Embryonic vascular stem-progenitors for treatment of ischemic retinopathies

Branch vein occlusion (BVO) and diabetic retinopathy (DR) are major causes of new onset blindness in the US.

These vascular disorders result in acellular capillaries secondary to ischemic death of retinal vascular endothelial cells (ECs) and contractile pericytes.

If acellular retinal blood vessels could be regenerated with autologous or cell-banked self-renewing vascular-pericytic stem-progenitors, ischemia could be relieved, and end stage blindness reversed or stabilized in these vasculopathies.

Our group established the feasibility of transplanting patient-specific embryonic vascular progenitors (VP) with pericytic potential directly into the eye, following differentiation from human induced pluripotent stem cells (hiPSC).

We also established a novel tankyrase/PARP inhibitor-based small molecule cocktail for reversion of conventional, lineage-primed hiPSC to ?naïve? hiPSCs (N-hiPSCs) that possessed a more primitive epiblast state with higher functional pluripotency.

The regenerative potential of naïve VP (N-VP) differentiated from normal and diseased N-hiPSC was significantly more prolific relative to primed, conventional hiPSC.

For example, naive diabetic vascular progenitors (N-DVP) differentiated from patient-specific naïve-reverted 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) from conventional, primed DhiPSC.

In this proposal, we develop the potential of N-VP for treatment of ischemic retinopathies.

We will employ a humanized animal model that mimics retinal ischemia [i.e., ischemia/reperfusion (I/R) injury] for testing the therapeutic capacity of human N-DVP to form patent blood vessels, rescue ischemic retina, and improve visual function.

We will test the in vivo developmental potential of N-DVP to efficiently differentiate to ECs and multipotent pericytic stem-progenitors following long-term engraftment in an ischemia-damaged retinal niche.

We will also aim to further improve our approach for generating unlimited amounts of epigenetically-plastic, pristine, non-diseased naïve embryonic progenitors for cellular therapies by probing how N-hiPSC reprogramming erases dysfunctional epigenetic donor cell memory and diabetes- associated metabolic aberrations with greater efficiency than conventional hiPSC reprogramming.

These studies will outline a future pathway for the efficient synchronous generation of naïve vascular and retinal stem-progenitors from the same N-hiPSC line for a more effective and comprehensive regeneration of diseased retina.

More broadly, we will develop the pre-clinical utility of this novel class of human vascular-pericytic stem cells that possess high epigenetic plasticity, improved functionality, and potentially high impact for ocular regenerative medicine.