Vascular progenitors generated from tankyrase inhibitor-regulated naïve diabetic human iPSC potentiate efficient revascularization of ischemic retina

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 diab...

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Bibliographic Details
Published in:	Nature communications 2020-03, Vol.11 (1), p.1195-20, Article 1195
Main Authors:	Park, Tea Soon, Zimmerlin, Ludovic, Evans-Moses, Rebecca, Thomas, Justin, Huo, Jeffrey S, Kanherkar, Riya, He, Alice, Ruzgar, Nensi, Grebe, Rhonda, Bhutto, Imran, Barbato, Michael, Koldobskiy, Michael A, Lutty, Gerard, Zambidis, Elias T
Format:	Article
Language:	eng
Subjects:	Adult Animals Blood Vessels - pathology Cell culture Cell Differentiation - drug effects Cell Line Cell Lineage - drug effects Cell Movement - drug effects Cellular Senescence - drug effects Diabetes Diabetes mellitus Diabetes Mellitus - pathology DNA Damage Enzyme Inhibitors - pharmacology Epigenesis, Genetic - drug effects Epigenetics Fibroblasts - drug effects Fibroblasts - pathology Gene expression Histone Code Humans Induced Pluripotent Stem Cells - drug effects Induced Pluripotent Stem Cells - pathology Inhibitors Ischemia Ischemia - pathology Ischemia - therapy Mice Neural stem cells Organoids - drug effects Organoids - pathology Pluripotency Poly(ADP-ribose) Polymerase Inhibitors - pharmacology Promoter Regions, Genetic - genetics Regeneration (physiology) Regenerative medicine Retina Retina - pathology Reversion Stem cell transplantation Stem cells Stem Cells - drug effects Stem Cells - pathology Stem Cells - ultrastructure Tankyrases - antagonists & inhibitors Tankyrases - metabolism Teratoma - pathology Transcription, Genetic - drug effects
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Summary:	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.
ISSN:	2041-1723 2041-1723