermal Stem Cells
8. Cultured Hair Follicle-Derived Stem Cells
9. Cultured Immature Dental Pulp Stem Cells
10. Cultured Umbilical Cord Stem Cells
11. Cultured Orbital Fat-Derived Stem Cells
12. Challenges and Future Perspectives
13. Conclusions
Types of Stem Cells | Success | Complications (Number of Animals) | Ease of Access | Number of Animals (Number of Studies) | Autologous Source | Ethical Concerns |
---|---|---|---|---|---|---|
Bone Marrow-Derived MSCs | +++ | – | ++ | 63 (8) 1 | Yes | No |
Embryonic SCs | + | Mild immune reaction * | + | 25 (4) 2 | No | Yes |
Epidermal SCs | ++++ | Perforation (1) | ++++ | 22 (3) | Yes | No |
HFSCs | +++ | – | ++++ | 31 (1) | Yes | No |
IDPSCs | +++ | – | ++ | 14 (2) | Yes | No |
OFSCs | ++ | – | ++ | 12 (1) | Yes | No |
UCSCs | ++ | Mild superficial inflammation (1) | ++ | 6 (1) | No | No |
Acknowledgments
Conflicts of Interest
References
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Sehic, A.; Utheim, Ø.A.; Ommundsen, K.; Utheim, T.P. Pre-Clinical Cell-Based Therapy for Limbal Stem Cell Deficiency. J. Funct. Biomater. 2015, 6, 863-888. https://doi.org/10.3390/jfb6030863
Sehic A, Utheim ØA, Ommundsen K, Utheim TP. Pre-Clinical Cell-Based Therapy for Limbal Stem Cell Deficiency. Journal of Functional Biomaterials. 2015; 6(3):863-888. https://doi.org/10.3390/jfb6030863
Chicago/Turabian StyleSehic, Amer, Øygunn Aass Utheim, Kristoffer Ommundsen, and Tor Paaske Utheim. 2015. "Pre-Clinical Cell-Based Therapy for Limbal Stem Cell Deficiency" Journal of Functional Biomaterials 6, no. 3: 863-888. https://doi.org/10.3390/jfb6030863