Epigenetic and niche-specific regulation of human hematopoietic stem cell development in the fetal bone marrow

• Applicant: Dr. Stephanie Frenz-Wießner
• Subject Area: Pediatric and Adolescent Medicine ; Developmental Biology ; Hematology, Oncology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 553830629

Hematopoietic stem cells (HSCs) sustain life-long blood production by balanced self-renewal properties. The establishment of an homeostatic HSC reservoir during human development involves complex, poorly understood HSC maturation processes in multiple consecutive niches. Especially, the transition of HSCs from the fetal liver to the early human fetal bone marrow (BM) niche presents a crucial step with drastic shifts in HSC properties and lineage output in the BM but lacks mechanistic understanding. Our preliminary multi-omic single-cell analysis of human embryonic and fetal HSCs revealed distinct chromatin configurations of key transcription factor isoforms and HSC genes, indicating the importance of epigenetic signatures in defining stage- and location-specific HSC properties. To understand the intrinsic and extrinsic molecular cues that regulate human HSC development, with a focus on the transition to the early fetal BM niche, we propose to: 1. Determine an epigenetic regulatory map of human HSC development. 2. Define the organization of the fetal BM niche for HSC development. Understanding the intrinsic and extrinsic molecular mechanisms regulating human HSC development will improve the generation and ex vivo expansion of HSCs for clinical applications, and will shed light on the pathogenesis of pediatric leukemias originating in utero, potentially informing novel treatment approaches

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professorin Hanna Mikkola, Ph.D.