Mystery cells that create blood stem cells in mammals identified
Imagine if one-day blood transfusions from strangers were not needed because they could be produced from cells that line your blood vessels.
medical researchers at UNSW Sydney have made an important first step by identifying—in mice—a mechanism that is used naturally in mammals to make blood from cells that line blood vessels. the identity of the cells that regulate this process had up until now been a mystery.
In a paper published recently in the journal Nature Cell Biology, a team of researchers describes how they solved this puzzle by identifying the cells in the embryo that can convert adult endothelial cells into blood stem cells. The cells are known as "Mesp1-derived PDGFRA+ stromal cells".
In mouse embryos, the first HSCs appear mid-gestationally (embryonic day 10.5, E10.5) from haemogenic endothelial cells lining the ventral surface of the dorsal aorta through endothelial-to haematopoietic transition (EHT) in a region known as the aorta gonad mesonephros (AGM).
These HSCs are amplified in the fetal liver and the placenta; they take up residence in the bone marrow, which will serve as the major adult site of haematopoiesis.
Haemogenic endothelium is specified between E8.5 and E10.5 and progresses through pre-HSC stages to generate HSCs in the AGM between E10.5 and E12.5.
The development of HSCs in the AGM is influenced by NOTCH19, WNT20, BMP21,22, and other signals from surrounding cells. These signals facilitate haematopoiesis in part by regulating the expression of critical haematopoietic transcription factors, including components of the FLI1, GATA2, and SCL transcriptional network, GFI1–GFI1B, and RUNX1.
mesoderm-derived PDGFRA+ stromal cells (Mesp1der PSCs) contribute to the haemogenic endothelium of the dorsal aorta and populate the E10.5–E11.5 aorta– gonad mesonephros but by E13.5 were replaced by neural-crest-derived PSCs (Wnt1der PSCs).
Co-aggregating non-haemogenic endothelial cells with Mesp1der PSCs but not Wnt1der PSCs resulted in activation of a haematopoietic transcriptional programme in endothelial cells and generation of LT-HSCs. Dose-dependent inhibition of PDGFRA or BMP, WNT, and NOTCH signalling interrupted this reprogramming event.
aorta–gonad–mesonephros Mesp1der PSCs could potentially be harnessed to manufacture LT-HSCs from endothelium.
the discovery could be an important step in regenerative medicine by providing a potential new tool to generate engraftable hematopoietic stem cells. more research is needed before this can be translated into clinical practice.
Mystery cells that create blood stem cells in mammals identified
Chandrakanthan, V., Rorimpandey, P., Zanini, F. et al. Mesoderm-derived PDGFRA+ cells regulate the emergence of hematopoietic stem cells in the dorsal aorta. Nat Cell Biol 24, 1211–1225 (2022). https://doi.org/10.1038/s41556-022-00955-3
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