Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Advances in Therapy
Published in: Advances in Therapy 3/2020

01-03-2020 | Review

Revisiting Existing Evidence of Corneal Endothelial Progenitors and Their Potential Therapeutic Applications in Corneal Endothelial Dysfunction

Authors: Yaa-Jyuhn J. Meir, Hung-Chi Chen, Chien-Chang Chen, Hui-Kang D. Ma

Published in: Advances in Therapy | Issue 3/2020

Login to get access

Abstract

Purpose

A recent successful clinical trial demonstrated that a less invasive cell-injection procedure is a viable medical modality for treating corneal endothelial dystrophy. This medical advance still relies on human corneal endothelial cell (HCEC) sources derived from rare cornea donations. The progenitor of the corneal endothelium, which has the characteristics of active proliferation and lineage restriction, will be an ideal cell source for expansion ex vivo. However, the distribution of progenitor-like cells in the corneal endothelial sheet has been under debate for more than a decade.

Methods

This paper re-examines the scientific evidence of the existence of human corneal endothelial progenitors (HCEPs) from the aspects of (1) the origin of cornea formation during ocular development, (2) manifestations from clinical studies, and (3) the distinctive properties of ex vivo-cultured subpopulations.

Results

The discrepancies regarding different types of progenitor-like cells in various locations of the cornea are based on the fact that the corneal endothelium is derived from different cell types with multiple origins during corneal formation.

