Retinal degeneration, particularly associated with aging, is a widespread and increasing health problem currently affecting 2.1 million people in the U.S. and imposing a substantial burden on the economy (~$2 billion annually). It is the leading cause of blindness worldwide. Cell transplantation strategies have shown tremendous promise, but are significantly limited by low levels of cell survival and integration (<1%). The proposed studies aim to elucidate the chemical and physical cues required to enable survival and integration of transplanted cells. This fundamental, quantitative understanding will provide a framework to guide future retinal regeneration strategies and design of materials to serve as effective cell delivery vehicles. The proposed project will also nurture a cohesive education plan including teaching and learning across education levels spanning from K-12 to postgraduate.
While the retinas of some lower vertebrate species do regenerate, the human retina does not. The role of lower vertebrate matrix composition, structure, and mechanical properties in tissue regeneration has not been explored, yet is likely significant and could be exploited to enable significant advances in regenerative medicine. The PI's recent preliminary results indicate that mammalian retinal progenitor cells display strikingly different behavior when introduced to the lower vertebrate (axolotl) retina, in a manner analogous to cell transplantation, relative to a mammalian retina. Specifically, the RPCs in the lower vertebrate retina exhibit markedly enhanced cell survival and integration into the retina - processes central to regeneration. This project will analyze the chemical and physical features of the lower vertebrate regeneration-permissive retinal microenvironment compared to that of adult mammalian retina. The research will include an in-depth study of human retinal progenitor cell response to lower vertebrate retinal matrix, including attachment, survival, differentiation and 3D migration, processes essential to successful cell transplantation strategies. The study will analyze cell response to both intact tissue and decellularized matrix, in the presence and absence of tissue-conditioned medium, to parse effects of cellular vs. acellular (matrix) components and soluble vs. insoluble cues. Importantly, an integrated systems-biology approach will quantitatively relate cell response to tissue/matrix/soluble factor cues and cell signaling events. This quantitative mechanistic understanding will provide a framework to guide future retinal regeneration strategies and biomaterial design. This award by the Biotechnology and Biochemical Engineering Program of the CBET Division is co-funded by the Biomaterials Program of the Division of Materials Research.
