# Biomechanical Determinants of Hematopoietic Stem Cell Potential

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2024 · $488,480

## Abstract

PROJECT SUMMARY
The availability of donor-matched sources of hematopoietic stem cells (HSCs) continues to limit access to and
outcomes following allogeneic HSC transplant. Unmet need for improved HSC sources has motivated global
improvements in donor recruitment and matching, as well as enterprising attempts to develop patient-derived or
universally compatible hematopoietic cells. At present, specification of HSCs in a dish has been inefficient, and
most methods using co-culture and expression of hematopoietic genes only produce progenitors with limited
lineage and engraftment potential.
Our studies show that biomechanical force caused by flow of blood through the vasculature is a critical regulator
of hematopoiesis and can promote engraftment of cells with long-term hematopoietic reconstitution potential. In
our prior funding period, we found that initiation of blood flow is a critical determinant of energy metabolism and
mitochondrial dynamics in the HSC precursor known as the hemogenic endothelium.
The objective of our current research is to define metabolic adaptations that promote definitive hematopoiesis, with
the long-term goal of exploiting biophysical cues such as shear stress in directed differentiation and expansion of
customized HSCs for therapeutic transplant and blood disease modeling. Specifically, we aim to define the
contribution of mitochondrial maturation to development of the hemogenic endothelium that gives rise to HSCs.
We will employ a combination of methods that provide single-cell resolution of metabolic activity, mitochondrial
ultrastructure, and hematopoietic function. Our first aim is designed to address the effects of interrupting
mitochondrial maturation on commitment of hemogenic endothelial precursors to the hematopoietic fate via
pharmacological targeting, biomimetic modeling with in vitro platforms, and cardiac mutant mouse models. In our
second aim, we leverage pilot data from complementary datasets that support a role for the mitochondrial
permeability transition pore (mPTP) in differentiation of arterial endothelium. We address how biphasic regulation
of mPTP opening over the continuum of the endothelial-to-hematopoietic transition (EHT) dictates acquisition of
hematopoietic fate. Consequences of disrupted or enhanced mPTP activity will be defined during EHT by
assessing indicators of metabolic and hematopoietic capacity. The proposed study will address a major deficiency
in our understanding of how mitochondrial maturation contributes to transition of endothelial to hematopoietic fate
and promises to inspire novel methods for generation of HSCs in vitro by metabolic reprogramming.

## Key facts

- **NIH application ID:** 10762440
- **Project number:** 5R01DK111599-07
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** PAMELA LYNN WENZEL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $488,480
- **Award type:** 5
- **Project period:** 2018-01-15 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10762440

## Citation

> US National Institutes of Health, RePORTER application 10762440, Biomechanical Determinants of Hematopoietic Stem Cell Potential (5R01DK111599-07). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10762440. Licensed CC0.

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