1. Vascular progenitors generated from tankyrase inhibitor-regulated naïve diabetic human iPSC potentiate efficient revascularization of ischemic retina
- Author
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Michael I. Barbato, Imran Ahmed Bhutto, Riya Kanherkar, Ludovic Zimmerlin, Justin Thomas, Jeffrey S. Huo, Elias T. Zambidis, Nensi Ruzgar, Tea Soon Park, G. A. Lutty, Rhonda Grebe, Michael A. Koldobskiy, Rebecca Evans-Moses, and Alice He
- Subjects
0301 basic medicine ,Transcription, Genetic ,General Physics and Astronomy ,Regenerative medicine ,Epigenesis, Genetic ,Cell therapy ,Mice ,0302 clinical medicine ,Diabetes complications ,Cell Movement ,Ischemia ,Enzyme Inhibitors ,Promoter Regions, Genetic ,Induced pluripotent stem cell ,lcsh:Science ,Cellular Senescence ,Tankyrases ,Multidisciplinary ,Stem Cells ,Teratoma ,Cell Differentiation ,Retinal diseases ,3. Good health ,Cell biology ,Histone Code ,Organoids ,Stem cell ,Reprogramming ,Adult ,Science ,Induced Pluripotent Stem Cells ,Poly(ADP-ribose) Polymerase Inhibitors ,Biology ,Article ,Retina ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,03 medical and health sciences ,Pluripotent stem cells ,Diabetes Mellitus ,Animals ,Humans ,Cell Lineage ,Epigenetics ,Progenitor cell ,General Chemistry ,Fibroblasts ,030104 developmental biology ,Cell culture ,Blood Vessels ,lcsh:Q ,030217 neurology & neurosurgery ,DNA Damage - Abstract
Here, we report that the functionality of vascular progenitors (VP) generated from normal and disease-primed conventional human induced pluripotent stem cells (hiPSC) can be significantly improved by reversion to a tankyrase inhibitor-regulated human naïve epiblast-like pluripotent state. Naïve diabetic vascular progenitors (N-DVP) differentiated from patient-specific naïve diabetic hiPSC (N-DhiPSC) possessed higher vascular functionality, maintained greater genomic stability, harbored decreased lineage-primed gene expression, and were more efficient in migrating to and re-vascularizing the deep neural layers of the ischemic retina than isogenic diabetic vascular progenitors (DVP). These findings suggest that reprogramming to a stable naïve human pluripotent stem cell state may effectively erase dysfunctional epigenetic donor cell memory or disease-associated aberrations in patient-specific hiPSC. More broadly, tankyrase inhibitor-regulated naïve hiPSC (N-hiPSC) represent a class of human stem cells with high epigenetic plasticity, improved multi-lineage functionality, and potentially high impact for regenerative medicine., hPSCs in culture acquire a more naïve pluripotent state upon tankyrase inhibition. Here, the authors show that tankyrase inhibitor-regulated naïve hiPSCs from diabetic donors generate more vascular progenitors and more efficient engraftment into mouse retina than conventional PSCs.
- Published
- 2020