Emerging Therapeutic Strategies for Limbal Stem Cell Deficiency
This article is part of Special Issue:
Ying Dong,
Han Peng,
Robert M. Lavker,
Corresponding Author
Ying Dong
Department of Ophthalmology, The First Affiliated Hospital, Chinese PLA General Hospital, Beijing 100048, China 301hospital.com.cn
Department of Dermatology, Northwestern University, Chicago, IL 60611, USA nwu.edu.cn
Search for more papers by this authorHan Peng
Department of Dermatology, Northwestern University, Chicago, IL 60611, USA nwu.edu.cn
Search for more papers by this authorRobert M. Lavker
Department of Dermatology, Northwestern University, Chicago, IL 60611, USA nwu.edu.cn
Search for more papers by this authorYing Dong,
Han Peng,
Robert M. Lavker,
Corresponding Author
Ying Dong
Department of Ophthalmology, The First Affiliated Hospital, Chinese PLA General Hospital, Beijing 100048, China 301hospital.com.cn
Department of Dermatology, Northwestern University, Chicago, IL 60611, USA nwu.edu.cn
Search for more papers by this authorHan Peng
Department of Dermatology, Northwestern University, Chicago, IL 60611, USA nwu.edu.cn
Search for more papers by this authorRobert M. Lavker
Department of Dermatology, Northwestern University, Chicago, IL 60611, USA nwu.edu.cn
Search for more papers by this authorAcademic Editor: Karim Mohamed-Noriega
Abstract
Identification and characterization of the limbal epithelial stem cells (LESCs) has proven to be a major accomplishment in anterior ocular surface biology. These cells have been shown to be a subpopulation of limbal epithelial basal cells, which serve as the progenitor population of the corneal epithelium. LESCs have been demonstrated to play an important role in maintaining corneal epithelium homeostasis. Many ocular surface diseases, including intrinsic (e.g., Sjogren’s syndrome) or extrinsic (e.g., alkali or thermal burns) insults, which impair LESCs, can lead to limbal stem cell deficiency (LSCD). LSCD is characterized by an overgrowth of conjunctival-derived epithelial cells, corneal neovascularization, and chronic inflammation, eventually leading to blindness. Treatment of LSCD has been challenging, especially in bilateral total LSCD. Recently, advances in LESC research have led to novel therapeutic approaches for treating LSCD, such as transplantation of the cultured limbal epithelium. These novel therapeutic approaches have demonstrated efficacy for ocular surface reconstruction and restoration of vision in patients with LSCD. However, they all have their own limitations. Here, we describe the current status of LSCD treatment and discuss the advantages and disadvantages of the available therapeutic modalities.
References
- 1 Cotsarelis G., Cheng S. Z., Dong G., Sun T. T., and Lavker R. M., Existence of slow-cycling limbal epithelial basal cells that can be preferentially stimulated to proliferate: implications on epithelial stem cells, Cell. (1989) 57, no. 2, 201–209, https://doi.org/10.1016/0092-8674(89)90958-6, 2-s2.0-0024523631.
- 2 Davanger M. and Evensen A., Role of the pericorneal papillary structure in renewal of corneal epithelium, Nature. (1971) 229, no. 5286, 560–561, https://doi.org/10.1038/229560a0, 2-s2.0-0015231945.
- 3 Schermer A., Galvin S., and Sun T. T., Differentiation-related expression of a major 64K corneal keratin in vivo and in culture suggests limbal location of corneal epithelial stem cells, Journal of Cell Biology. (1986) 103, no. 1, 49–62, https://doi.org/10.1083/jcb.103.1.49.
- 4 Priya C. G., Prasad T., Prajna N. V., and Muthukkaruppan V., Identification of human corneal epithelial stem cells on the basis of high ABCG2 expression combined with a large N/C ratio, Microscopy Research and Technique. (2013) 76, no. 3, 242–248, https://doi.org/10.1002/jemt.22159, 2-s2.0-84874375942.
- 5 Thoft R. A., Wiley L. A., and Sundarraj N., The multipotential cells of the limbus, Eye. (1989) 3, no. 2, 109–113, https://doi.org/10.1038/eye.1989.17, 2-s2.0-0024819327.
