Mesenchymal Stem Cells can Restore and Maintain Corneal Endothelial Function

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Project Summary In this project, we propose to investigate the ability of mesenchymal stem cell (MSCs) to differentiate into functionally active corneal endothelial cells (CECs) to be transplanted in the diseased eye. As sources of MSCs, bone marrow MSCs (BM-MSCs), limbus MSCs (L-MSCs), and adipose derived MSCs (A-MSCs) will be evaluated. We will (1) determine the differentiation potential of different MSCs by varying numerous parameters and evaluate different molecular pathways involved in their differentiation, and (2) determine the ability of the differentiated cells to regenerate functionally active endothelium in diseased conditions. The differentiation, characterization, biocompatibility, and functionalization studies proposed here through in vitro, ex vivo, and in vivo studies will offer qualitative and quantitative information of the degree of biointegration and regenerative potential of the differentiated cells in contact with the host´s corneal cells and extracellular matrix. We expect that CECs differentiated from MSCs can proliferate in vivo after transplantation, maintaining the optimal hydration of the corneal stroma. If autologous or allogeneic MSCs can be differentiated to CECs and transplanted to recover normal endothelial function in patients suffering from endothelial diseases, without causing any immune or inflammatory response and without using whole donor corneas (DCs), this could simplify the treatment of corneal endothelial diseases and increase availability of DCs for other types of keratoplasty. Thus, I believe, this proposed research plan has the potential to revolutionize the treatment of corneal diseases, not only those affecting the corneal endothelium but also those affecting other corneal layers. The research aims are supported by the training plan focused on the acquisition of relevant multidisciplinary expertise in the field of cell and molecular biology, physiopathology, tissue-engineering, gene therapy, and material science. To this end, a “Mentoring Team” which includes the lead mentor, Dr. James Chodosh (MEE/ SERI), along with co-mentors, Dr. Miguel Gonzalez (SERI/UOC) and Professor Shigeto Shimmura (Keidai), has been assembled. Moreover, three independent collaborators will support our team in (1) the design of the studies related to MSCs differentiation and characterization (Dr. Garzon), (2) understanding of molecular pathways involved in the differentiation (Dr. Sabater), and (3) the nanoparticle based MRI detectable therapeutic strategies design (Dr. Patra). This group of mentors and collaborators will guide me during the K99 phase to achieve my long term career goal of becoming an academic scientist, and leader in my field with a strong independent research background. I envision that this award will provide me with an excellent platform to transition to an independent research faculty member (this includes the transition into the R00 phase) and in the long term, to successfully compete for independent NIH funding (R01 grant). My training will additionally be complemented by specialization courses during the mentored phase in the development, improvement of presentation and writing skills (grants and manuscripts), manuscript review, mentoring, and development of leadership abilities and lab management skills.