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B. G. Ballios, M. J. Cooke, M. S. Shoichet, D. van der Kooy; Development of a Stem Cell Delivery System to Treat Retinal Degenerative Diseases. Invest. Ophthalmol. Vis. Sci. 2010;51(13):430.
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© ARVO (1962-2015); The Authors (2016-present)
The therapeutic potential of adult retinal stem cells (RSCs) - multipotent cells capable of differentiating into any retinal cell type - avoids ethical concerns surrounding the transplantation of embryonic/fetal tissue. Subretinal cell transplantation is limited by poor cell survival, distribution and integration into host tissue. To overcome this, a stem cell delivery system was developed, taking advantage of the minimally-invasive, injectable and biodegradable properties of a blend of hyaluronan (HA) and methylcellulose (MC) - HAMC.
Natural polymer hydrogels were screened in vitro for desired physical properties (flow and gelation time) and biological properties (cell growth and survival). Agarose, collagen, chitosan/glycerol-phosphate, and HAMC were included based on literature precedent for injectability and simple gelation mechanisms. Adult stem cell growth and survival was analyzed in vitro by RSC sphere diameter and live-dead assays. HAMC was pursued in adult mouse subretinal transplantation studies to investigate biodegradability and potential as a cell delivery vehicle by injection of GFP+ RSC progeny.
In the screen, several hydrogels were eliminated: chitosan/glycerol-phosphate based on long gelation time, collagen because of retarded cell growth relative to media controls, and agarose based on cell spreading and morphological differentiation. A blend of 0.5/0.5 wt% HA/MC supported in vitro stem cell growth and survival as spheres and single cells similar to control media over 6 days. HAMC maintained 3D cellular distribution at physiological temperature in vitro, and prevented cellular aggregation. The blend was a viscous solution on injection with physical properties ideal for subretinal delivery, and degraded over 7 days in vivo. Transplanted RSC progeny integrated into the retinal pigment epithelium layer. When delivered in HAMC, cells were more contiguously distributed over larger areas of retina compared to delivery in saline, which showed restricted, patch-like integration and cellular aggregation.
HAMC is a promising vehicle for cellular delivery to the degenerating retina, overcoming previously reported barriers to tissue integration such as cellular aggregation and non-contiguous distribution.
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