- 6 Tsai R. J. and Tseng S. C., Human allograft limbal transplantation for corneal surface reconstruction, Cornea. (1994) 13, no. 5, 389–400, https://doi.org/10.1097/00003226-199409000-00003, 2-s2.0-0028148031.
- 7 de Paiva C. S., Chen Z., Corrales R. M., Pflugfelder S. C., and Li D. Q., ABCG2 transporter identifies a population of clonogenic human limbal epithelial cells, Stem Cells. (2005) 23, no. 1, 63–73.
- 8 Ksander B. R., Kolovou P. E., Wilson B. J. et al., ABCB5 is a limbal stem cell gene required for corneal development and repair, Nature. (2014) 511, no. 7509, 353–357, https://doi.org/10.1038/nature13426, 2-s2.0-84904431168.
- 9 Barbaro V., Testa A., Di Lorio E., Mavilio F., Pellegrini G., and De Luca M., C/EBPdelta regulates cell cycle and self-renewal of human limbal stem cells, Journal of Cell Biology. (2007) 177, no. 6, 1037–1049, https://doi.org/10.1083/jcb.200703003, 2-s2.0-34250763743.
- 10 Pellegrini G., Dellambra E., Golisano O. et al., p63 identifies keratinocyte stem cells, Proceedings of the National Academy of Sciences of the United States of America. (2001) 98, no. 6, 3156–3161, https://doi.org/10.1073/pnas.061032098, 2-s2.0-0035853118.
- 11 Ouyang H., Xue Y., Lin Y. et al., WNT7A and PAX6 define corneal epithelium homeostasis and pathogenesis, Nature. (2014) 511, no. 7509, 358–361, https://doi.org/10.1038/nature13465, 2-s2.0-84904416274.
- 12 Higa K., Kato N., Yoshida S. et al., Aquaporin 1-positive stromal niche-like cells directly interact with N-cadherin-positive clusters in the basal limbal epithelium, Stem Cell Research. (2013) 10, no. 2, 147–155, https://doi.org/10.1016/j.scr.2012.11.001, 2-s2.0-84871821029.
- 13 Chee K. Y., Kicic A., and Wiffen S. J., Limbal stem cells: the search for a marker, Clinical & Experimental Ophthalmology. (2006) 34, no. 1, 64–73, https://doi.org/10.1111/j.1442-9071.2006.01147.x, 2-s2.0-33644914499.
- 14 Thomas P. B., Liu Y. H., Zhuang F. F. et al., Identification of Notch-1 expression in the limbal basal epithelium, Molecular Vision. (2007) 13, 337–344.
- 15 Schlotzer-Schrehardt U. and Kruse F. E., Identification and characterization of limbal stem cells, Experimental Eye Research. (2005) 81, no. 3, 247–264, https://doi.org/10.1016/j.exer.2005.02.016, 2-s2.0-23944433665.
- 16 Rodrigues M., Ben-Zvi A., Krachmer J., Schermer A., and Sun T. T., Suprabasal expression of a 64-kilodalton keratin (no. 3) in developing human corneal epithelium, Differentiation. (1987) 34, no. 1, 60–67, https://doi.org/10.1111/j.1432-0436.1987.tb00051.x, 2-s2.0-0023202097.
- 17 Kurpakus M. A., Maniaci M. T., and Esco M., Expression of keratins K12, K4 and K14 during development of ocular surface epithelium, Current Eye Research. (1994) 13, no. 11, 805–814, https://doi.org/10.3109/02713689409025135, 2-s2.0-0027945326.
- 18 Boulton M. and Albon J., Stem cells in the eye, International Journal of Biochemistry & Cell Biology. (2004) 36, no. 4, 643–657, https://doi.org/10.1016/j.biocel.2003.10.013, 2-s2.0-1542269023.
- 19 Lavker R. M., Dong G., Cheng S. Z., Kudoh K., Cotsarelis G., and Sun T. T., Relative proliferative rates of limbal and corneal epithelia. Implications of corneal epithelial migration, circadian rhythm, and suprabasally located DNA-synthesizing keratinocytes, Investigative Ophthalmology & Visual Science. (1991) 32, no. 6, 1864–1875.
