# Reprogramming Gene Regulatory Networks to a Hematopoietic Stem Cell State

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2024 · $511,437

## Abstract

PROJECT SUMMARY/ABSTRACT
 Hematopoiesis is a continuous process of blood-cell production occurring through the orchestrated activity
of hematopoietic stem cells (HSCs). Although HSCs have tremendous clinical utility due to their ability to
reconstitute the hematopoietic system by transplantation, their benefit remains limited by the lack of matched
donors. Direct reprogramming of endothelial cells into HSCs via induction of reprogramming factors has recently
emerged as a promising alternative. The overall goal of our proposal is to reveal the molecular mechanisms by
which the reprogramming factors FOSB, GFI1, RUNX1, and SPI1 (FGRS) revert endothelial cells to functional
reprogrammed HSCs (reHSCs). Understanding the basis by which the genetic networks become rewired for this
profound cell type conversion will provide insights into diverse forms of reprogramming, development, and
disease. We discovered that early in the reprogramming process, FGRS directly coordinate two tasks: selection
and activation of multipotent HSC enhancers and disruption of endothelial enhancers and transcription factors
(TFs). We hypothesize that the effect of FGRS on endothelial TF binding is as crucial for reprogramming as the
activation of multipotency enhancers, and we propose to dissect the underlying molecular mechanisms for these
processes. Using single-cell multiomic (scRNA & ATAC-seq) profiling, we further discovered that in intermediate
reprogramming, the relatively homogenous starting endothelial cells are replaced by heterogeneous HSC
populations. How the transition from somatic (endothelial) to multipotent (HSC) regulatory programs occurs in
individual cells undergoing in vitro reprogramming remains unknown. To potentiate in vivo reprogramming, we
generated a novel transgenic mouse model that allows constant FGRS expression in all somatic tissues and
facilitates the recording of all key bifurcating events that lead to HSC establishment and maintenance. Based on
our studies, we propose to dissect the molecular and cellular mechanisms by which FGRS promote cell fate
changes in the context of endothelial-to-HSC reprogramming. In our first aim, we will uncover the molecular
mechanisms by which FGRS target and modulate endothelial and HSC gene regulatory networks. In the second
aim, we will delineate the intrinsic and extrinsic signaling pathways that promote endothelial-to-HSC
reprogramming. We expect that our program will yield fundamental insights into the control of mammalian cell
identity and may lead to novel strategies to generate therapeutically relevant HSCs with high efficiency.

## Key facts

- **NIH application ID:** 10863810
- **Project number:** 5R01HL170286-02
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Konstantinos Chronis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $511,437
- **Award type:** 5
- **Project period:** 2023-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10863810

## Citation

> US National Institutes of Health, RePORTER application 10863810, Reprogramming Gene Regulatory Networks to a Hematopoietic Stem Cell State (5R01HL170286-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10863810. Licensed CC0.

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