# Defining regulators of hematopoietic stem cell self-renewal and lineage potential

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA SANTA CRUZ · 2020 · $37,805

## Abstract

PROPOSAL SUMMARY
The goal of my proposal is to understand the mechanisms regulating the self-renewal and lineage potential of
hematopoietic stem cells (HSCs) and how HSC fate and function can be controlled by manipulation of
epigenetic parameters. The context of my study is unique, because we have discovered a fetal,
developmentally restricted HSC (drHSC) with unusual properties: the drHSCs are capable of long-term,
multilineage reconstitution (LTMR) upon serial transplantation, but do not persist into adulthood during normal
development. The ability of drHSCs to self-renew and persist is therefore induced upon transplantation.
Further, while capable of generating all the “traditional” hematopoietic cell types investigated to date, the
drHSCs are lymphoid biased and have superior B1a cell reconstitution capacity compared to the co-existing
fetal liver (FL) HSCs. Amazingly, the lymphoid bias and B1a capacity are retained over many months in serial
transplantation experiments. The two core properties that define functional HSCs – self-renewal and
lineage potential – are therefore uniquely regulated in drHSCs. I will leverage these unique properties to
understand the molecular and epigenetic mechanisms that govern HSC fate and function, and how these
mechanisms are both stable (as in the case of drHSC lineage potential) and dynamic (as in the case of
induced persistence). I will also take advantage of my ability to isolate three distinct populations of HSCs: the
drHSCs, co-existing fetal HSCs (fHSCs), and adult HSCs (aHSCs). Together, this will enable me to ask
fundamental questions in HSC biology from a unique perspective and with novel strategies: How is long-term
persistence of drHSCs induced upon transplantation, whereas their lineage bias is retained? Is lineage
potential exclusively a loss-of-function phenomenon or do adult HSCs have differentiation capabilities that fetal
HSCs lack? If so, how are these gained? How can one HSC population be “reprogrammed” into another HSC
subtype? I propose to pursue these questions by assessing epigenetic and transcriptome dynamics (Aim 1),
and by functionally manipulating HSC potential using CRISPRi mouse models (Aim 2). Outcomes from this
proposal will be provide fundamental proof-of-concept experiments for HSC manipulation with the long-term
goal of applying these tools to increase the efficacy of stem cell transplant therapies.

## Key facts

- **NIH application ID:** 9911115
- **Project number:** 1F31HL151199-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA SANTA CRUZ
- **Principal Investigator:** Atesh K Worthington
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $37,805
- **Award type:** 1
- **Project period:** 2020-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9911115

## Citation

> US National Institutes of Health, RePORTER application 9911115, Defining regulators of hematopoietic stem cell self-renewal and lineage potential (1F31HL151199-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9911115. Licensed CC0.

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