Flow Upregulated Scap Dictates Hematopoiesis
Authors: Fang Longhou 
Published: December 2024

Surbhi Chauhary1, Michihiro Kobayashi2, Pamela Wenzel3, Momoko Yoshimoto2, Longhou Fang1,4
1Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute. Houston Methodist, 6550 Fannin Street, Texas 77030, USA.
2Center for Immunology, Department of Investigative Medicine, Western Michigan University Homer Stryker MD School of Medicine
3Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States.
4Physiology, Biophysics, and Systems Biology Program, Weill Cornell Medical College, Cornell University, New York 10065, USA.
Deficiencies in hematopoietic stem cell (HSC) donor sources are a significant cause of poor engraftment outcomes in patients with myelodysplasia and other hematopoietic disorders. The imperative to enhance HSC quality has driven extensive research into the developmental processes of HSCs, particularly through the endothelial-to-hematopoietic transition. Among the myriad regulators of hematopoiesis, mechanoregulatory pathways have emerged as pivotal players in HSC development. Within the anatomical hotspots of HSC specification, blood flow-generated forces activate two closely related mechanosensitive transcriptional cofactors, Yes-associated protein (YAP) and transcriptional coactivator with a PDZ-binding domain (TAZ). While YAP and TAZ can function independently, YAP has been reported to support HSC specification1. However, the role of TAZ in HSC specification remains unknown.
Our preliminary studies have established a functional role for TAZ in HSC specification. This HSC fate determination occurs from hemogenic endothelial cells (HECs), a rare population of endothelial cells with hematopoietic potential. We found that blood flow activates TAZ in HECs, which in turn upregulates SCAP, a chaperone that binds and activates sterol regulatory element-binding protein 1 (SREBP1). SCAP subsequently increases the expression of SREBP1-regulated polyunsaturated fatty acid (PUFA) target genes2. Functionally, we demonstrated that the knockout of TAZ, SCAP, or SREBP1 impairs hematopoiesis in mice and zebrafish. These preliminary studies and existing literature suggest an essential signaling pathway in HSC specification, wherein flow-activated TAZ promotes SCAP/SREBP1-mediated PUFA biosynthesis. Understanding these regulatory mechanisms will reveal a novel innate pathway-endogenous PUFA biosynthesis-for HSC specification.
Our research team has pioneered the study of biomechanical forces3, 4 and cholesterol metabolism5 in hematopoiesis. We recently showed that SREBP2, the master transcription factor of cholesterol biosynthesis, which is also activated by SCAP, controls HSC specification. Surprisingly, cholesterogenic activity remains unchanged or even suppressed in HECs under flow conditions4. Thus, our project focusing on SREBP1-regulated PUFA biosynthesis aims to uncover previously unknown mechanisms dictating HSC fate. Insights gained from this research could pave the way for novel therapeutic strategies in HSC generation.
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