Conclusions

Resolving this long-standing issue in corneal biology will enable various types of progenitors to be isolated and their potencies regarding the formation of functional endothelial cells to be examined. Additionally, an effective niche system for quantitatively producing therapeutic cells can be formulated to satisfy the burning need associated with corneal endothelial dystrophy in the future.
Literature
1.
Gain P, Remy J, He Z, et al. Global survey of corneal transplantation and eye banking. JAMA Ophthalmol. 2016;134(2):167–73.PubMed
2.
Price MO, Price FW. Endothelial keratoplasty review. Clin Exp Ophthalmol. 2010;38(2):128–40.PubMed
3.
Koizumi N, Okumura N, Kinoshita S. Development of new therapeutic modalities for corneal endothelial disease focused on the proliferation of corneal endothelial cells using animal models. Exp Eye Res. 2012;95(1):60–7.PubMed
4.
Kinoshita S, Koizumi N, Ueno M, et al. Injection of cultured cells with a ROCK inhibitor for bullous keratopathy. NEJM. 2018;378(11):995–1003.PubMed
5.
Chen S, Zhu Q, Sun H, et al. Advances in culture, expansion and mechanistic studies of corneal endothelial cells: a systematic review. J Biomed Sci. 2019;26:2.PubMedPubMedCentral
6.
Yokoo S, Yamagami S, Yanagi Y, et al. Human corneal endothelial cell precursors isolated by sphere-forming assay. Invest Ophthalmol Vis Sci. 2005;46:1626–31.PubMed
7.
Yamagami S, Yokoo S, Mimura T, et al. Distribution of precursors in human corneal stromal cells and endothelial cells. Ophthalmology. 2007;114:433–9.PubMed
8.
Hirata-Tominaga K, Nakamura T, Okumura N, et al. Corneal endothelial cell fate is maintained by LGR5 through the regulation of hedgehog and Wnt pathway. Stem Cells. 2013;31(7):1396–407.PubMed
9.
Hara S, Hayashi R, Soma T, et al. Identification and potential application of human corneal endothelial progenitor cells. Stem Cells Dev. 2014;23:2190–201.PubMed
10.
Katikireddy KR, Schmedt T, Price MO, Price FW, Jurkunas UV. Existence of neural crest-derived progenitor cells in normal and Fuchs endothelial dystrophy corneal endothelium. Am J Pathol. 2016;186(10):2736–50.PubMedPubMedCentral
11.
McCabe KL, Lanza R. Corneal replacement tissue. In: Lanza R, Langer R, Vacanti J, editors. Principles of tissue engineering. Amsterdam: Elsevier; 2014; pp. 1413–1425.
12.
Barry PA, Petroll WM, Andrews PM, Cavanagh HD, Jester JV. The spatial organization of corneal endothelial cytoskeletal proteins and their relationship to the apical junctional complex. Invest Ophthalmol Vis Sci. 1995;36(6):1115–24.PubMed
13.
14.
Joyce N. Proliferative capacity of corneal endothelial cells. Exp Eye Res. 2012;95(1):16–23.PubMed
15.
Senoo T, Joyce NC. Cell cycle kinetics in corneal endothelium from old and young donors. Invest Ophthalmol Vis Sci. 2000;41(3):660–7.PubMed
16.
Yoshida K, Kase S, Nakayama K, et al. Involvement of p27 KIP1 in the proliferation of the developing corneal endothelium. Invest Ophthalmol Vis Sci. 2004;45(7):2163.PubMed
17.
Joyce NC, Meklir B, Joyce SJ, Zieske JD. Cell cycle protein expression and proliferative status in human corneal cells. Invest Ophthalmol Vis Sci. 1996;37:645–55.PubMed
18.
Marsuda M, Sawa M, Edelhauser HF, Stephen PB, Neufeld AH, Kenyon KR. Cellular migration and morphology in corneal endothelial wound repair. Invest Ophthalmol Vis Sci. 1985;26(4):443–9.
19.
Sherrard ES. The corneal endothelium in vivo: its response to mild trauma. Exp Eye Res. 1976;22(4):347–57.PubMed
20.
Murphy C, Alvarado J, Juster R, Maglio M. Prenatal and postnatal cellularity of the human corneal endothelium. A quantitative histologic study. Invest Ophthalmol Vis Sci. 1984;25(3):312–22.PubMed
21.
Bourne WM, Nelson LIL, Hodge DO. Central corneal endothelial cell changes over a ten-year period. Invest Ophthalmol Vis Sci. 1997;38(3):779–82.PubMed
22.
Kim KW, Park SH, Lee SJ, Kim JC. Ribonuclease 5 facilitates corneal endothelial wound healing via activation of PI3-kinase/Akt pathway. Sci Rep. 2016;6:31162.PubMedPubMedCentral
