Abstract
AbstractIn optic neuropathies, including glaucoma, retinal ganglion cells (RGCs) die. Cell transplantation and endogenous regeneration offer strategies for retinal repair, however, developmental programs required for this to succeed are incompletely understood. To address this, we explored cellular reprogramming with transcription factor (TF) regulators of RGC development which were integrated into human pluripotent stem cells (PSCs) as inducible gene cassettes. When the pioneer factor NEUROG2 was combined with RGC-expressed TFs (ATOH7, ISL1, and POU4F2) some conversion was observed and when pre-patterned by BMP inhibition, RGC-like induced neurons (RGC-iNs) were generated with high efficiency in just under a week. These exhibited transcriptional profiles that were reminiscent of RGCs and exhibited electrophysiological properties, including AMPA-mediated synaptic transmission. Additionally, we demonstrated that small molecule inhibitors of DLK/LZK and GCK-IV can block neuronal death in two pharmacological axon injury models. Combining developmental patterning with RGC-specific TFs thus provided valuable insight into strategies for cell replacement and neuroprotection.
Funder
U.S. Department of Health & Human Services | NIH | National Eye Institute
Foundation Fighting Blindness
Research to Prevent Blindness
BrightFocus Foundation
California Institute for Regenerative Medicine
U.S. Department of Health & Human Services | National Institutes of Health
Michael Luzich in honor of Norman and Carol Luzich for providing generous funding for this work.
Glaucoma Research Foundation
Publisher
Springer Science and Business Media LLC
Subject
Cell Biology,Developmental Biology,Biomedical Engineering,Medicine (miscellaneous)
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