iPSC-derived cells stimulate ABCG2⁺/NES⁺ endogenous trabecular meshwork cell proliferation and tissue regeneration

Abstract

A major risk factor for glaucoma, the first leading cause of irreversible blindness worldwide, is the decellularisation of the trabecular meshwork (TM) in the conventional outflow pathway. Stem cell-based therapy, particularly the utilisation of induced pluripotent stem cells (iPSCs), presents an enticing potential for tissue regeneration and intraocular pressure (IOP) maintenance in glaucoma. We have previously observed that differentiated iPSCs can stimulate endogenous cell proliferation in the TM, a pivotal factor in TM regeneration and aqueous humour outflow restoration. In this study, we investigated the response of TM cells in vivo after interacting with iPSC-derived cells and identified two subpopulations responsible for this relatively long-term tissue regeneration: ATP Binding Cassette Subfamily G Member 2 (ABCG2)-positive cells and Nestin (NES)-positive cells. We further uncovered that alterations of these responsive cells are linked to ageing and different glaucoma etiologies, suggesting that ABCG2⁺ subpopulation decellularization could serve as a potential risk factor for TM decellularization in glaucoma. Taken together, our findings illustrated the proliferative subpopulations in the conventional outflow pathway when stimulated with iPSC-derived cells and defined them as TM precursors, which may be applied to develop novel therapeutic approaches for glaucoma.

References

[1] Carreon T, van der Merwe E, Fellman RL, Johnstone M, Bhattacharya SK. Aqueous outflow - a continuum from trabecular meshwork to episcleral veins. Prog Retin Eye Res. 2017;57:108-133.

[2] Kuehn MH, Vranka JA, Wadkins D, Jackson T, Cheng L, Ledolter J. Circumferential trabecular meshwork cell density in the human eye. Exp Eye Res. 2021;205:108494.

[3] Weinreb RN, Aung T, Medeiros FA. The pathophysiology and treatment of glaucoma: a review. JAMA. 2014;311(18):1901-1911.

[4] Keller KE, Aga M, Bradley JM, Kelley MJ, Acott TS. Extracellular matrix turnover and outflow resistance. Exp Eye Res. 2009;88(4):676-682.

[5] Alvarado J, Murphy C, Juster R. Trabecular meshwork cellularity in primary open-angle glaucoma and nonglaucomatous normals. Ophthalmology. 1984;91(6):564-579.

[6] Alvarado J, Murphy C, Polansky J, Juster R. Age-related changes in trabecular meshwork cellularity. Invest Ophthalmol Vis Sci. 1981;21(5):714-727.

[7] Zhu W, Zhang X, Wu S, Wang N, Kuehn MH. iPSCs-based therapy for trabecular meshwork. Handb Exp Pharmacol. 2023;281:277-300.

[8] O'Callaghan J, Delaney C, O'Connor M, et al. Matrix metalloproteinase-3 (MMP-3)-mediated gene therapy for glaucoma. Sci Adv. 2023;9(16):eadf6537.

[9] Shim MS, Liton PB. The physiological and pathophysiological roles of the autophagy lysosomal system in the conventional aqueous humor outflow pathway: more than cellular clean up. Prog Retin Eye Res. 2022;90:101064.

[10] Coulon SJ, Schuman JS, Du Y, Bahrani Fard MR, Ethier CR, Stamer WD. A novel glaucoma approach: stem cell regeneration of the trabecular meshwork. Prog Retin Eye Res. 2022;90:101063.

[11] Tanna AP, Johnson M. Rho kinase inhibitors as a novel treatment for glaucoma and ocular hypertension. Ophthalmology. 2018;125(11):1741-1756.

[12] Williams AL, Bohnsack BL. The ocular neural crest: specification, migration, and then what?Front Cell Dev Biol. 2020;8:595896.

[13] Weigele J, Bohnsack BL. Genetics underlying the interactions between neural crest cells and eye development. J Dev Biol. 2020;8(4):26.

[14] Jedari B, Rahmani A, Naderi M, Nadri S. MicroRNA-7 promotes neural differentiation of trabecular meshwork mesenchymal stem cell on nanofibrous scaffold. J Cell Biochem. 2020;121(4):2818-2827.

[15] Gage PJ, Rhoades W, Prucka SK, Hjalt T. Fate maps of neural crest and mesoderm in the mammalian eye. Invest Ophthalmol Vis Sci. 2005;46(11):4200-4208.

[16] Tripathi BJ, Tripathi RC. Neural crest origin of human trabecular meshwork and its implications for the pathogenesis of glaucoma. Am J Ophthalmol. 1989;107(6):583-590.

[17] Xiong S, Kumar A, Tian S, et al. Stem cell transplantation rescued a primary open-angle glaucoma mouse model. Elife. 2021;10:10.