- 20 Lavker R. M., Tseng S. C., and Sun T. T., Corneal epithelial stem cells at the limbus: looking at some old problems from a new angle, Experimental Eye Research. (2004) 78, no. 3, 433–446, https://doi.org/10.1016/j.exer.2003.09.008, 2-s2.0-0842288676.
- 21 Barrandon Y. and Green H., Three clonal types of keratinocyte with different capacities for multiplication, Proceedings of the National Academy of Sciences of the United States of America. (1987) 84, no. 8, 2302–2306, https://doi.org/10.1073/pnas.84.8.2302, 2-s2.0-0011478490.
- 22 Eberwein P. and Reinhard T., Concise reviews: the role of biomechanics in the limbal stem cell niche: new insights for our understanding of this structure, Stem Cells. (2015) 33, no. 3, 916–924, https://doi.org/10.1002/stem.1886, 2-s2.0-84923253937.
- 23 Tseng S. C., He H., Zhang S., and Chen S. Y., Niche regulation of limbal epithelial stem cells: relationship between inflammation and regeneration, Ocular Surface. (2016) 14, no. 2, 100–112, https://doi.org/10.1016/j.jtos.2015.12.002, 2-s2.0-84963979589.
- 24 Yazdanpanah G., Jabbehdari S., and Djalilian A. R., Limbal and corneal epithelial homeostasis, Current Opinion in Ophthalmology. (2017) 28, no. 4, 348–354, https://doi.org/10.1097/icu.0000000000000378, 2-s2.0-85017433260.
- 25 Li J., Chen S. Y., Zhao X. Y., Zhang M. C., and Xie H. T., Rat limbal niche cells prevent epithelial stem/progenitor cells from differentiation and proliferation by inhibiting notch signaling pathway in vitro, Investigative Ophthalmology & Visual Science. (2017) 58, no. 7, 2968–2976, https://doi.org/10.1167/iovs.16-20642, 2-s2.0-85020804016.
- 26 Dziasko M. A., Tuft S. J., and Daniels J. T., Limbal melanocytes support limbal epithelial stem cells in 2D and 3D microenvironments, Experimental Eye Research. (2015) 138, 70–79, https://doi.org/10.1016/j.exer.2015.06.026, 2-s2.0-84936073976.
- 27 Dua H. S., Shanmuganathan V. A., Powell-Richards A. O., Tighe P. J., and Joseph A., Limbal epithelial crypts: a novel anatomical structure and a putative limbal stem cell niche, British Journal of Ophthalmology. (2005) 89, no. 5, 529–532, https://doi.org/10.1136/bjo.2004.049742, 2-s2.0-17644389509.
- 28 Yeung A. M., Schlotzer-Schrehardt U., Kulkarni B., Tint N. L., Hopkinson A., and Dua H. S., Limbal epithelial crypt: a model for corneal epithelial maintenance and novel limbal regional variations, Archives of Ophthalmology. (2008) 126, no. 5, 665–669, https://doi.org/10.1001/archopht.126.5.665, 2-s2.0-43549121501.
- 29 Grieve K., Ghoubay D., Georgeon C. et al., Three-dimensional structure of the mammalian limbal stem cell niche, Experimental Eye Research. (2015) 140, 75–84, https://doi.org/10.1016/j.exer.2015.08.003, 2-s2.0-84940385404.
- 30 Tsai R. J. and Tsai R. Y., From stem cell niche environments to engineering of corneal epithelium tissue, Japanese Journal of Ophthalmology. (2014) 58, no. 2, 111–119, https://doi.org/10.1007/s10384-014-0306-8, 2-s2.0-84896491370.
- 31 Sejpal K., Ali M. H., Maddileti S. et al., Cultivated limbal epithelial transplantation in children with ocular surface burns, JAMA Ophthalmology. (2013) 131, no. 6, 731–736, https://doi.org/10.1001/jamaophthalmol.2013.2308, 2-s2.0-84879053886.
- 32 Nubile M., Lanzini M., Miri A. et al., In vivo confocal microscopy in diagnosis of limbal stem cell deficiency, American Journal of Ophthalmology. (2013) 155, no. 2, 220–232, https://doi.org/10.1016/j.ajo.2012.08.017, 2-s2.0-84872284018.
