# Embryonic vascular stem-progenitors for treatment of ischemic retinopathies

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2024 · $442,564

## Abstract

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 medicin...

## Key facts

- **NIH application ID:** 10771978
- **Project number:** 5R01EY032113-04
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** ELIAS T. ZAMBIDIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $442,564
- **Award type:** 5
- **Project period:** 2021-02-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10771978

## Citation

> US National Institutes of Health, RePORTER application 10771978, Embryonic vascular stem-progenitors for treatment of ischemic retinopathies (5R01EY032113-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10771978. Licensed CC0.

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