[18] Du Y, Roh DS, Mann MM, Funderburgh ML, Funderburgh JL, Schuman JS. Multipotent stem cells from trabecular meshwork become phagocytic TM cells. Invest Ophthalmol Vis Sci. 2012;53(3):1566-1575.

[19] Acott TS, Samples JR, Bradley JM, Bacon DR, Bylsma SS, Van Buskirk EM. Trabecular repopulation by anterior trabecular meshwork cells after laser trabeculoplasty. Am J Ophthalmol. 1989;107(1):1-6.

[20] Raviola G. Schwalbe line's cells: a new cell type in the trabecular meshwork of Macaca mulatta. Invest Ophthalmol Vis Sci. 1982;22(1):45-56.

[21] Wang X, Cao Q, Wu S, et al. Magnetic nano-platform enhanced iPSC-derived trabecular meshwork delivery and tracking efficiency. Int J Nanomedicine. 2022;17:1285-1307.

[22] Sui S, Yu H, Wang X, et al. iPSC-derived trabecular meshwork cells stimulate endogenous TM cell division through gap junction in a mouse model of glaucoma. Invest Ophthalmol Vis Sci. 2021;62(10):28.

[23] Zhu W, Godwin CR, Cheng L, Scheetz TE, Kuehn MH. Transplantation of iPSC-TM stimulates division of trabecular meshwork cells in human eyes. Sci Rep. 2020;10(1):2905.

[24] Zhu W, Jain A, Gramlich OW, Tucker BA, Sheffield VC, Kuehn MH. Restoration of aqueous humor outflow following transplantation of iPSC-derived trabecular meshwork cells in a transgenic mouse model of glaucoma. Invest Ophthalmol Vis Sci. 2017;58(4):2054-2062.

[25] Zhu W, Gramlich OW, Laboissonniere L, et al. Transplantation of iPSC-derived TM cells rescues glaucoma phenotypes in vivo. Proc Natl Acad Sci U S A. 2016;113(25):E3492-E3500.

[26] Zode GS, Kuehn MH, Nishimura DY, et al. Reduction of ER stress via a chemical chaperone prevents disease phenotypes in a mouse model of primary open angle glaucoma. J Clin Invest. 2011;121(9):3542-3553.

[27] Yam GH, Pi S, Du Y, Mehta JS. Posterior corneoscleral limbus: architecture, stem cells, and clinical implications. Prog Retin Eye Res. 2023;96:101192.

[28] Kumar A, Xu Y, Du Y. Stem cells from human trabecular meshwork hold the potential to develop into ocular and non-ocular lineages after long-term storage. Stem Cells Dev. 2020;29(1):49-61.

[29] Gonzalez P, Epstein DL, Luna C, Liton PB. Characterization of free-floating spheres from human trabecular meshwork (HTM) cell culture in vitro. Exp Eye Res. 2006;82(6):959-967.

[30] Miron A, Ni Dhubhghaill S, Kocaba V, Jager MJ, Melles GRJ, Oellerich S. Early and late-onset cell migration from peripheral corneal endothelium. PloS One. 2023;18(5):e0285609.

[31] Gautam P, Hamashima K, Chen Y, et al. Multi-species single-cell transcriptomic analysis of ocular compartment regulons. Nat Commun. 2021;12(1):5675.

[32] van Zyl T, Yan W, McAdams A, et al. Cell atlas of aqueous humor outflow pathways in eyes of humans and four model species provides insight into glaucoma pathogenesis. Proc Natl Acad Sci U S A. 2020;117(19):10339-10349.

[33] Rausch RL, Libby RT, Kiernan AE. Trabecular meshwork morphogenesis: a comparative analysis of wildtype and anterior segment dysgenesis mouse models. Exp Eye Res. 2018;170:81-91.

[34] Ramirez JM, Ramirez AI, Salazar JJ, Rojas B, De Hoz R, Trivino A. Schlemm's canal and the collector channels at different developmental stages in the human eye. Cells Tissues Organs. 2004;178(3):180-185.

[35] Cvekl A, Tamm ER. Anterior eye development and ocular mesenchyme: new insights from mouse models and human diseases. Bioessays. 2004;26(4):374-386.

[36] 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.

[37] Reme C, d'Epinay SL. Periods of development of the normal human chamber angle. Doc Ophthalmol. 1981;51(3):241-268.

[38] Kupfer C, Kaiser-Kupfer MI. Observations on the development of the anterior chamber angle with reference to the pathogenesis of congenital glaucomas. Am J Ophthalmol. 1979;88(3 Pt 1):424-426.

[39] Grierson I, Howes RC. Age-related depletion of the cell population in the human trabecular meshwork. Eye (Lond). 1987;1(Pt 2):204-210.

[40] Zhang Y, Toris CB, Liu Y, Ye W, Gong H. Morphological and hydrodynamic correlates in monkey eyes with laser induced glaucoma. Exp Eye Res. 2009;89(5):748-756.

RIGHTS & PERMISSIONS

2024 2024 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.