- 33 Rossen J., Amram A., Milani B. et al., Contact lens-induced limbal stem cell deficiency, Ocular Surface. (2016) 14, no. 4, 419–434, https://doi.org/10.1016/j.jtos.2016.06.003, 2-s2.0-84992361742.
- 34 Chan E., Le Q., Codriansky A., Hong J., Xu J., and Deng S. X., Existence of normal limbal epithelium in eyes with clinical signs of total limbal stem cell deficiency, Cornea. (2016) 35, no. 11, 1483–1487, https://doi.org/10.1097/ico.0000000000000914, 2-s2.0-84976565323.
- 35 Kim K. H. and Mian S. I., Diagnosis of corneal limbal stem cell deficiency, Current Opinion in Ophthalmology. (2017) 28, no. 4, 355–362, https://doi.org/10.1097/icu.0000000000000387, 2-s2.0-85017725714.
- 36 Lemp M. A. and Mathers W. D., Corneal epithelial cell movement in humans, Eye. (1989) 3, no. 4, 438–445, https://doi.org/10.1038/eye.1989.65, 2-s2.0-0024785460.
- 37 Chan E. H., Chen L., Yu F., and Deng S. X., Epithelial thinning in limbal stem cell deficiency, American Journal of Ophthalmology. (2015) 160, no. 4, 669–677, https://doi.org/10.1016/j.ajo.2015.06.029, 2-s2.0-84941418025.
- 38 Tseng S. C., Prabhasawat P., Barton K., Gray T., and Meller D., Amniotic membrane transplantation with or without limbal allografts for corneal surface reconstruction in patients with limbal stem cell deficiency, Archives of Ophthalmology. (1998) 116, no. 4, 431–441, https://doi.org/10.1001/archopht.116.4.431.
- 39 Barreiro T. P., Santos M. S., Vieira A. C., de Nadai Barros J., Hazarbassanov R. M., and Gomes J. A., Comparative study of conjunctival limbal transplantation not associated with the use of amniotic membrane transplantation for treatment of total limbal deficiency secondary to chemical injury, Cornea. (2014) 33, no. 7, 716–720, https://doi.org/10.1097/ico.0000000000000139, 2-s2.0-84902242085.
- 40 Liang L., Sheha H., Li J., and Tseng S. C., Limbal stem cell transplantation: new progresses and challenges, Eye. (2009) 23, no. 10, 1946–1953, https://doi.org/10.1038/eye.2008.379, 2-s2.0-70350158504.
- 41 Kheirkhah A., Johnson D. A., Paranjpe D. R., Raju V. K., Casas V., and Tseng S. C., Temporary sutureless amniotic membrane patch for acute alkaline burns, Archives of Ophthalmology. (2008) 126, no. 8, 1059–1066, https://doi.org/10.1001/archopht.126.8.1059, 2-s2.0-49449107490.
- 42 Westekemper H., Figueiredo F. C., Siah W. F., Wagner N., Steuhl K. P., and Meller D., Clinical outcomes of amniotic membrane transplantation in the management of acute ocular chemical injury, British Journal of Ophthalmology. (2017) 101, no. 2, 103–107, https://doi.org/10.1136/bjophthalmol-2015-308037, 2-s2.0-84966470175.
- 43 Sangwan V. S., Burman S., Tejwani S., Mahesh S. P., and Murthy R., Amniotic membrane transplantation: a review of current indications in the management of ophthalmic disorders, Indian Journal of Ophthalmology. (2007) 55, no. 4, 251–260, https://doi.org/10.4103/0301-4738.33036.
- 44 Sahu S. K., Govindswamy P., Sangwan V. S., and Thomas R., Midterm results on ocular surface reconstruction using cultivated autologous oral mucosal epithelial transplantation, American Journal of Ophthalmology. (2007) 143, no. 1, https://doi.org/10.1016/j.ajo.2006.09.015, 2-s2.0-33845474752.
- 45 Meallet M. A., Espana E. M., Grueterich M., Ti S. E., Goto E., and Tseng S. C., Amniotic membrane transplantation with conjunctival limbal autograft for total limbal stem cell deficiency, Ophthalmology. (2003) 110, no. 8, 1585–1592, https://doi.org/10.1016/s0161-6420(03)00503-7, 2-s2.0-0041528258.
