PubMed · 16978049
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Nagwa S El-Badri. 2006. The mesenchymal stem cell advantage.. https://doi.org/10.1089/scd.2006.15.473
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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.
Hematopoietic stem cells (HSCs) rapidly expand during fetal development and after stress. Here, we identify B-cell lymphoma-2-associated factor 1 (BCLAF1) as a regulator of HSC repopulation activity, with roles in the expansion of fetal HSCs and hematopoietic reconstitution after stem cell transplantation. Using mice with hematopoietic-specific and inducible deletion of Bclaf1, we find that BCLAF1 promotes fetal HSC development but is dispensable for the maintenance of adult HSCs at steady state. Loss of BCLAF1 in either fetal or adult HSCs significantly impairs their self-renewal and multilineage reconstitution activity after stem cell transplantation. Single-cell RNA sequencing of fetal hematopoietic progenitors reveals that loss of BCLAF1 reduces long-term HSCs and restrains the expression of stress response genes. BCLAF1 associates with chromatin throughout the genome of fetal and adult hematopoietic cells, likely through indirect mechanisms, to regulate transcriptional programs. These results establish a novel function for the transcriptional regulator BCLAF1 in limiting stress responses in HSCs, thereby preserving HSC development during embryogenesis and repopulation function after stem cell transplant.
Intrahepatic splenosis is a rare disorder of ectopic erythropoiesis in the liver. Although traumatic splenic rupture is the common factor in public cases, the mechanism of long latency is still unknown. The correlation between aging and hepatitis virus infection with the diagnosed occurrence was reported in a limited number of cases; nevertheless, it suggested that ectopic erythropoiesis in the liver could be induced by the hepatic disorder. Based on the susceptibility of the splenic erythropoiesis response to hypoxia and the inevitability of hypoxia caused by aging or pathological changes, we hypothesized that the two events caused the occurrence of the intrahepatic splenosis, the migration of the erythrocytic progenitor cells via the portal vein following traumatic splenic rupture, and the local induction of erythropoiesis by hypoxia.