# Mechanisms of Flow-driven Transcriptional Control of Hematopoietic Stem Cell Development by YAP

> **NIH NIH K01** · BOSTON CHILDREN'S HOSPITAL · 2022 · $153,846

## Abstract

Project Summary/Abstract
 Hematopoietic stem cells (HSCs) are capable of producing all erythroid, myeloid and lymphoid blood
cells of an organism. Coupled with their unique capacity for self-renewal, successful transplantation of healthy
HSCs is the only therapy currently available that can completely replace and restore the blood system in patients
with leukemia and lymphoma. Despite this need, HSCs presently cannot be efficiently created or cultured in vitro,
suggesting that extrinsic factors supporting their growth and development in vivo are lacking from existing
protocols. Previous work from our lab demonstrated that blood flow is an essential non-genetic environmental
cue required for HSC production in vertebrate embryos, mediated in part by stimulating mechanical activation of
the Yes-associated protein (YAP) transcription factor (TF). This proposal intends to resolve the physical, genetic
and molecular mechanisms underlying mechanically-activated, YAP-driven HSC production. YAP, while a potent
co-activator of gene expression, lacks DNA-binding ability of its own. To understand the molecular logic behind
flow/YAP-driven hematopoiesis, the goal of the first aim is to employ chemical, physical and genetic perturbation
of shear stress and cyclic stretch in live zebrafish embryos to assess the impact of these individual components
of hemodynamic force on HSC production from hemogenic endothelium (HE). To this will be added tissue-
specific transcriptomic and genome-wide YAP/DNA interaction profiling from sorted HE from wildtype zebrafish,
flow-deficient and yap-/- animals (with normal blood flow) in order to discriminate flow-dependent gene regulatory
modules and transcriptional targets that rely on YAP. Hypothesis-driven candidate TFs will be tested in vivo and
in vitro to evaluate YAP-interaction ability and uncover key partners required for normal YAP-dependent
hematopoiesis. In the second aim, the zebrafish system will be used to investigate candidate membrane-
localized proteins, Piezos and Integrins, as components linking hemodynamic forces with YAP activation. These
studies stand to provide a comprehensive “membrane-to-nucleus” paradigm for how blood flow activates YAP
to guide developmental hematopoiesis, which may improve current efforts to generate or expand HSCs.
 As a postdoctoral fellow, Dr. Sugden will conduct his research in the laboratory of Dr. Trista North at
Boston Children's Hospital. Her expertise in extrinsic regulation of developmental hematopoiesis, together with
dedicated co-mentorship by Dr. George Daley (an expert in stem cell biology and hematology) and a strong
advisory team provide an exceptionally well-supported environment for career development and research
training. Dr. Sugden will build on a solid background in developmental genetics and live-imaging, by adding new
technologies in transcription factor/DNA interaction profiling, transcriptomics and in vitro methods to study protein
interactions. A rigorous res...

## Key facts

- **NIH application ID:** 10425468
- **Project number:** 5K01DK129409-02
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Wade William Sugden
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $153,846
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10425468

## Citation

> US National Institutes of Health, RePORTER application 10425468, Mechanisms of Flow-driven Transcriptional Control of Hematopoietic Stem Cell Development by YAP (5K01DK129409-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10425468. Licensed CC0.

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