23.
McGowan SL, Edelhauser HF, Pfister RR, Whikehart DR. Stem cell markers in the human posterior limbus and corneal endothelium of unwounded and wounded corneas. Mol Vis. 2007;13:1984–2000.PubMed
24.
Konomi K, Zhu C, Harris D, Joyce NC. Comparison of the proliferative capacity of human corneal endothelial cells from the central and peripheral areas. Invest Ophthalmol Vis Sci. 2005;46:4086–91.PubMed
25.
Mimura T, Joyce NC. Replication competence and senescence in central and peripheral human corneal endothelium. Invest Ophthalmol Vis Sci. 2006;47:1387–96.PubMed
26.
Bednarz J, Richard G, Bohnke M, Engelmann K. Differences in proliferation and migration of corneal endothelial cells after cell transplantation in vitro. Ger J Ophthalmol. 1996;5:346–51.PubMed
27.
Zhu C, Joyce NC. Proliferative response of corneal endothelial cells from young and older donors. Invest Ophthalmol Vis Sci. 2004;45:1743–51.PubMed
28.
Okumura N, Kay EP, Nakahara M, et al. Inhibition of TGF-beta signaling enables human corneal endothelial cell expansion in vitro for use in regenerative medicine. PLoS One. 2013;8:e58000.PubMedPubMedCentral
29.
Peh GS, Beuerman RW, Colman A, et al. Human corneal endothelial cell expansion for corneal endothelium transplantation: an overview. Transplantation. 2011;91:811–9.PubMed
30.
Hamuro J, Ueno M, Toda M, Sotozono C, Montoya M, Kinoshita S. Cultured human corneal endothelial cell aneuploidy dependence on the presence of heterogeneous subpopulations with distinct differentiation phenotypes. Invest Ophthalmol Vis Sci. 2016;57(10):4385–92.PubMed
31.
Hamuro J, Toda M, Asada K, et al. Cell Homogeneity indispensable for regenerative medicine by cultured human corneal endothelial cells. Invest Ophthalmol Vis Sci. 2016;57(11):4749–61.PubMed
32.
Cheong YK, Ngoh ZX, Peh GS, et al. Identification of cell surface markers glypican-4 and CD200 that differentiate human corneal endothelium from stromal fibroblasts. Invest Ophthalmol Vis Sci. 2013;54:4538–47.PubMed
33.
Toda M, Ueno M, Hiraga A, et al. Production of homogeneous cultured human corneal endothelial cells indispensable for innovative cell therapy. Invest Ophthalmol Vis Sci. 2017;58:2011–20.PubMed
34.
Okumura N, Hirano H, Numata R, et al. Cell surface markers of functional phenotypical corneal endothelial cells. Invest Ophthalmol Vis Sci. 2014;55(11):7610–8.PubMed
35.
Hamuro J, Ueno M, Asada K, et al. Metabolic plasticity in cell state homeostasis and differentiation of cultured human corneal endothelial cells. Invest Ophthalmol Vis Sci. 2016;57(10):4452–63.PubMed
36.
Ueno M, Asada K, Toda M, et al. MicroRNA profiles qualify phenotypic features of cultured human corneal endothelial cells. Invest Ophthalmol Vis Sci. 2016;57(13):5509–17.PubMed
37.
Pei YF, Rhodin JAG. The prenatal development of the mouse eye. Anat Rec. 1970;168:105–26.PubMed
38.
Dublin I. Comparative embryologic studies of the early development of the cornea and the pupillary membrane in reptiles, birds, and mammals. Acta Anat (Basel). 1970;76:381–408.
39.
Kidson SH, Kume T, Deng K, Winfrey V, Hogan BL. The forkhead/winged-helix gene, Mf1, is necessary for the normal development of the cornea and formation of the anterior chamber in the mouse eye. Dev Biol. 1999;211:306–22.PubMed
40.
Reneker LW, Silversides DW, Xu L, Overbeek PA. Formation of corneal endothelium is essential for anterior segment development. Development. 2000;127:533–42.PubMed
41.
Flugel-Koch C, Ohlmann A, Piatigorsky J, Tamm ER. Overexpression of TGF-b1 alters early development of cornea and lens in transgenic mice. Dev Dyn. 2002;225:111–25.PubMed
42.
Wulle KG. The development of the productive and draining system of the aqueous humor in the human eye. Adv Ophthalmol. 1972;26:269–355.
43.
Smith RS, Zabaleta A, Savinova OV, John SW. The mouse anterior chamber angle and trabecular meshwork develop without cell death. BMC Dev Biol. 2001;1:3.PubMedPubMedCentral
