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While adult bone marrow (BM) hematopoietic stem and progenitor cells (HSPCs) and their extrinsic regulation is well studied, little is known about the composition, function, and extrinsic regulation of the first HSPCs to enter the BM during development. Here, we functionally interrogate murine BM HSPCs from E15.5 through P0. Our work reveals that fetal BM HSPCs are present by E15.5, but distinct from the HSPC pool seen in fetal liver, both phenotypically and functionally, until near birth. We also generate a transcriptional atlas of perinatal BM HSPCs and the BM niche in mice across ontogeny, revealing that fetal BM lacks HSPCs with robust intrinsic stem cell programs, as well as niche cells supportive of HSPCs. In contrast, stem cell programs are preserved in neonatal BM HSPCs, which reside in a niche expressing HSC supportive factors distinct from those seen in adults. Collectively, our results provide important insights into the factors shaping hematopoiesis during this understudied window of hematopoietic development., (© 2022. The Author(s).)

Hematopoietic stem and progenitor cells (HSPCs) govern the daily expansion and turnover of billions of specialized blood cells. Given their clinical utility, much effort has been made toward understanding the dynamics of hematopoietic production from this pool of stem cells. An understanding of hematopoietic stem cell clonal dynamics during blood ontogeny could yield important insights into hematopoietic regulation, especially during aging and repeated exposure to hematopoietic stress-insults that may predispose individuals to the development of hematopoietic disease. Here, we review the current state of research regarding the clonal complexity of the hematopoietic system during embryogenesis, adulthood, and hematologic disease., (Copyright © 2020 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)

Hematopoietic stem and progenitor cells (HSPCs) maintain hematopoiesis throughout the lifetime of an organism. HSPC dysfunction can lead to disorders such as myelodysplastic syndrome (MDS). Spliceosome mutations are prevalent in MDS, but how splicing regulates HSPCs remains poorly understood. Using a zebrafish loss-of-function mutant for the top mutated splicing factor in MDS, splicing factor 3b, subunit 1 (sf3b1), we found that impaired splicing hindered HSPC specification. To identify Sf3b1-regulated transcripts, we performed RNA-sequencing on kdrl:gfp+ endothelial cells from sf3b1 mutant and unaffected siblings at 24hpf. ∼900 genes were mis-spliced with significant enrichment for Signaling Transducer and Activator of Transcription 3 (Stat3) pathway components. Mis-spliced Stat3 signaling components observed in sf3b1 mutants were predicted to dampen protein levels or inhibit functionality, and Stat3 target genes were significantly downregulated in sf3b1 mutants. Constitutively-active Stat3 overexpression in sf3b1 mutants partially suppressed the HSPC defect. Induced mis-splicing of stat3 using morpholinos caused a significant HSPC decrease in sf3b1 heterozygotes at 28hpf, but elicited no effect in wildtype embryos, demonstrating a synthetic lethal interaction. Inhibiting Stat3 with small molecule STATTIC similarly reduced HSPCs in heterozygous but not wildtype embryos. We next tested if STAT3 inhibition selectively affected SF3B1-mutated human cells. K562 cells expressing the MDS-associated SF3B1-K666N mutation were more sensitive to STAT3 inhibition with STATTIC than wildtype cells. Similarly, primary SF3B1-mutant MDS patient cells produced fewer hematopoietic colonies when treated with STATTIC than controls. Together, STAT3 inhibition is a conserved synthetic lethal vulnerability for SF3B1-mutated cells with potential to treat splicing factor-mutated MDS. [ABSTRACT FROM AUTHOR]