Activation of adult mammalian retinal stem cells in vivo via antagonism of BMP and sFRP2

Kenneth N Grisé; Brenda L K Coles; Nelson X Bautista; Derek van der Kooy

doi:10.1186/s13287-021-02630-0

Activation of adult mammalian retinal stem cells in vivo via antagonism of BMP and sFRP2

Stem Cell Res Ther. 2021 Oct 30;12(1):560. doi: 10.1186/s13287-021-02630-0.

Authors

Kenneth N Grisé¹, Brenda L K Coles², Nelson X Bautista², Derek van der Kooy^{2

3}

Affiliations

¹ Department of Molecular Genetics, University of Toronto, Donnelly Centre Rm 1110, 160 College Street, Toronto, ON, M5S 3E1, Canada. ken.grise@mail.utoronto.ca.
² Department of Molecular Genetics, University of Toronto, Donnelly Centre Rm 1110, 160 College Street, Toronto, ON, M5S 3E1, Canada.
³ Institute of Medical Science, University of Toronto, Toronto, ON, M5S 1A8, Canada.

Abstract

Background: The adult mammalian retina does not have the capacity to regenerate cells lost due to damage or disease. Therefore, retinal injuries and blinding diseases result in irreversible vision loss. However, retinal stem cells (RSCs), which participate in retinogenesis during development, persist in a quiescent state in the ciliary epithelium (CE) of the adult mammalian eye. Moreover, RSCs retain the ability to generate all retinal cell types when cultured in vitro, including photoreceptors. Therefore, it may be possible to activate endogenous RSCs to induce retinal neurogenesis in vivo and restore vision in the adult mammalian eye.

Methods: To investigate if endogenous RSCs can be activated, we performed combinatorial intravitreal injections of antagonists to BMP and sFRP2 proteins (two proposed mediators of RSC quiescence in vivo), with or without growth factors FGF and Insulin. We also investigated the effects of chemically-induced N-methyl-N-Nitrosourea (MNU) retinal degeneration on RSC activation, both alone and in combination withthe injected factors. Further, we employed inducible Msx1-Cre^ERT2 genetic lineage labeling of the CE followed by stimulation paradigms to determine if activated endogenous RSCs could migrate into the retina and differentiate into retinal neurons.

Results: We found that in vivo antagonism of BMP and sFRP2 proteins induced CE cells in the RSC niche to proliferate and expanded the RSC population. BMP and sFRP2 antagonism also enhanced CE cell proliferation in response to exogenous growth factor stimulation and MNU-induced retinal degeneration. Furthermore, Msx1-Cre^ERT2 genetic lineage tracing revealed that CE cells migrated into the retina following stimulation and/or injury, where they expressed markers of mature photoreceptors and retinal ganglion cells.

Conclusions: Together, these results indicate that endogenous adult mammalian RSCs may have latent regenerative potential that can be activated by modulating the RSC niche and hold promise as a means for endogenous retinal cell therapy to repair the retina and improve vision.

Keywords: Adult stem cells; Ciliary epithelium; Ciliary marginal zone; Eye; Niche; Proliferation; Regeneration; Retina; Retinal stem cells; Retinogenesis; Stem cells; Vision.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation
Cell Proliferation
Cells, Cultured
Mammals
Retina* / metabolism
Stem Cells* / metabolism

Grants and funding

FDN-148407/CIHR/Canada