Investigating the developmental programming of hematopoietic stem and progenitor cells

The National Heart, Lung, and Blood Institute awarded the University of Wisconsin - Madison $152,168 on February 5, 2026, under the Cardiovascular Diseases Research program (CFDA 93.837) to investigate the developmental programming of hematopoietic stem and progenitor cells using an integrin A4 mutant zebrafish model.

The research characterizes how hematopoietic stem and progenitor cells interact with their microenvironment during mammalian development. The award funds analysis of transcriptomic and epigenomic differences between wild-type and integrin A4 mutant hematopoietic stem and progenitor cells after their migration from the caudal hematopoietic tissue niche to the presumptive adult kidney marrow niche. The work includes gene set enrichment analysis and chromatin accessibility analysis to identify regulatory factors controlling hematopoietic stem and progenitor cell reprogramming and maturation, with particular focus on inflammatory signaling pathways and transcription factors such as ETS1 and AP-1. Study aims include characterizing the proliferative capacity, inflammatory profile, and stem cell capacity of hematopoietic stem and progenitor cells that successfully or unsuccessfully lodge in the developmental niche.

Performance runs from February 5, 2026, through August 31, 2027, at the Madison, Wisconsin campus. The University of Wisconsin System, operating through its University of Wisconsin - Madison division, is the recipient.

Abstract

Hematopoietic stem and progenitor cells (hspcs) reside in a microenvironment that regulates their behavior by interactions with niche support cells. During development of the mammalian embryo hspcs are born in the dorsal aorta and migrate to the fetal liver, where they expand and differentiate. Fetal liver hspcs are proliferative and when transplanted have a greater capacity for reconstituting the blood system compared to quiescent adult hspcs. However, the genetic networks regulating fetal liver hspcs, and their maturation, are poorly understood. To dissect these networks, we are characterizing a viable integrin Α4 (ITGA4) mutant zebrafish model with perturbed interaction between hspcs and the mammalian fetal liver equivalent-the caudal hematopoietic tissue (CHT). Preliminary analysis of hspcs at 5 days post fertilization (DPF), after migration from the CHT to the presumptive adult kidney marrow niche, detected transcriptomic and epigenomic differences between wild-type (WT) and ITGA4 mutant hspcs, indicating reprogramming of hspcs after interaction with the CHT niche. Gene set enrichment analysis (gsea) of differentially expressed genes between WT and ITGA4 mutant hspcs showed enrichment of inflammatory signaling in ITGA4 mutant hspcs which did not lodge in the CHT niche. Motif analysis of accessible chromatin regions unique to ITGA4 mutant hspcs revealed potential regulatory factors of hspc reprogramming, such as ETS1 and AP-1 factors. We hypothesize that bypass of the CHT niche prevents correct hspc programming and transition to quiescence, causing ITGA4 mutant hspcs to remain in an immature state. In aim 1, we will analyze the proliferative capacity, inflammatory profile, and stem cell capacity of hspcs that did (WT) or did not lodge in the CHT niche (ITGA4 mutant) to characterize the programming event initiated by ITGA4-mediated interactions between hspcs and the CHT niche. In aim 2, we will map the epigenomic landscape and perform multiomic analysis of WT and ITGA4 mutant hspcs to determine the gene regulatory networks underlying the developmental switch of hspcs from proliferation to quiescence. We will utilize our unique zebrafish system and multiomic approaches to dissect the developmental networks of hspc regulation. By understanding the transitions between proliferative and quiescent hspc states, our findings could translate into novel approaches for stem cell expansion and improved stem cell therapy.