44.
Reme C, d’Epinay SL. Periods of development of the normal human chamber angle. Doc Ophthalmol. 1981;51:241–68.PubMed
45.
Johnston MC, Noden DM, Hazelton RD, Coulombre JL, Coulombre AJ. Origins of avian ocular and periocular tissues. Exp Eye Res. 1979;29:27–43.PubMed
46.
Trainor PA, Tam PP. Cranial paraxial mesoderm and neural crest cells of the mouse embryo: co-distribution in the craniofacial mesenchyme but distinct segregation in branchial arches. Development. 1995;121:2569–82.PubMed
47.
Hay ED. Development of the vertebrate cornea. Int Rev Cytol. 1980;63:263–322.PubMed
48.
Duke-Elder S, Cook C. Part 1. Embryology (System of Ophthalmology, Vol. III). In: Duke-Elder S, editor. Normal and abnormal development. London: Springer; 1963.
49.
Raviola G. Schwalbe line’s cells: a new cell type in the trabecular meshwork of Macaca mulatta. Invest Ophthalmol Vis Sci. 1982;22:45–56.PubMed
50.
Schimmelpfennig BH. Direct and indirect determination of nonuniform cell density distribution in human corneal endothelium. Invest Ophthalmol Vis Sci. 1984;25:223–9.PubMed
51.
Daus W, Volcker HE, Meysen H, et al. Vital staining of the corneal endothelium–increased possibilities of diagnosis. Fortschr Ophthalmol. 1989;86:259–64.PubMed
52.
Amann J, Holley GP, Lee SB, et al. Increased endothelial cell density in the paracentral and peripheral regions of the human cornea. Am J Ophthalmol. 2003;135:584–90.PubMed
53.
He Z, Campolmi N, Gain P, et al. Revisited microanatomy of the corneal endothelial periphery: new evidence for continuous centripetal migration of endothelial cells in humans. Stem Cells. 2012;30:2523–34.PubMed
54.
55.
Whikehart DR, Parikh CH, Vaughn AV, Mishler K, Edelhauser HF. Evidence suggesting the existence of stem cells for the human corneal endothelium. Mol Vis. 2005;11:816–24.PubMed
56.
Zhang Y, Cai S, Tseng SCG, Zhu YT. Isolation and expansion of multipotent progenitors for human trabecular meshwork. Sci Rep. 2018;8:2814.PubMedPubMedCentral
57.
58.
Joyce NC, Harris DL, Mello DM. Mechanisms of mitotic inhibition in corneal endothelium: contact inhibition and TGF-beta2. Invest Ophthalmol Vis Sci. 2002;43:2152–9.PubMed
59.
Joyce NC, Zhu CC, Harris DL. Relationship among oxidative stress, DNA damage, and proliferative capacity in human corneal endothelium. Invest Ophthalmol Vis Sci. 2009;50:2116–22.PubMed
60.
Konomi K, Joyce NC. Age and topographical comparison of telomere lengths in human corneal endothelial cells. Mol Vis. 2007;13:1251–8.PubMed
61.
Xiao X, Wang Y, Gong H, et al. Molecular evidence of senescence in corneal endothelial cells of senescence-accelerated mice. Mol Vis. 2009;15:747–61.PubMedPubMedCentral
62.
Wollensak G, Green WR. Analysis of sex-mismatched human corneal transplants by fluorescence in situ hybridization of the sex-chromosomes. Exp Eye Res. 1999;68:341–6.PubMed
63.
Lagali NS, Stenevi U, Claesson M, et al. Donor and recipient endothelial cell population of the transplanted human cornea: a two-dimensional imaging study. Invest Ophthalmol Vis Sci. 2010;51:1898–904.PubMed
64.
Arbelaez JG, Price MO, Price FW Jr. Long-term follow-up and complications of stripping Descemet membrane without placement of graft in eyes with Fuchs endothelial dystrophy. Cornea. 2014;33(12):1295–9.PubMed
65.
Balachandran C, Ham L, Verschoor CA, Ong TS, van der Wees J, Melles GR. Spontaneous corneal clearance despite graft detachment in Descemet membrane endothelial keratoplasty. Am J Ophthalmol. 2009;148(227–234):e1.
66.
Baydoun L, Ham L, Borderie V, et al. Endothelial survival after Descemet membrane endothelial keratoplasty: effect of surgical indication and graft adherence status. JAMA Ophthalmol. 2015;133:1277–85.PubMed
67.
Van den Bogerd B, Dhubhghaill SN, Koppen C, Tassignon MJ, Zakaria N. A review of the evidence for in vivo corneal endothelial regeneration. Surv Ophthalmol. 2018;63:149–65.PubMed
68.
