Differentiation of human embryonic stem cells into cone photoreceptors through simultaneous inhibition of BMP, TGFβ and Wnt signaling

• DOI: 10.1242/dev.125385
• Publication Date: 2015-10-06T11:27:59Z
• Authors: Shufeng Zhou; Anthony Flamier; Mohamed Abdouh; Nicolas Tétreault; Andrea Barabino; Shashi Wadhwa; Gilbert Bernier
• Keywords: 0301 basic medicine; Analysis of Variance; Reverse Transcriptase Polymerase Chain Reaction; Blotting, Western; Cell Differentiation; Flow Cytometry; Immunohistochemistry; Retina; Cell Line; Wnt Proteins; Mice; 03 medical and health sciences; Transforming Growth Factor beta; Bone Morphogenetic Proteins; Retinal Cone Photoreceptor Cells; Animals; Humans; Intercellular Signaling Peptides and Proteins; Embryonic Stem Cells; In Situ Hybridization; Signal Transduction

Cone photoreceptors are required for color discrimination and high-resolution central vision lost in macular degenerations, cone cone/rod dystrophies. transplantation could represent a therapeutic solution. However, an abundant source of human cones remains difficult to obtain. Work performed model organisms suggests that anterior neural cell fate is induced ‘by default' if BMP, TGFβ Wnt activities blocked, photoreceptor genesis operates through S-cone default pathway. We report here Coco (Dand5), member the Cerberus gene family, expressed developing adult mouse retina. Upon exposure recombinant COCO, embryonic stem cells (hESCs) differentiated into photoreceptors, developed inner segment-like protrusion, degrade cGMP when exposed light. Addition thyroid hormone resulted transition from unique population toward mixed M/S-cone population. When cultured at confluence prolonged period time, COCO-exposed hESCs spontaneously cellular sheet composed polarized photoreceptors. COCO showed dose-dependent synergistic activity with IGF1 blocking BMP/TGFβ/Wnt signaling, while its cone-inducing was blocked manner by or Wnt-related proteins. Our work thus provides platform produce developmental, biochemical studies supports hypothesis differentiation pathway during retinal development.