Uncovering the emergence of HSCs in the human fetal bone marrow by single-cell RNA-seq analysis.

During fetal development, human hematopoietic stem cells (HSCs) colonize the bone marrow (BM), where they self-renew and sustain hematopoiesis throughout life; however, the precise timepoint at which HSCs seed the BM is unclear. We used single-cell RNA-sequencing to map the transcriptomic landscape of human fetal BM and spleen hematopoietic stem/progenitor cells (HSPCs) and their microenvironment from 10 to 14 post-conception weeks (PCWs). We further demonstrated that functional HSCs capable of reconstituting long-term multi-lineage hematopoiesis in adult NOG mice do not emerge in the BM until 12 PCWs. In contrast, functional HSCs were not detected in the spleen by 14 PCWs. By comparing the niche-HSPC interactions between BM and spleen, we identified ligand-receptor pairs likely to be involved in fetal HSC migration and maintenance. Our work paves the way for research into the mechanisms underlying HSC colonization in human fetal BM and provides invaluable resources for future studies on HSC development.

Zheng Z ，He H ，Tang XT ，Zhang H ，Gou F ，Yang H ，Cao J ，Shi S ，Yang Z ，Sun G ，Xie X ，Zeng Y ，Wen A ，Lan Y ，Zhou J ，Liu B ，Zhou BO ，Cheng T ，Cheng H ... -  《-》

Circulation and chemotaxis of fetal hematopoietic stem cells.

Christensen JL ，Wright DE ，Wagers AJ ，Weissman IL ... -  《-》

Murine fetal bone marrow does not support functional hematopoietic stem and progenitor cells until birth.

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.

Hall TD ，Kim H ，Dabbah M ，Myers JA ，Crawford JC ，Morales-Hernandez A ，Caprio CE ，Sriram P ，Kooienga E ，Derecka M ，Obeng EA ，Thomas PG ，McKinney-Freeman S ... -  《-》

Mobilization dynamics of bone marrow hematopoietic stem cells during hematopoietic regeneration.

Under stress hematopoiesis, previous studies have suggested the migration of hematopoietic stem cells (HSCs) from bone marrow (BM) to extramedullary sites such as the spleen. However, there is little direct evidence of HSC migration from the BM to the spleen. Here, we induced myeloablation via 5-fluorouracil (5-FU) and showed direct evidence of HSC migration from BM to spleen during hematopoietic regeneration via a photoconvertible fluorophore. Moreover, during steady state, HSCs preferentially migrated to BM rather than spleen, but during hematopoietic regeneration, HSCs preferred spleen as a migration site equivalently or greater. Furthermore, in the early phase, HSCs egressed from BM through the attenuated HSC retention. However, HSCs in the late phase gained significantly enhanced cell-autonomous motility, which was independent of chemotaxis. Collectively, HSC mobilization from BM, before the migration to the spleen, was dynamically changed from passive to active events during hematopoietic regeneration.

Johansson A ，Khalilnezhad A ，Takizawa H ，Mizuno H ，Suda T ，Umemoto T ... -  《-》

Single-cell RNA sequencing to track novel perspectives in HSC heterogeneity.

As the importance of cell heterogeneity has begun to be emphasized, single-cell sequencing approaches are rapidly adopted to study cell heterogeneity and cellular evolutionary relationships of various cells, including stem cell populations. The hematopoietic stem and progenitor cell (HSPC) compartment contains HSC hematopoietic stem cells (HSCs) and distinct hematopoietic cells with different abilities to self-renew. These cells perform their own functions to maintain different hematopoietic lineages. Undeniably, single-cell sequencing approaches, including single-cell RNA sequencing (scRNA-seq) technologies, empower more opportunities to study the heterogeneity of normal and pathological HSCs. In this review, we discuss how these scRNA-seq technologies contribute to tracing origin and lineage commitment of HSCs, profiling the bone marrow microenvironment and providing high-resolution dissection of malignant hematopoiesis, leading to exciting new findings in HSC biology.

Zhang P ，Li X ，Pan C ，Zheng X ，Hu B ，Xie R ，Hu J ，Shang X ，Yang H ... -  《Stem Cell Research & Therapy》