# Regulation of functionally discrete hematopietic stem cells

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $592,073

## Abstract

PROJECT SUMMARY
Once rapid embryonic and neonatal cellular expansion is completed, hematopoietic stem cells (HSC) withdraw
from the cell cycle, and serve as a reservoir to sustain the production of all blood cells throughout adult life.
HSCs are functionally heterogenous and contain cells with disparate differentiation and durable engraftment
potential. However, molecular drivers of adult HSC remain enigmatic. We have developed several mouse
models and deep genomics data sets which support the existence of discrete HSC cell states that differ both
molecularly and functionally. Moreover, we find that HSC history of division may account for these genomic
differences; placing these populations in a hierarchical structure based on divisional history. Further, our data
suggest that HSC dramatically remodel the mitochondrial network upon entry into cell cycle and that
mitochondria do not return to a homeostatic state after returning to quiescence. We hypothesize that HSC are
hierarchically organized in functionally distinct HSC states, and that this organization can be resolved by their
divisional history for which mitochondria provide memory. The proposed work will first incisively establish the
molecular architecture of discrete HSC states, including drivers of the most functional population, then define
the role of mitochondria in functional programming of discrete HSC populations, including how alterations in
mitochondria maintenance contribute to a decline in fitness. The overarching goal is to define the cell states
encountered by HSC and their derivatives, as well as to provide mechanistic insight into the underlying
transcriptional circuits and cell biological changes indicative of transition between states. We expect the
proposed research to contribute to a fundamental understanding of the hematopoietic system – information
that can be used to develop new modalities for HSC expansion, validate grafts before BMT, or safely
genetically manipulate HSC for gene therapy.

## Key facts

- **NIH application ID:** 9886000
- **Project number:** 1R01DK121062-01A1
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Marie-Dominique Filippi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $592,073
- **Award type:** 1
- **Project period:** 2020-03-12 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9886000

## Citation

> US National Institutes of Health, RePORTER application 9886000, Regulation of functionally discrete hematopietic stem cells (1R01DK121062-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9886000. Licensed CC0.

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