# The role of mitochondria in hematopoietic stem cell self-renewal

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2022 · $606,862

## Abstract

Abstract
Hematopoietic stem cells (HSC) sustain the production of all blood and immune cells throughout life by
differentiating into all blood lineages and regenerate long-lived HSC, ie self-renew. However, although HSC
have high regenerative potential, the actual capacity of ‘self-renewal’, ie regenerating a daughter cell that has
identical properties’ is limited. It is known that HSC progressively lose regenerative potential with divisional
history. A clear understanding of the mechanism responsible for HSC functional decline under homeostatic
conditions is still lacking. This lack of knowledge has hampered our ability to maintain HSC functions through
divisions. The overall goal of this grant application is to understand which physiological mechanisms get
triggered in HSCs with replication, which reduce the activity of the HSC pool. We have discovered that once
HSCs get activated, mitochondria irreversibly remodel and do not return to homeostatic conditions. HSCs
accumulate dysfunctional mitochondria due to a progressive decline in mitochondrial quality control
mechanisms, including reduced mitochondrial turnover and dynamism such that HSCs carry mitochondria have
that are different in shape and functions. Mechanistically, HSC lose mitochondrial fission activity [ie, loss of the
fission regulator Drp1 activity], which causes a decrease in HSC regenerative potential. We hypothesize that
HSC mitochondrial remodeling drives HSC functional decline under homeostatic conditions. The main
objectives of this proposal are to understand the contribution and mechanisms of how changes in the quality
of mitochondria determine HSC functions. Aim1 will further investigate how a change in mitochondrial dynamism
and turnover alter HSC functions. We will examine mitochondria remodeling with HSC replication and the impact
it has on HSC functions; mechanistically determine which molecular pathways drive mitochondrial defects and
HSC attrition; determine the role of mitochondria in human HSC in physiologically relevant models. Aim2 will
investigate mechanisms responsible for the loss of mitochondrial quality controls in HSCs with a focus on
cardiolipin. We will examine the role of cardiolipin as causal factor of mitochondrial dysfunctions in HSCs. We
will test therapeutic potentials for lipid supplementation in ameliorating HSC functions in vivo.
The proposed studies provide a unique opportunity to examine the specific contribution of abnormal
mitochondrial functions to HSC functional decline with divisions under homeostatic conditions. It will investigate
the novel concept that HSCs accumulate dysfunctional mitochondria to drive their functional decline under
homeostatic conditions, perhaps as a mean of HSC internal biological clock, which may lead to the identification
of novel approaches for pharmacological intervention to maintain HSC functions through divisions.

## Key facts

- **NIH application ID:** 10320951
- **Project number:** 5R01HL151654-02
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Marie-Dominique Filippi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $606,862
- **Award type:** 5
- **Project period:** 2021-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10320951

## Citation

> US National Institutes of Health, RePORTER application 10320951, The role of mitochondria in hematopoietic stem cell self-renewal (5R01HL151654-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10320951. Licensed CC0.

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