- 46 Dhamodaran K., Subramani M., Matalia H., Jayadev C., Shetty R., and Das D., One for all: a standardized protocol for ex vivo culture of limbal, conjunctival and oral mucosal epithelial cells into corneal lineage, Cytotherapy. (2016) 18, no. 4, 546–561, https://doi.org/10.1016/j.jcyt.2016.01.003, 2-s2.0-84960146307.
- 47 Feng Y., Borrelli M., Reichl S., Schrader S., and Geerling G., Review of alternative carrier materials for ocular surface reconstruction, Current Eye Research. (2014) 39, no. 6, 541–552, https://doi.org/10.3109/02713683.2013.853803, 2-s2.0-84899890049.
- 48 Kenyon K. R. and Tseng S. C., Limbal autograft transplantation for ocular surface disorders, Ophthalmology. (1989) 96, no. 5, 709–722.
- 49 Frucht-Pery J., Siganos C. S., Solomon A., Scheman L., Brautbar C., and Zauberman H., Limbal cell autograft transplantation for severe ocular surface disorders, Graefe’s Archive for Clinical and Experimental Ophthalmolog. (1998) 236, no. 8, 582–587, https://doi.org/10.1007/s004170050125, 2-s2.0-0031850019.
- 50 Krakauer M., Welder J. D., Pandya H. K., Nassiri N., and Djalilian A. R., Adverse effects of systemic immunosuppression in keratolimbal allograft, Journal of Ophthalmology. (2012) 2012, 5, 576712, https://doi.org/10.1155/2012/576712, 2-s2.0-84873814210.
- 51 Holland E. J., Mogilishetty G., Skeens H. M. et al., Systemic immunosuppression in ocular surface stem cell transplantation: results of a 10-year experience, Cornea. (2012) 31, no. 6, 655–661, https://doi.org/10.1097/ico.0b013e31823f8b0c, 2-s2.0-84861098225.
- 52 Daya S. M., Watson A., Sharpe J. R. et al., Outcomes and DNA analysis of ex vivo expanded stem cell allograft for ocular surface reconstruction, Ophthalmology. (2005) 112, no. 3, 470–477, https://doi.org/10.1016/j.ophtha.2004.09.023, 2-s2.0-14644388076.
- 53 Sangwan V. S., Basu S., MacNeil S., and Balasubramanian D., Simple limbal epithelial transplantation (SLET): a novel surgical technique for the treatment of unilateral limbal stem cell deficiency, British Journal of Ophthalmology. (2012) 96, no. 7, 931–934, https://doi.org/10.1136/bjophthalmol-2011-301164, 2-s2.0-84862904465.
- 54 Amescua G., Atallah M., Nikpoor N., Galor A., and Perez V. L., Modified simple limbal epithelial transplantation using cryopreserved amniotic membrane for unilateral limbal stem cell deficiency, American Journal of Ophthalmology. (2014) 158, no. 3, 469.e2–475.e2, https://doi.org/10.1016/j.ajo.2014.06.002, 2-s2.0-84908371540.
- 55
Arya S. K.,
Bhatti A.,
Raj A., and
Bamotra R. K., Simple limbal epithelial transplantation in acid injury and severe dry eye, Journal of Clinical and Diagnostic Research. (2016) 10, no. 6, https://doi.org/10.7860/JCDR/2016/19306.7997, 2-s2.0-84973300766.
10.7860/JCDR/2016/19306.7997 Google Scholar
- 56
Bhalekar S.,
Basu S.,
Lal I., and
Sangwan V. S., Successful autologous simple limbal epithelial transplantation (SLET) in previously failed paediatric limbal transplantation for ocular surface burns, BMJ Case Reports. (2013) 2013, pii: bcr2013009888https://doi.org/10.1136/bcr-2013-009888, 2-s2.0-84878989710.
10.1136/bcr-2013-009888 Google Scholar
- 57 Hernandez-Bogantes E., Amescua G., Navas A. et al., Minor ipsilateral simple limbal epithelial transplantation (mini-SLET) for pterygium treatment, British Journal of Ophthalmology. (2015) 99, no. 12, 1598–1600, https://doi.org/10.1136/bjophthalmol-2015-306857.
