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

Tea Soon Park, Ludovic Zimmerlin, Rebecca Evans-Moses, Justin Thomas, Jeffrey S. Huo, Riya Kanherkar, Alice He, Nensi Ruzgar, Rhonda Grebe, Imran Bhutto, Michael Barbato, Michael A. Koldobskiy, Gerard Lutty and Elias T. Zambidis ()
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Tea Soon Park: The Johns Hopkins School of Medicine
Ludovic Zimmerlin: The Johns Hopkins School of Medicine
Rebecca Evans-Moses: The Johns Hopkins School of Medicine
Justin Thomas: The Johns Hopkins School of Medicine
Jeffrey S. Huo: The Johns Hopkins School of Medicine
Riya Kanherkar: The Johns Hopkins School of Medicine
Alice He: The Johns Hopkins School of Medicine
Nensi Ruzgar: The Johns Hopkins School of Medicine
Rhonda Grebe: Wilmer Eye Institute, The Johns Hopkins School of Medicine
Imran Bhutto: Wilmer Eye Institute, The Johns Hopkins School of Medicine
Michael Barbato: The Johns Hopkins School of Medicine
Michael A. Koldobskiy: The Johns Hopkins School of Medicine
Gerard Lutty: Wilmer Eye Institute, The Johns Hopkins School of Medicine
Elias T. Zambidis: The Johns Hopkins School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-20

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14764-5

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