# Identifying the precursor to hematopoietic stem cells in the mouse embryo and improving its engraftment upon transplantation

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA-IRVINE · 2020 · $192,389

## Abstract

PROJECT SUMMARY
There is a fundamental gap in understanding how hematopoietic stem cells (HSCs) first emerge during
embryonic development. This includes 1) the identity of the HSC precursor (pre-HSCs), and 2) why
HSCs (but not pre-HSCs) are able to seed the bone marrow and engraft upon transplantation into adult
hosts. Without first addressing these questions, the potential to apply that knowledge to improve the
engraftment of HSCs, or pluripotent stem cell (PSC) derived HSCs, upon transplantation as treatments
for blood diseases will remain unrealized. The long-term goal of this research team is to better
understand the molecular mechanisms that regulate HSC emergence and maturation in the embryo.
The overall objective in this application is to identify pre-HSCs in the embryo and determine why they
cannot engraft in adults. The central hypothesis is that an embryonic population called “eKLS” contains
pre-HSCs that cannot engraft into bone marrow due to the absence of homing molecules on their
surface, such as the chemokine receptor Cxcr4. This hypothesis has been formulated on the basis of
two lines of preliminary data: First, that sorted eKLS cells can engraft and become HSCs when
transplanted into neonatal mice, and second, that eKLS cells lack expression of Cxcr4 and other
homing factors. The rationale for the proposed research is that, once pre-HSCs have been identified,
they can be compared to adult HSCs to better understand what factors are critical for engraftment.
This hypothesis will be tested by pursuing two specific aims: 1) To determine whether eKLS cells or
another embryonic cell gives rise to HSCs in vivo, and 2) To determine whether the ability to respond to
Cxcr4/Cxcl12 signaling distinguishes pre-HSCs from HSCs. Under the first aim, the neonatal
transplantation system will be used to identify which embryonic populations and in which embryonic
tissues contain pre-HSCs. Under the second aim, Cxcr4 and other homing factors will be expressed in
eKLS cells to determine whether they can imbue those cells with the ability to engraft in adult recipients.
The research proposed in this application is conceptually innovative because it focuses on the
differences between HSCs and their immediate precursors as a way to understand how HSCs emerge
and mature during embryonic development. The proposed research is significant because it could lead
to breakthroughs in the engraftabilty of HSCs and/or PSC-derived HSCs upon transplantation. This
could dramatically improve the safety and efficacy of HSC transplantation as a treatment for nearly any
blood disease.

## Key facts

- **NIH application ID:** 9849274
- **Project number:** 5R21CA224022-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** MATTHEW A INLAY
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $192,389
- **Award type:** 5
- **Project period:** 2019-01-10 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9849274

## Citation

> US National Institutes of Health, RePORTER application 9849274, Identifying the precursor to hematopoietic stem cells in the mouse embryo and improving its engraftment upon transplantation (5R21CA224022-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9849274. Licensed CC0.

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