# Role and Regulation of a Novel, Developmentally Restricted Hematopoietic Stem Cell

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA SANTA CRUZ · 2022 · $455,327

## Abstract

PROJECT SUMMARY/ABSTRACT
Our long-term research goals are to understand the mechanisms that regulate stem cell fate decisions. In this
first renewal application of this award, we propose to pursue the regulation of self-renewal and lineage potential
of the developmentally restricted hematopoietic stem cells (drHSCs) that we discovered in the current award
period. Although this population fulfills the most stringent criteria for functional HSC, their life-span during normal
development is restricted to a limited developmental window. A functional HSC that does not persist into
adulthood had never been observed before and therefore defines a novel wave of definitive hematopoiesis with a
distinct endpoint. Here, we focus on understanding the contradictory regulation of drHSC self-renewal and
multipotency: upon transplantation, drHSC self-renewal is induced, whereas their intrinsic lineage bias is
preserved. Amazingly, the latter – lymphoid bias and exceptional B1a reconstitution potential – is maintained
over many months even upon the repeated stress of serial transplantation. In contrast, a single, short-term
exposure to stress induces the ability of drHSCs to persist long-term. We propose to pursue the epigenetic
mechanisms governing this paradox. We will perform comprehensive molecular and cellular comparisons of
drHSCs, co-existing fetal liver HSCs, and adult HSCs, and pursue rigorous functional analysis in competitive
reconstitution assays. Importantly, we will couple single-cell transcriptional profiles with functional HSC capacity
in efficient yet rigorous in vivo assays. Using CRISPRi/a-mediated transcriptional manipulation, we will directly
test the requirements for reprogramming HSC self-renewal and lineage potential in vivo. Our transgenic models
are uniquely suited for understanding how the core properties of HSCs – self-renewal and multilineage potential -
are established during development and maintained for life and we are excited to put these powerful tools to
work to pioneer developmental hematopoietic fate decisions.

## Key facts

- **NIH application ID:** 10407592
- **Project number:** 5R01DK100917-08
- **Recipient organization:** UNIVERSITY OF CALIFORNIA SANTA CRUZ
- **Principal Investigator:** CAMILLA FORSBERG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $455,327
- **Award type:** 5
- **Project period:** 2013-09-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10407592

## Citation

> US National Institutes of Health, RePORTER application 10407592, Role and Regulation of a Novel, Developmentally Restricted Hematopoietic Stem Cell (5R01DK100917-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10407592. Licensed CC0.

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