Okumura N, Koizumi N, Kay EP, et al. The ROCK inhibitor eye drop accelerates corneal endothelium wound healing. Invest Ophthalmol Vis Sci. 2013;54:2493–502.PubMed
69.
Borkar DS, Veldman P, Colby KA. Treatment of Fuchs endothelial dystrophy by Descemet stripping without endothelial keratoplasty. Cornea. 2016;35:1267–73.PubMed
70.
Melles GR, Ong TS, Ververs B, van der Wees J. Preliminary clinical results of Descemet membrane endothelial keratoplasty. Am J Ophthalmol. 2008;145:222–7.PubMed
71.
Price MO, Giebel AW, Fairchild KM, Price FW Jr. Descemet’s membrane endothelial keratoplasty: prospective multicenter study of visual and refractive outcomes and endothelial survival. Ophthalmology. 2009;116:2361–8.PubMed
72.
Tan DT, Dart JK, Holland EJ, Kinoshita S. Corneal transplantation. Lancet. 2012;379:1749–61.PubMed
73.
Schlögl A, Tourtas T, Kruse FE, Weller JM. Long-term clinical outcome after Descemet membrane endothelial keratoplasty. Am J Ophthalmol. 2016;169:218–26.PubMed
74.
Wacker K, Baratz KH, Maguire LJ, McLaren JW, Patel SV. Descemet stripping endothelial keratoplasty for Fuchs’ endothelial corneal dystrophy: five-year results of a prospective study. Ophthalmology. 2016;123:154–60.PubMed
75.
Croze RH, Buchholz DE, Radeke MJ, et al. ROCK inhibition extends passage of pluripotent stem cell-derived retinal pigmented epithelium. Stem Cells Transl Med. 2014;3:1066–78.PubMedPubMedCentral
76.
77.
Yoshihara M, Ohmiya H, Hara S, et al. Discovery of molecular markers to discriminate corneal endothelial cells in the human body. PLoS One. 2015;10(3):e0117581.PubMedPubMedCentral
78.
Yoshihara M, Hara S, Tsujikawa M, et al. Restricted presence of POU6F2 in human corneal endothelial cells uncovered by extension of the promoter-level expression atlas. EBioMedicine. 2017;25:175–86.PubMedPubMedCentral
79.
80.
Soh YQ, Peh GSL, Mehta JS. Translation issues for human corneal endothelial tissue engineering. J Tissue Eng Regen Med. 2017;11(9):2425–42.PubMed
81.
82.
Chen Y, Huang K, Nakatsu MN, Xue Z, Deng SX, Fan G. Identification of novel molecular markers through transcriptomic analysis in human fetal and adult corneal endothelial cells. Hum Mol Genet. 2013;22:1271–9.PubMed
83.
Ding V, Chin A, Peh G, Mehta JS, Choo A. Generation of novel monoclonal antibodies for the enrichment and characterization of human corneal endothelial cells (hCENC) necessary for the treatment of corneal endothelial blindness. MAbs. 2014;6(6):1439–52.PubMedPubMedCentral
Metadata
Title
Revisiting Existing Evidence of Corneal Endothelial Progenitors and Their Potential Therapeutic Applications in Corneal Endothelial Dysfunction
Authors
Yaa-Jyuhn J. Meir
Hung-Chi Chen
Chien-Chang Chen
Hui-Kang D. Ma
Publication date
01-03-2020
Publisher
Springer Healthcare
Published in
Advances in Therapy / Issue 3/2020
Print ISSN: 0741-238X
Electronic ISSN: 1865-8652
DOI
https://doi.org/10.1007/s12325-020-01237-w

Other articles of this Issue 3/2020

Advances in Therapy 3/2020 Go to the issue

Original Research

Evaluating the Effect of Standard of Care Treatment on Burden of Chronic Hepatitis B: A Retrospective Analysis of the United States Veterans Population

Original Research

Prognostic Performance of SOFA, qSOFA, and SIRS in Kidney Transplant Recipients Suffering from Infection: A Retrospective Observational Study

Original Research

Efficacy and Safety of Intravitreal Aflibercept Treat-and-Extend Regimens in Exudative Age-Related Macular Degeneration: 52- and 96-Week Findings from ALTAIR

Original Research

Anorectal Functional Outcomes Following Doppler-Guided Transanal Hemorrhoidal Dearterialization: Evidence from Vietnam

Original Research

Development of a Resource Impact Model for Clinics Treating Pre-Operative Iron Deficiency Anemia in Ireland

Original Research

Impact of Endometriosis Diagnostic Delays on Healthcare Resource Utilization and Costs
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits