# Metabolic regulation of stem cell niche development and function

> **NIH NIH R01** · EMORY UNIVERSITY · 2024 · $485,267

## Abstract

Project Summary
Hematopoietic stem cells (HSCs) and progenitors are tightly regulated by both cell intrinsic mechanisms and the
microenvironment (also known as niches) created by specialized bone marrow (BM) stromal cells. However,
how stem cell or progenitor niches are developed, maintained, and remodeled in response to stress is poorly
characterized. Lack of such fundamental knowledge hinders our ability to understand certain hematological
diseases directly or indirectly involving the BM microenvironment. HSCs, the precursor cells that give rise to all
blood lineages, are maintained in discrete anatomical microenvironments during embryonic development, and
they ultimately migrate from the fetal liver to the BM (“homing”) at the perinatal stage. Yet our understanding of
the mechanisms regulating this process remains limited. We previously demonstrated a crucial cell-intrinsic role
of PTPMT1, a mitochondria-based Pten-like phosphatidylinositol phosphate phosphatase, in hematopoietic cell
development − Knockout of PTPMT1 from the hematopoietic system resulted in hematopoietic failure due to the
bioenergetic/metabolic stress, cell cycle arrest, and differentiation block of HSCs. Using the PTPMT1 knockout
model, we recently examined the role of coordinated cellular metabolism in the stem cell microenvironment by
generating and characterizing PTPMT1fl/fl/Prx1-Cre+ mice, in which PTPMT1 was deleted from BM stromal cells
(and limb bud progenitor-derived other mesenchymal cells). Surprisingly, deletion of PTPMT1 from BM stromal
cells resulted in profound hematopoietic defects: 1). Nearly eighty percent of PTPMT1fl/fl/Prx1-Cre+ mice died
within 3 weeks of birth. The migration/homing of HSCs (wild-type) from the fetal liver to the BM was impaired in
these animals – HSCs in the BM of knockout mice decreased by ~5-fold compared to those in control mice 2
weeks after birth, while there were ~13 times more hematopoietic foci (CD45+) in the liver of knockout mice. 2).
B lymphocyte development was blocked in the pro-B stage in PTPMT1fl/fl/Prx1-Cre+ mice. These striking
observations led us to hypothesize that PTPMT1-mediated metabolism plays an important role in establishing or
maintaining supportive stem cell niches in the BM. The objective of the current proposal is to further determine
the underlying cellular and molecular mechanisms. By studying this particular mitochondrial protein, we aim to
decipher the metabolic regulation of HSC niche development/maintenance/remodeling. We plan to test our
hypothesis by pursuing the following three aims. 1). To identify the niche cells in which PTPMT1 depletion-
induced bioenergetic/metabolic stress causes HSC homing defects during perinatal development. 2). To
determine the functional relevance of PTPMT1-mediated metabolism in HSC niche cells to steady-state and
stress hematopoiesis in adults. 3). To identify the bioactive molecules that account for the effects of PTPMT1-
depletion from the niche on HSCs, and the mecha...

## Key facts

- **NIH application ID:** 10840796
- **Project number:** 5R01HL162725-03
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** CHENG-KUI QU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $485,267
- **Award type:** 5
- **Project period:** 2022-07-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10840796

## Citation

> US National Institutes of Health, RePORTER application 10840796, Metabolic regulation of stem cell niche development and function (5R01HL162725-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10840796. Licensed CC0.

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