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Activation of the retina's regenerative potential by embryonic stem cell-derived microvesicles


Retinal degenerative diseases are a leading cause of irreversible blindness. While the retina of amphibians and birds has a remarkable capacity for near complete regeneration - Müller cells now recognized as the likely source of this regeneration - no spontaneous regeneration has been observed in the mammalian retina. Therapies to augment retinal repair could improve the quality of life of millions of individuals.

In my studies, I examined the possibility of augmenting the retina's endogenous regenerative capacity using embryonic stem cell-derived microvesicles (ESMVs) released by embryonic stem cells (ESCs). I found that ESMVs contain multiple mRNAs encoding the core transcription factors known to induce pluripotency in somatic cells and microRNAs of the 290 cluster, pivotal in the control of the ESC-specific cell cycle.

In vitro, I demonstrated that ESMVs selectively transfer their mRNA and microRNA cargo to human Müller cells and induce in them morphological, mRNA, and microRNA expression changes. I observed upregulation of mRNAs involved in induction and maintenance of stem cell pluripotency, early ocular genes, and genes important for retinal protection and remodeling, as well as downregulation of inhibitory and scar-related genes; and upregulation of microRNAs promoting pluripotency and cell proliferation and downregulation of those involved in differentiation and cell cycle arrest. Moreover, a subset of the ESMV-treated Müller cells expressed markers of amacrine, ganglion, and rod photoreceptor cells. These results suggested that ESMVs induce dedifferentiation of Müller cells to a stem cell phenotype and differentiation towards other retinal lineages.

I then conducted preliminary studies on the ability of ESMVs to augment retinal regeneration in vivo, injecting ESMVs into mouse retinas damaged with NMDA. I observed many proliferating cells in ESMV-treated and none in non-treated retinas. The majority of these cells expressed the Müller cell marker CRALBP, and a subset of them, the amacrine neuronal markers Syntaxin 1a and GAD67. ERGs demonstrated functional improvement in several ESMV-treated retinas. My findings suggest that ESMVs may have the potential to augment retinal endogenous regenerative capacity. Further studies of the effects of ESMVs on the regeneration of damaged retinas may lead to the discovery of novel therapeutic approaches for retinal degenerations.

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