- 58 Mittal V., Jain R., Mittal R., Vashist U., and Narang P., Successful management of severe unilateral chemical burns in children using simple limbal epithelial transplantation (SLET), British Journal of Ophthalmology. (2016) 100, no. 8, 1102–1108, https://doi.org/10.1136/bjophthalmol-2015-307179, 2-s2.0-84954304686.
- 59 Vazirani J., Ali M. H., Sharma N. et al., Autologous simple limbal epithelial transplantation for unilateral limbal stem cell deficiency: multicentre results, British Journal of Ophthalmology. (2016) 100, no. 10, 1416–1420, https://doi.org/10.1136/bjophthalmol-2015-307348, 2-s2.0-84962184445.
- 60 Vazirani J., Basu S., Kenia H. et al., Unilateral partial limbal stem cell deficiency: contralateral versus ipsilateral autologous cultivated limbal epithelial transplantation, American Journal of Ophthalmology. (2014) 157, no. 3, 584.e2–590.e2, https://doi.org/10.1016/j.ajo.2013.11.011, 2-s2.0-84894080311.
- 61 Basu S., Ali H., and Sangwan V. S., Clinical outcomes of repeat autologous cultivated limbal epithelial transplantation for ocular surface burns, American Journal of Ophthalmology. (2012) 153, no. 4, 643–650, https://doi.org/10.1016/j.ajo.2011.09.016, 2-s2.0-84859102503.
- 62 Basu S., Sureka S. P., Shanbhag S. S., Kethiri A. R., Singh V., and Sangwan V. S., Simple limbal epithelial transplantation: long-term clinical outcomes in 125 cases of unilateral chronic ocular surface burns, Ophthalmology. (2016) 123, no. 5, 1000–1010, https://doi.org/10.1016/j.ophtha.2015.12.042, 2-s2.0-84958213796.
- 63 Gupta N., Joshi J., Farooqui J. H., and Mathur U., Results of simple limbal epithelial transplantation in unilateral ocular surface burn, Indian Journal of Ophthalmology. (2018) 66, no. 1, 45–52, https://doi.org/10.4103/ijo.ijo_602_17, 2-s2.0-85040111769.
- 64 Pellegrini G., Traverso C. E., Franzi A. T., Zingirian M., Cancedda R., and De Luca M., Long-term restoration of damaged corneal surfaces with autologous cultivated corneal epithelium, The Lancet. (1997) 349, no. 9057, 990–993, https://doi.org/10.1016/s0140-6736(96)11188-0, 2-s2.0-0030896153.
- 65 Rama P., Matuska S., Paganoni G., Spinelli A., De Luca M., and Pellegrini G., Limbal stem-cell therapy and long-term corneal regeneration, New England journal of medicine. (2010) 363, no. 2, 147–155, https://doi.org/10.1056/nejmoa0905955, 2-s2.0-77954394144.
- 66 Cheng J., Zhai H., Wang J., Duan H., and Zhou Q., Long-term outcome of allogeneic cultivated limbal epithelial transplantation for symblepharon caused by severe ocular burns, BMC Ophthalmology. (2017) 17, no. 1, https://doi.org/10.1186/s12886-017-0403-9, 2-s2.0-85010903656.
- 67 Kawashima M., Kawakita T., Satake Y., Higa K., and Shimazaki J., Phenotypic study after cultivated limbal epithelial transplantation for limbal stem cell deficiency, Archives of Ophthalmology. (2007) 125, no. 10, 1337–1344, https://doi.org/10.1001/archopht.125.10.1337, 2-s2.0-35348934402.
- 68 Gangaraju V. K. and Lin H., MicroRNAs: key regulators of stem cells, Nature Reviews Molecular Cell Biology. (2009) 10, no. 2, 116–125, https://doi.org/10.1038/nrm2621, 2-s2.0-58849163959.
- 69 Tiscornia G. and Izpisua Belmonte G. C., MicroRNAs in embryonic stem cell function and fate, Genes & Development. (2010) 24, no. 24, 2732–2741, https://doi.org/10.1101/gad.1982910, 2-s2.0-78650223089.
- 70 Yi R., Poy M. N., Stoffel M., and Fuchs E., A skin microRNA promotes differentiation by repressing “stemness”, Nature. (2008) 452, no. 7184, 225–229, https://doi.org/10.1038/nature06642, 2-s2.0-40749111551.
