# Mesenchymal Stromal Cells Regulate Hematopoietic Stem Cell Aging

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $431,329

## Abstract

Hematopoietic stem cell (HSC) function undergoes significant changes during development and upon aging.
Aged HSCs have low and myeloid-biased regenerative potential compared to young HSCs. This myeloid-
biased differentiation of HSCs is postulated to be at least partially responsible for the impaired adaptive
immune system observed in elder population, a significant health concern for elders increasing the incidence of
infectious diseases. The prevailing view is that HSC aging is regulated by both HSC intrinsic and extrinsic
changes. A significant barrier in understanding how HSC aging is affected by cell extrinsic changes is the fact
that aging affects multiple organs, and that HSCs are regulated by multiple organs and cell types within the
HSC supportive microenvironment (HSC niche) in the bone marrow. Here, we propose to dissect the complex
biology of aging by introducing age-related changes to one cell type within the HSC niche, the mesenchymal
stromal cells (MSCs), and determine whether changes in MSCs cause age-related changes in HSCs and
hematopoiesis. We have found that an anti-senescence factor Bmi1 is highly expressed in MSCs compared to
other cells in the bone marrow, and that Bmi1 expression levels in MSCs decline with age. We then discovered
that conditionally deleting Bmi1 from MSCs causes senescence and expands adipocytes in the bone marrow,
similar to what happens in human aging. These age-related changes in MSC function caused age-related
changes in HSC and hematopoiesis, including anemia, loss of bone marrow cellularity, and strikingly, myeloid-
biased differentiation of HSCs. All of these changes in HSCs and hematopoiesis are hallmarks of aging in
HSCs and hematopoiesis. We thus hypothesized that age-related changes induced in MSCs by deleting Bmi1
causes age-related changes in HSCs. Our long term goal is to understand how HSC aging is regulated cell
extrinsically by the HSC niche. Our new model provides a unique opportunity to focus on changes in HSC
function caused specifically by changes in bone marrow MSCs. We have two broad aims to study how Bmi1 in
MSCs regulate HSCs and hematopoiesis. In aim 1, we will determine whether the HSC and hematopoiesis
phenotypes after deleting Bmi1 from MSCs become exacerbated with advanced age or by inflammation. We
will also examine whether HSC engraftment and mobilization are also affected by deleting Bmi1 from MSCs. In
aim 2, we will determine whether induction of senescence or adipogenesis upon Bmi1 deletion from MSCs
impairs the HSC niche function, by conditionally deleting senescence regulators Ink4a/Arf, or adipogenesis
regulators PPARγ and Prdm16. We will also examine the molecular mechanism by which Bmi1 regulates
PPARγ and Prdm16. Upon completion of this work, we will have a deep understanding of how changes in HSC
niche induced by altered MSC function causes age-related changes in HSCs. This may lead to novel
intervention to increase HSC function via MSC in vitro and in vivo, and b...

## Key facts

- **NIH application ID:** 9849257
- **Project number:** 5R01DK107413-05
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Daisuke Nakada
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $431,329
- **Award type:** 5
- **Project period:** 2016-01-01 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9849257

## Citation

> US National Institutes of Health, RePORTER application 9849257, Mesenchymal Stromal Cells Regulate Hematopoietic Stem Cell Aging (5R01DK107413-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9849257. Licensed CC0.

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