Year: 2025
Type: article
Abstract: Self-renewing hematopoietic stem cells (HSCs) generate all blood cells and give rise to long-term reconstitution of the hematopoietic system after transplantation, but the molecular mechanisms that specifically regulate HSCs remain poorly defined. Here, we found that HSCs displayed a distinct messenger RNA alternative splicing pattern and preferentially expressed Rbfox2 , an alternative splicing regulator, compared with multipotent progenitors (MPPs). Deletion of Rbfox2 from the hematopoietic compartment specifically depleted HSCs, but not progenitors in the adult bone marrow. Rbfox1 did not function redundantly with Rbfox2 in HSCs. Mechanistically, Rbfox2 loss led to proteostasis stress, including increased protein synthesis rate and accumulated misfolded/unfolded protein contents, in HSCs, but not in progenitors. Small molecules that restore proteostasis rescued HSC defects in Rbfox2 -deficient mice. Our work thus reveals that HSCs, but not progenitors, selectively rely on Rbfox2 for their self-renewal and maintenance.
Source: Science Advances
Authors: Longfei Gao, Desmond Dickson, Huijuan Feng, Chaolin Zhang, Lei Ding
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,500
Funders: National Science Foundation, American Heart Association, Rita Allen Foundation, Leukemia and Lymphoma Society, Irma T. Hirschl Trust, New York State Stem Cell Science, National Institutes of Health, National Heart, Lung, and Blood Institute, NIH Office of the Director, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke
Awards: G1640258492, Track 4: Advanced CI Coordination Ecosystem: Monitoring and Measurement Services, G1942050796, G1988905891, G31132299, G3823197303, Track 1: ACCESS Resource Allocations Marketplace and Platform Services (RAMPS), G4252471225, G4471275195, ACO: An Open CI Ecosystem to Advance Scientific Discovery (OpenCI), Track 3: COre National Ecosystem for CyberinfrasTructure (CONECT), G5412191109, Track 2: Customized Multi-tier Assistance, Training, and Computational Help (MATCH) for End User ACCESS to CI, Understanding the Nature and Regulation of Extramedullary Hematopoiesis in the Liver, Developing Next Generation Genetics for Understanding Hematopoietic Stem Cell Biology, Cancer Center Support Grant
OpenAlex ID: W4416965505