# Regulatory mechanisms of hematopoietic stem cell functions post-transplant

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2024 · $642,754

## 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. HSC sustain injury after bone marrow transplantation and become less functional.
A clear understanding of the mechanism responsible for HSC functional decline with HSC transplantation is still
lacking. This lack of knowledge has hampered our ability to maintain HSC functions through divisions and
improve HSCT outcomes. The overall goal of this grant application is to understand the mechanisms behind
HSC functional decline after bone marrow transplantation. 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 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. In addition, we found that HSC with high repopulation activity
in vivo have high levels of mitophagy. In contrast mitophagy is drastically reduced in HSC after transplantation.
We hypothesize that mitochondrial defects drive HSC functional decline after transplantation. The main
objectives of this project are to understand why abnormal mitochondria in HSC are not removed after bone
marrow transplantation and the impact it has on HSC functions (Aim1). Aim2 will investigate the impact of
abnormal mitochondria on HSC metabolism with a focus the mitochondrial retrograde signaling ATF4-on
carbon/folate pathway. We will test effect of metabolite supplementation in ameliorating HSC functions in vivo
during bone marrow transplantation, using both murine bone marrow transplantation and xenotransplant model
of human CD34+ into immunodeficient recipients. The proposed studies provide a unique opportunity to
examine the specific contribution of abnormal mitochondrial functions to HSC functional decline during and after
bone marrow transplantation. It will investigate the novel concept that HSCs accumulate dysfunctional
mitochondria that reprogram their metabolism driving their functional decline, which may lead to the
identification of novel approaches for pharmacological intervention to maintain HSC functions through divisions.

## Key facts

- **NIH application ID:** 10818900
- **Project number:** 1R01HL167731-01A1
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Marie-Dominique Filippi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $642,754
- **Award type:** 1
- **Project period:** 2024-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10818900

## Citation

> US National Institutes of Health, RePORTER application 10818900, Regulatory mechanisms of hematopoietic stem cell functions post-transplant (1R01HL167731-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10818900. Licensed CC0.

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