Journal
STEM CELLS TRANSLATIONAL MEDICINE
Volume 1, Issue 3, Pages 188-199Publisher
ALPHAMED PRESS
DOI: 10.5966/sctm.2011-0005
Keywords
Tissue-specific stem cells; Differentiation; Cell transplantation; Adult stem cells
Categories
Funding
- Medical Research Council [90465, G0900002]
- Helen Hamlyn Trust
- Fight for Sight
- Moorfields Special Trustees
- National Institute for Health Research (NIHR)
- NIHR Biomedical Research Centre at Moorfields Eye Hospital
- University College London Institute of Ophthalmology
- Inlaks Foundation, India
- Medical Research Council [G0900002, G0701341] Funding Source: researchfish
- National Institute for Health Research [II-FS-0909-13068] Funding Source: researchfish
- National Institutes of Health Research (NIHR) [II-FS-0909-13068] Funding Source: National Institutes of Health Research (NIHR)
- MRC [G0900002, G0701341, G0300259] Funding Source: UKRI
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Muller glia with stem cell characteristics have been identified in the adult human eye, and although there is no evidence that they regenerate retina in vivo, they can be induced to grow and differentiate into retinal neurons in vitro. We differentiated human Muller stem cells into retinal ganglion cell (RGC) precursors by stimulation with fibroblast growth factor 2 together with NOTCH inhibition using the gamma-secretase inhibitor N[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT). Differentiation into RGC precursors was confirmed by gene and protein expression analysis, changes in cytosolic [Ca2+] in response to neurotransmitters, and green fluorescent protein (GFP) expression by cells transduced with a transcriptional BRN3b-GFP reporter vector. RGC precursors transplanted onto the inner retinal surface of Lister hooded rats depleted of RGCs by N-methyl-D-aspartate aligned onto the host RGC layer at the site of transplantation but did not extend long processes toward the optic nerve. Cells were observed extending processes into the RGC layer and expressing RGC markers in vivo. This migration was observed only when adjuvant anti-inflammatory and matrix degradation therapy was used for transplantation. RGC precursors induced a significant recovery of RGC function in the transplanted eyes as determined by improvement of the negative scotopic threshold response of the electroretinogram (indicative of RGC function). The results suggest that transplanted RGC precursors may be capable of establishing local interneuron synapses and possibly release neurotrophic factors that facilitate recovery of RGC function. These cells constitute a promising source of cells for cell-based therapies to treat retinal degenerative disease caused by RGC dysfunction. STEM CELLS TRANSLATIONAL MEDICINE 2012;1:188-199
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