# Modulating HSC-niche interactions to understand aging and improve transplantation

> **NIH NIH R01** · STANFORD UNIVERSITY · 2020 · $407,580

## Abstract

PROJECT SUMMARY/ABSTRACT
The goals of this proposal are: (1) to elucidate specific mechanisms by which hematopoietic (blood-forming)
stem cells (HSCs) and factors within their microenvironment (i.e., niche) lead to age-associated changes in blood
formation; and (2) to identify related HSC and niche mechanisms that enhance HSC engraftment after
transplantation. More specifically, we aim to achieve these goals, respectively: (1) by manipulating Lnk (Sh2b3)
expression in HSCs to identify intrinsic regulators of HSC aging and the myeloid-bypass differentiation pathway
(see below); and (2) by identifying “supporter” cells in the niche, and their corresponding molecular mechanisms,
that enable HSC engraftment. This project will provide a mechanistic basis to devise strategies to treat age-
associated hematologic disorders and improve methods of HSC transplantation (HSCT), thereby addressing two
important medical needs. HSCT is a curative therapy for a number of hematological diseases (including
immunodeficiencies, autoimmunities, and leukemias) but is still risky, in part due to the necessary pre-HSCT
bone marrow conditioning, usually irradiation or chemotherapy. Such conditioning is necessary to make “space”
or clear niches in the bone marrow for donor HSCs to engraft, but also causes significant morbidity. With the
overall goal of improving our understanding of HSC-niche interactions, this research program: (1) will identify
novel strategies to sustain HSC function during aging, potentially preventing or treating age-associated
hematologic disorders; and (2) to improve HSC transplantation, potentially by reducing the need for toxic pre-
conditioning. Aim 1 is based on findings that: (i) Lnk-deficient HSCs do not exhibit the typical age-associated
myeloid bias of wild-type HSCs; (ii) within the immunophenotypically-defined HSC compartment are functionally
distinct self-renewing myeloid-restricted progenitor cells (MyRPs) that are directly generated from HSCs through
a myeloid-bypass pathway; and (iii) MyRPs increase in frequency with age. Through analysis of Lnk-deficient
HSCs, which are defective in MyRP generation, we will identify mechanisms regulating myeloid-bypass
differentiation. From transcriptomics analysis, we will identify new putative regulators of MyRP production and
HSC aging, and confirm these through functional assays. Aim 2 is based on the finding that Lnk-deficient HSCs
have greater engraftment potential than wild-type HSCs in HSCT, even in the absence of preconditioning. We
will identify non-HSC bone marrow cell types that enhance HSC engraftment. We elucidate cellular mechanisms
that contribute to this “supporter cell” function using 2D and 3D microscopy to trace bone marrow colonization
following transplantation. In summary, this research proposal will use Lnk-deficiency as a system to both
understand fundamental mechanisms of HSC aging and identify strategies to improve HSC transplantation
engraftment rates. This research project...

## Key facts

- **NIH application ID:** 10013282
- **Project number:** 5R01HL147124-03
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Hiromitsu Nakauchi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $407,580
- **Award type:** 5
- **Project period:** 2018-09-06 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10013282

## Citation

> US National Institutes of Health, RePORTER application 10013282, Modulating HSC-niche interactions to understand aging and improve transplantation (5R01HL147124-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10013282. Licensed CC0.

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