- 71 Liu Z., Zhan W., Zeng M., Chen J., Zou H., and Min Z., Enhanced functional properties of human limbal stem cells by inhibition of the miR-31/FIH-1/P21 axis, Acta Ophthalmologica. (2017) 95, no. 6, e495–e502, https://doi.org/10.1111/aos.13503, 2-s2.0-85021316005.
- 72 Peng H., Hamanaka R. B., Katsnelson J. et al., MicroRNA-31 targets FIH-1 to positively regulate corneal epithelial glycogen metabolism, FASEB Journal. (2012) 26, no. 8, 3140–3147, https://doi.org/10.1096/fj.11-198515, 2-s2.0-84864773117.
- 73 Peng H., Kaplan N., Hamanaka R. B. et al., microRNA-31/factor-inhibiting hypoxia-inducible factor 1 nexus regulates keratinocyte differentiation, Proceedings of the National Academy of Sciences of the United States of America. (2012) 109, no. 35, 14030–14034, https://doi.org/10.1073/pnas.1111292109, 2-s2.0-84865563911.
- 74 Peng H., Kaplan N., Yang W., Getsios S., and Lavker R. M., FIH-1 disrupts an LRRK1/EGFR complex to positively regulate keratinocyte migration, American Journal of Pathology. (2014) 184, no. 12, 3262–3271, https://doi.org/10.1016/j.ajpath.2014.08.014, 2-s2.0-84913570688.
- 75 Lavker R. M., Jia Y., and Ryan D. G., The tiny world of microRNAs in the cross hairs of the mammalian eye, Human Genomics. (2009) 3, no. 4, 332–348, https://doi.org/10.1186/1479-7364-3-4-332.
- 76 Lin D., Halilovic A., Yue P. et al., Inhibition of miR-205 impairs the wound-healing process in human corneal epithelial cells by targeting KIR4.1 (KCNJ10), Investigative Ophthalmology & Visual Science. (2013) 54, no. 9, 6167–6178, https://doi.org/10.1167/iovs.12-11577, 2-s2.0-84883858134.
- 77 Hsu C. C., Peng C. H., Hung K. H. et al., Stem cell therapy for corneal regeneration medicine and contemporary nanomedicine for corneal disorders, Cell Transplantation. (2015) 24, no. 10, 1915–1930, https://doi.org/10.3727/096368914x685744, 2-s2.0-84943270348.
- 78 Peng H., Park J. K., Katsnelson J. et al., microRNA-103/107 family regulates multiple epithelial stem cell characteristics, Stem Cells. (2015) 33, no. 5, 1642–1656, https://doi.org/10.1002/stem.1962, 2-s2.0-84928564078.
- 79 Park J. K., Yang W., Katsnelson J., Lavker R. M., and Peng H., MicroRNAs enhance keratinocyte proliferative capacity in a stem cell-enriched epithelium, PLoS One. (2015) 10, no. 8, e0134853, https://doi.org/10.1371/journal.pone.0134853, 2-s2.0-84941992330.
- 80 Klionsky D. J., Abdelmohsen K., Abe A. et al., Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition), Autophagy. (2016) 12, no. 1, 1–222, https://doi.org/10.1080/15548627.2015.1100356, 2-s2.0-85013763791.
- 81 Peng H., Park J. K., and Lavker R. M., Eyeing autophagy and macropinocytosis in the corneal/limbal epithelia, Autophagy. (2017) 13, no. 5, 975–977, https://doi.org/10.1080/15548627.2017.1287658, 2-s2.0-85017431412.
- 82 Peng H., Park J. K., and Lavker R. M., Autophagy and macropinocytosis: keeping an eye on the corneal/limbal epithelia, Investigative Ophthalmology & Visual Science. (2017) 58, no. 1, 416–423, https://doi.org/10.1167/iovs.16-21111, 2-s2.0-85010894714.
- 83 Eslani M., Baradaran-Rafii A., and Ahmad S., Cultivated limbal and oral mucosal epithelial transplantation, Seminars in Ophthalmology. (2012) 27, no. 3-4, 80–93, https://doi.org/10.3109/08820538.2012.680641, 2-s2.0-84863807791.
