# Hematopoietic stem and progenitor cell regulation of the niche through extracellular vesicles

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2022 · $440,000

## Abstract

ABSTRACT
Adoptive transfer of hematopoietic stem and progenitor cells (HSPC) can provide effective treatment for non-
malignant disorders in the form of allogeneic hematopoietic stem cell transplantation (HSCT) or as a platform
for autologous gene therapy. Bone marrow (BM) niches are the operationally-defined core units that sustain
hematopoietic function, where signals from non-hematopoietic support cells adapt HSPC output to organismal
demand. HSPC occupancy in the BM, however, is a competitive process, and HSCT patients typically require
conditioning to eliminate endogenous hematopoiesis and “create space”, thereby promoting homing and
engraftment in highly vascularized niches. Secretory activity is a fundamental HSPC property, but the impact
of signals that emerge from HSPC, and their cellular targets in the niche are not well understood. The gap in
knowledge regarding the crosstalk between HSPC and vascular niche endothelial cells specifically, may hold
important biological insight and opportunities to improve competitive HSPC niche fitness, and a potentially
novel strategy to offset the toxicity and long-term side effects from HSCT conditioning treatments. The
secretion of nanometer sized extracellular vesicles (EVs) that traffic protein and RNA cargo is a constitutive
cellular function. Intriguingly, mobilized CD34+ HSPC -which provide known advantages to engraftment after
HSCT- have been shown to release EVs (EVCD34) that are highly abundant in microRNA-126, an “angiomiR”
that regulates Akt/mTOR signaling, which in turn is central to EC hematopoiesis support. Others showed that
adoptively transferred EVCD34, rich in miR-126, enhance EC proliferation and function. Our principal
hypothesis is that EVHSPC trafficking of miR-126 actively shapes EC function in the vascular BM niche
to enhance occupancy and improve repopulation. Three aims will test our hypothesis. In Aim 1 we will
determine the cell-autonomous impact of EVHSPC secretion on self-renewal and repopulation potency under
conditions of homeostasis and stress. Aim 2 will test the role of endothelial cells as predominant cellular
targets for EV trafficking in the BM niche. Aim 3 will dissect the specific role of miR-126 and in regulating BM
endothelial cell fates and the involved signaling pathways. As a proof of principle study, this proposal places
an experimental and mechanistic focus on EVHSPC, but insight into the biologic role of the HSPC secretome in
the BM niche will be broad. Translationally, our long-term goal is the development of new, non-toxic
approaches to improve outcomes after allogeneic HSCT and autologous gene therapy.

## Key facts

- **NIH application ID:** 10500352
- **Project number:** 1R01HL164633-01
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Peter Kurre
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $440,000
- **Award type:** 1
- **Project period:** 2022-07-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10500352

## Citation

> US National Institutes of Health, RePORTER application 10500352, Hematopoietic stem and progenitor cell regulation of the niche through extracellular vesicles (1R01HL164633-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10500352. Licensed CC0.

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