# Restoration of myocardial reparative function of diabetic progenitor cells by epigenetic modulation

> **NIH NIH R01** · TEMPLE UNIV OF THE COMMONWEALTH · 2020 · $560,299

## Abstract

In the absence of effective endogenous repair mechanisms after ischemic injury, cell-based therapies have emerged
as a potential novel therapeutic approach in ischemic tissue repair. After the initial characterization of putative bone
marrow-derived endothelial progenitor cells (EPC) and their potential to promote cardiac and critical limb ischemia
neovascularization and to attenuate ischemic injury, more than a decade of intense preclinical research, led to the
BM progenitors/EPC-based clinical trials. However, despite early enthusiasm, cell based therapies yielded modest
clinical results. Modest clinical outcomes of cell-based therapies may reflect the cellular dysfunction that is known to
ensue in EPC/progenitor cells obtained from diabetic animals as well as patients. Compelling evidence indicates that
EPCs dysfunction represents a mechanism for impaired vascular repair and angiogenesis in diabetes, subsequently
leading to vascular dysfunction. Therefore, understanding the molecular basis of diabetes-induced EPC dysfunction
and potentially reversing EPC dysfunction may represent a strategy to enhance cell-based therapeutics for
myocardial/ischemic limb repair in diabetic patients. Increasing evidence also indicates that the mechanism
underlying hyperglycemic memory and EPC dysfunction may involve epigenetic mechanisms involving enhanced
epigenetic repressive marks on vascular genes leading to their epigenetic silencing. Moreover, since hyperglycemic
memory is inherited through cell division, and altered epigenetic patterns in diabetic EPCs can be transmitted to
daughter cells. Understanding the epigenetic basis of EPC dysfunction in diabetics and epigenetic reprogramming of
diabetic EPCs, is therefore, of paramount importance for cell based therapies in diabetic patients. Therefore, our
central hypothesis is that epigenetic repressive marks in diabetic EPCs render them dysfunctional and epigenetic
modifying agents targeting those repressive marks can reprogram diabetic EPCs to a more functional and reparative
phenotype. This project aims to study, in detail, phenotypic, epigenetic and molecular characterization of
reprogrammed diabetic EPCs from diabetic mice as well as human CD34+ hematopoietic stem cells from diabetic
patients and their exosome derivatives and test the ischemic myocardial repair capacity of these reprogrammed
diabetic EPCs in physiologically relevant model of MI and hind limb ischemia. This overall aim will be achieved by
conducting experiments organized under the following three specific aims: 1) To evaluate phenotypic stability and
reparative potential of epigenetically reprogrammed diabetic EPCs; 2) To determine the specific epigenetic
modifications in reprogrammed EPCs and establish a role of HDAC1 and G9a methytransferase in reprogramming
process and 3) To establish epigenetic reprogramming rescues functional and reparative deficits in human CD34+
stem cells from patients with Type 2 diabetes.

## Key facts

- **NIH application ID:** 9903831
- **Project number:** 1R01HL143892-01A1
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** Raj Kishore
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $560,299
- **Award type:** 1
- **Project period:** 2019-12-10 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9903831

## Citation

> US National Institutes of Health, RePORTER application 9903831, Restoration of myocardial reparative function of diabetic progenitor cells by epigenetic modulation (1R01HL143892-01A1). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9903831. Licensed CC0.

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