# Niche signals in HSC genesis

> **NIH NIH RC2** · FRED HUTCHINSON CANCER RESEARCH CENTER · 2020 · $640,964

## Abstract

PROJECT SUMMARY
Hematopoietic stem cells (HSC) have well established clinical applications in the treatment of heritable and
acquired blood disorders. However, their therapeutic potential could be significantly broadened by engineering
novel methods to generate HSC de novo from pluripotent stem cells or from directly reprogrammed adult cells.
Toward this goal, we have established endothelial cell (EC) niche based culture methods that provide the
necessary conditions to support the specification and self-renewal of HSC from embryonic hemogenic
precursors, and more recently, from adult ECs using transcription factor (TF)-mediated conversion that bypasses
a pluripotent intermediate. We hypothesize that recreating the signals necessary and sufficient to develop a
clinically meaningful system for HSC generation in vitro will necessitate a comprehensive, systems approach to
deconstruct the niche provided signals required for HSC specification and self-renewal. Thus, the overall goal of
this grant is to leverage unique expertise of the collaborating laboratories to elucidate the signaling interactions
regulating HSC specification and self-renewal from embryonic hemogenic precursors or TF-reprogrammed adult
EC in the context of the EC niche. Our approach consists of three overlapping aims. The first aim will identify EC
niche-provided signals necessary for embryonic HSC specification and self-renewal. The second aim will identify
the unique HSC programs induced by these signals that regulate the transition from embryonic hemogenic
precursor to bone fide repopulating HSC. The third will identify comparable programs that regulate the transition
from adult EC to HSC during TF-mediated reprogramming in the EC niche. Key to these studies will be innovative
functional assays, transcriptional profiling methods, and computational approaches that will enable us to resolve
cellular complexity of niche cells and their interactions with developing embryonic or reprogrammed HSC at the
single cell level. The role of identified signal factors in stage-specific support of HSC specification will be validated
and further refined in vitro by gain and loss of function studies in the context of niche EC. Furthermore, to extend
these studies to stromal cell-free systems as a step toward clinical translation, we will also test the contribution
of identified signal factors in HSC specification and self-renewal in the context of stage-specific modulation of
Notch activation using engineered Notch agonists. To achieve the goals of this proposal, we have developed a
multidisciplinary collaboration involving unique expertise in each of our laboratories, including basic HSC and
EC niche cell biology, direct TF based cellular conversion, clinical HSC transplantation, genome wide
assessment of rare stem cell populations at single cell resolution, and innovative computational approaches to
deconstruct core signal pathways regulating developmental transitions. Altogether, we expect the ...

## Key facts

- **NIH application ID:** 9979872
- **Project number:** 5RC2DK114777-04
- **Recipient organization:** FRED HUTCHINSON CANCER RESEARCH CENTER
- **Principal Investigator:** IRWIN D BERNSTEIN
- **Activity code:** RC2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $640,964
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9979872

## Citation

> US National Institutes of Health, RePORTER application 9979872, Niche signals in HSC genesis (5RC2DK114777-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9979872. Licensed CC0.

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