# Dissection of Hematopoietic Stem and Progenitor Cell Differentiation during Embryogenesis

> **NIH NIH F31** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2024 · $48,974

## Abstract

PROJECT SUMMARY
Hematopoietic Stem Cells (HSCs) are clinically valuable because they display regenerative properties of self-
renewal and the ability to produce an entire hematopoietic system through multilineage differentiation. In other
words, HSC can make all mature blood cell types such as myeloid, erythroid, and lymphoid and they sustain
those blood types long-term in the organism. These regenerative properties make them an idea therapeutic tool
for treating hematological malignancies by transplantation from a healthy donor, however a shortage of donors
has prompted the effort to generate HSCs from alternative sources such as patient derived iPSCs. Knowledge
about molecular mechanisms of HSC formation is needed to aid those efforts. HSCs are formed in early
embryonic development alongside other HSC-independent Progenitor Cells (HPCs). One major difference
between them is that HPCs are more limited in their differentiation repertoire compared to HSCs. We aim to
study the differences between HSCs and HPCs to further advance our understanding of the specific molecular
drivers of HSC regenerative properties. Understanding how HSCs acquire the ability to differentiate and self-
renew in development can aid the efforts for generating them in vitro from alternative sources such as patient
derived tissues or cord blood sources. Current molecular markers are insufficient for distinguishing HSCs from
all other HPC subtypes. Moreover, most experimental systems require the removal of these cells from their
native environment to study their functionality using in vitro culture assays or transplantation, which will measure
the potential of a cell but may not reflect its actual endogenous function. Genetic experiments in mice and
zebrafish showed that HSC and HPC fate can be molecularly uncoupled, implying that unique drivers of HSC
formation exist. What genes are responsible for the formation of the rare population of HSCs independently from
HPCs? To address this question, we established a genetic lineage tracing approach that measures HSC and
HPC differentiation without removing them from their native environment. Using this assay, we found that HSCs
show a significant delay in their ability to differentiate to myeloid and lymphoid lineages relative to HPCs, and
this finding agrees with others in the field. The assay allows us to assess HSC differentiation in vivo, uncoupled
from HPCs. We propose to use this functional tool in combination with other molecular and genetic assays to
address the following aims: (1) Determine the differentiation potential of HSCs and HPCs in vivo and (2) Perform
a reverse genetic screen for regulators of HSC differentiation. Our findings can aid the efforts to generate HSCs
from alternative sources for clinical use.

## Key facts

- **NIH application ID:** 10877674
- **Project number:** 5F31HL167600-02
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Anastasia Nizhnik
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 5
- **Project period:** 2023-04-16 → 2026-04-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10877674

## Citation

> US National Institutes of Health, RePORTER application 10877674, Dissection of Hematopoietic Stem and Progenitor Cell Differentiation during Embryogenesis (5F31HL167600-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10877674. Licensed CC0.

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