June 2021
Volume 62, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2021
Lineage specification and molecular characterization of cone photoreceptor progenitors in the developing mammalian retina
Brian G Ballios; Justin Belair-Hickey; Saeed Khalili; Kenneth Grise; Brenda BLK Coles; Jeff Liu; Gilbert Bernier; Valerie Wallace; Gary Bader; Molly S Shoichet; Derek van der Kooy
Author Affiliations & Notes
  • Brian G Ballios
    Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Ontario, Canada
  • Justin Belair-Hickey
    Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
  • Saeed Khalili
    Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
  • Kenneth Grise
    Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
  • Brenda BLK Coles
    Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
  • Jeff Liu
    Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
  • Gilbert Bernier
    Centre de recherche, Hopital Maisonneuve-Rosemont, Montreal, Quebec, Canada
  • Valerie Wallace
    Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Ontario, Canada
  • Gary Bader
    Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
  • Molly S Shoichet
    Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada
  • Derek van der Kooy
    Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
  • Footnotes
    Commercial Relationships   Brian Ballios, None; Justin Belair-Hickey, None; Saeed Khalili, None; Kenneth Grise, None; Brenda Coles, None; Jeff Liu, None; Gilbert Bernier, None; Valerie Wallace, None; Gary Bader, None; Molly Shoichet, None; Derek van der Kooy, None
  • Footnotes
    Support  Canadian Institutes of Health Research (CIHR); Fighting Blindness Canada (FBC) / Krembil Foundation; BrightFocus Foundation; Canada First Research Excellence Fund (CFREF) / Medicine by Design (MbD)
Investigative Ophthalmology & Visual Science June 2021, Vol.62, 2932. doi:
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      Brian G Ballios, Justin Belair-Hickey, Saeed Khalili, Kenneth Grise, Brenda BLK Coles, Jeff Liu, Gilbert Bernier, Valerie Wallace, Gary Bader, Molly S Shoichet, Derek van der Kooy; Lineage specification and molecular characterization of cone photoreceptor progenitors in the developing mammalian retina. Invest. Ophthalmol. Vis. Sci. 2021;62(8):2932.

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Abstract

Purpose : Adult retinal stem cells (RSCs) give rise to all retinal cell types. Clonal RSC progeny treated with taurine/retinoic acid (T+RA) produce 95% rod progeny, while coco (BMP/Wnt/TGFβ triple-inhibitor) induces 60% cones. We hypothesized that cone lineage-specific progenitors, specified using exogenous factors, display unique transcriptome signatures that can identify stage-specific molecular markers. No markers exist for these lineage-specific progenitors and literature is divided on their existence in vivo.

Methods : Adult RSCs were isolated from mouse and human donor eyes, while neural retinal progenitor cells (RPCs) were isolated from the embryonic mouse retina. We used single cell/well sorting to isolate individual progenitor clones.

Results : Embryonic RPCs (E14) show similar rod differentiation in T+RA (>95%) compared to adult RSCs and increased cone differentiation in coco (>90%). Coco permitted differentiation from single non-pigmented RSC progeny to >95% cone-only clones, while single pigmented RSC progeny were unable to produce any cones. Constant coco exposure causes E12, E14 and E19 RPCs to adopt a cone-restricted fate. We compared gene expression between RSC-derived and endogenous cones with RNAseq, and profiled the transcriptome throughout rod and cone differentiation from embryonic RPCs. Principal component analysis showed a distinct progression of rod and cone lineages. Pathway analysis showed clustering of stem cell-derived and endogenous cones, as well as candidate progenitor markers. SOX15 may be a unique marker of a cone restricted progenitor; its expression follows other factors that bias photoreceptor differentiation, including OTX2 and OLIG2. SOX15 is expressed in early proliferating RPCs in vivo, and persists in some early-born post-mitotic cells, but not photoreceptors. SOX15 knockdown reduced colony formation from E14 RPCs, but not E19 RPCs or adult RSCs. After 4-6 weeks of coco, 60% of human RSC progeny differentiated into cones; both the time-course and efficiency is similar to mouse RSC progeny.

Conclusions : Exogenous signals instruct early lineage decisions in fate-restricted retinal progenitors, and we identify potentially new markers. SOX15 may promote cone differentiation by prolonging or promoting proliferation of early RPCs, or by inhibiting factors that specify alternative, late-born, cell fates and promoting a default cone differentiation.

This is a 2021 ARVO Annual Meeting abstract.

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
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Copyright © 2024 Association for Research in Vision and Ophthalmology.
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