Vascular Progenitors Generated from Tankyrase Inhibitor-Regulated Diabetic Induced Pluripotent Stem Cells Potentiate Efficient Revascularization of Ischemic Retina

Vascular regenerative therapies with conventional human induced pluripotent stem cells (hiPSC) currently remain limited by high interline variability of differentiation and poor efficiency for generating functionally transplantable vascular progenitors (VP). Here, we report the advantage of a new class of tankyrase inhibitor-regulated naive hiPSC (N-hiPSC) for significantly improving vascular cell therapies. Conventional hiPSC reprogrammed from type-1 diabetic donor fibroblasts (DhiPSC) were stably reverted to N-hiPSC with a cocktail of LIF and three small molecules inhibiting the tankyrase, MEK, and GSK3beta signaling pathways (LIF-3i). Naive diabetic hiPSC (N-DhiPSC) possessed higher functional pluripotency, higher proliferation, decreased lineage priming, and more stable genomic integrity than conventional DhiPSC. VP differentiated from N-DhiPSC expanded more efficiently, and displayed higher in vitro vascular functionality than VP from isogenic conventional DhiPSC cultures. Moreover, N-DhiPSC-derived VP survived, migrated, and engrafted in vivo into the deep vasculature of the neural retinal layers with significantly higher efficiencies than isogenic primed D-hiPSC-VP in a murine model of ischemic retinopathy. Epigenetic analyses of CpG DNA methylation and histone configurations at developmental promoters of N-hiPSC revealed tight regulation of lineage-specific gene expression and a de-repressed naive epiblast-like epigenetic state that was highly poised for multi-lineage transcriptional activation. We propose that autologous or cell-banked vascular/pericytic progenitors derived from tankyrase inhibitor-regulated N-hiPSC will more effectively reverse the pathology that drives vascular disorders such as diabetic retinopathy.