期刊
DEVELOPMENT
卷 142, 期 19, 页码 3294-3306出版社
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/dev.125385
关键词
Coco; Dand5; Cerl2; Differentiation; Retina; Cone photoreceptors; hES cells; Mouse; Human
资金
- Foundation Fighting Blindness Canada
- Turmel Family Foundation for Macular Degeneration Research
- Canadian Stem Cell Network
- C. Durand Foundation
- GO Foundation
- Natural Science and Engineering Research Council of Canada [250970-2012]
- Reseau Vision du Quebec
- University of Montreal Molecular Biology Program
- Fonds de Recherche en Sante du Quebec
Cone photoreceptors are required for color discrimination and high-resolution central vision and are lost in macular degenerations, cone and cone/rod dystrophies. Cone transplantation could represent a therapeutic solution. However, an abundant source of human cones remains difficult to obtain. Work performed in model organisms suggests that anterior neural cell fate is induced 'by default' if BMP, TGF beta and Wnt activities are blocked, and that photoreceptor genesis operates through an S-cone default pathway. We report here that Coco (Dand5), a member of the Cerberus gene family, is expressed in the developing and adult mouse retina. Upon exposure to recombinant COCO, human embryonic stem cells (hESCs) differentiated into S-cone photoreceptors, developed an inner segment-like protrusion, and could degrade cGMP when exposed to light. Addition of thyroid hormone resulted in a transition from a unique S-cone population toward a mixed M/S-cone population. When cultured at confluence for a prolonged period of time, COCO-exposed hESCs spontaneously developed into a cellular sheet composed of polarized cone photoreceptors. COCO showed dose-dependent and synergistic activity with IGF1 at blocking BMP/TGF beta/Wnt signaling, while its cone-inducing activity was blocked in a dose-dependent manner by exposure to BMP, TGF beta or Wnt-related proteins. Our work thus provides a unique platform to produce human cones for developmental, biochemical and therapeutic studies and supports the hypothesis that photoreceptor differentiation operates through an S-cone default pathway during human retinal development.
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