Human Induced Pluripotent Stem Cell Derived Mesoderm Subset Ameliorates Diabetic Retinopathy by Reestablishing Retinal Function and Restoring Protective Signaling Cascades in Type 2 Diabetes
Boston University - Center for Regenerative Medicine; Boston University - Pulmonary Center; Mohammed Bin Rashid University of Medicine and Health Sciences
Human induced pluripotent stem cells (hiPSC) differentiated into a specific mesoderm subset expressing vascular endothelial growth factor receptor 2, neural cell adhesion molecule 1, and apelin G protein-coupled receptor APJ (called KNA+), possessed all of the phenotypic and functional endothelial colony forming cell potential that resides in differentiating hiPSC. Thus, we postulated KNA+ mesoderm treatment would correct diabetic retinal capillary vasodegeneration. KNA+ cells derived from diabetic (D) and non-diabetic (N) patient-derived hiPSC displayed comparable phenotypic and functional properties. N-KNA+ or D-KNA+ intravitreal injections into type II diabetic ( db/db ) murine eyes led to retinal vascular engraftment, showed no toxicity, visual acuity was significantly improved, and diabetes-induced scotopic and photopic ERG defects were corrected. Proteomic arrays revealed that hiPSC-derived KNA+ cell administration restored several aberrant cell signaling pathways in the neural retina. These results support the efficacy of both hiPSC-derived D-KNA+ and N-KNA+ cells in correcting vasodegeneration in the diabetic murine retina.
Gil, Chang-Hyun and Chakraborty, Dibyendu and Vieira, Cristiano P. and Prasain, Nutan and Li Calzi, Sergio and Hu, Ping and Banno, Kimihiko and Jamal, Mohamed and Huang, Chao and Sielski, Micheli S. and Lin, Yang and Huang, Xinxin and Dupont, Mariana D. and Floyd, Jason L. and Prasad, Ram and Longhini, Ana and McGill, Trevor J. and Chung, Hyung-Min and Murphy, Michael P. and Kotton, Darrell N. and Boulton, Michael E. and Yoder, Mervin C. and Grant, Maria B., Human Induced Pluripotent Stem Cell Derived Mesoderm Subset Ameliorates Diabetic Retinopathy by Reestablishing Retinal Function and Restoring Protective Signaling Cascades in Type 2 Diabetes (July 2020). Available at SSRN: https://ssrn.com/abstract=3640846 or http://dx.doi.org/10.2139/ssrn.3640846
This version of the paper has not been formally peer reviewed.
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