- 84 Nakamura T., Inatomi T., Sotozono C., Amemiya T., Kanamura N., and Kinoshita S., Transplantation of cultivated autologous oral mucosal epithelial cells in patients with severe ocular surface disorders, British Journal of Ophthalmology. (2004) 88, no. 10, 1280–1284, https://doi.org/10.1136/bjo.2003.038497, 2-s2.0-4744360280.
- 85 Nakamura T. and Kinoshita S., New hopes and strategies for the treatment of severe ocular surface disease, Current Opinion in Ophthalmology. (2011) 22, no. 4, 274–278, https://doi.org/10.1097/icu.0b013e3283477d4d, 2-s2.0-79959275149.
- 86 Prabhasawat P., Ekpo P., Uiprasertkul M. et al., Long-term result of autologous cultivated oral mucosal epithelial transplantation for severe ocular surface disease, Cell and Tissue Banking. (2016) 17, no. 3, 491–503, https://doi.org/10.1007/s10561-016-9575-4, 2-s2.0-84981210828.
- 87 Sotozono C., Inatomi T., Nakamura T. et al., Cultivated oral mucosal epithelial transplantation for persistent epithelial defect in severe ocular surface diseases with acute inflammatory activity, Acta Ophthalmologica. (2014) 92, no. 6, e447–e453, https://doi.org/10.1111/aos.12397, 2-s2.0-84906313985.
- 88 Sotozono C., Inatomi T., Nakamura T. et al., Visual improvement after cultivated oral mucosal epithelial transplantation, Ophthalmology. (2013) 120, no. 1, 193–200, https://doi.org/10.1016/j.ophtha.2012.07.053, 2-s2.0-84872007958.
- 89 Nakamura T., Takeda K., Inatomi T., Sotozono C., and Kinoshita S., Long-term results of autologous cultivated oral mucosal epithelial transplantation in the scar phase of severe ocular surface disorders, British Journal of Ophthalmology. (2011) 95, no. 7, 942–946, https://doi.org/10.1136/bjo.2010.188714, 2-s2.0-79959346658.
- 90 Gaddipati S., Muralidhar R., Sangwan V. S., Mariappan I., Vemuganti G. K., and Balasubramanian D., Oral epithelial cells transplanted on to corneal surface tend to adapt to the ocular phenotype, Indian Journal of Ophthalmology. (2014) 62, no. 5, 644–648.
- 91 Satija N. K., Gurudutta G. U., Sharma S. et al., Mesenchymal stem cells: molecular targets for tissue engineering, Stem Cells and Development. (2007) 16, no. 1, 7–23, https://doi.org/10.1089/scd.2006.9998, 2-s2.0-33847632532.
- 92 Zannettino A. C., Paton S., Arthur A. et al., Multipotential human adipose-derived stromal stem cells exhibit a perivascular phenotype in vitro and in vivo, Journal of Cellular Physiology. (2008) 214, no. 2, 413–421, https://doi.org/10.1002/jcp.21210, 2-s2.0-37349030439.
- 93 Funderburgh J. L., Funderburgh M. L., and Du Y., Stem cells in the limbal stroma, Ocular Surface. (2016) 14, no. 2, 113–120, https://doi.org/10.1016/j.jtos.2015.12.006, 2-s2.0-84963959981.
- 94 Holan V., Trosan P., Cejka C. et al., A comparative study of the therapeutic potential of mesenchymal stem cells and limbal epithelial stem cells for ocular surface reconstruction, Stem Cells Translational Medicine. (2015) 4, no. 9, 1052–1063, https://doi.org/10.5966/sctm.2015-0039, 2-s2.0-84940092824.
- 95 Almaliotis D., Koliakos G., Papakonstantinou E. et al., Mesenchymal stem cells improve healing of the cornea after alkali injury, Graefe’s Archive for Clinical and Experimental Ophthalmolog. (2015) 253, no. 7, 1121–1135, https://doi.org/10.1007/s00417-015-3042-y, 2-s2.0-84933181699.
- 96 Shaharuddin B., Osei-Bempong C., Ahmad S. et al., Human limbal mesenchymal stem cells express ABCB5 and can grow on amniotic membrane, Regenerative medicine. (2016) 11, no. 3, 273–286, https://doi.org/10.2217/rme-2016-0009, 2-s2.0-84964091195.
