PubMed · 40971295
Differentiation latency and dormancy signatures define fetal liver hematopoietic stem cells at single-cell resolution.
Abstract
Decoding the mechanisms governing the self-renewal of hematopoietic stem cells (HSCs) during their expansion in the fetal liver (FL) could unlock novel therapeutic strategies to expand transplantable HSCs, a long-standing challenge. To explore intrinsic and extrinsic regulation of FL-HSC self-renewal at single-cell resolution, we engineered a culture platform replicating the FL endothelial niche that supports the amplification of serially engraftable HSCs. Leveraging this platform together with single-cell index flow cytometry, live imaging, transplantation assays, and single-cell RNA sequencing, we demonstrate that differentiation latency, cell-division symmetry, and transcriptional signatures of biosynthetic dormancy are distinguishing properties of rare FL-HSCs capable of serial multilineage hematopoietic reconstitution. Our findings support a paradigm in which intrinsic programs and niche-derived signals together facilitate the symmetric self-renewal of FL-HSCs while delaying their active participation in hematopoiesis. Our study also provides a resource for future investigations into intrinsic and extrinsic signaling pathways governing FL-HSC self-renewal.
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Takashi Ishida, Juliane Mercoli, Adam M Heck, Ian Phelps, Barbara Varnum-Finney, Stacey Dozono, Cynthia Nourigat-McKay, Katie Kraskouskas, Rachel Wellington, Olivia Waltner, Dana L Jackson, Colleen Delaney, Shahin Rafii, Irwin D Bernstein, Kimberly A Aldinger, Birth Defects Research Laboratory (BDRL),, Cole Trapnell, Helong G Zhao, Brandon Hadland. 2025-09-18. Differentiation latency and dormancy signatures define fetal liver hematopoietic stem cells at single-cell resolution.. https://doi.org/10.1016/j.celrep.2025.116289
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