p57Kip2 regulates embryonic haematopoietic stem cell numbers by controlling the size of the sympathoadrenal progenitor pool

Haematopoietic stem cells (HSCs) are of major clinical importance, and finding methods for their in vitro generation is a prime research focus. We demonstrate that the cell cycle inhibitor p57Kip2/Cdkn1c limits HSC numbers by restricting the size of the sympathetic nervous system (SNS) and the amount of HSC-supportive catecholamines secreted by these cells, specifically in the aorta-gonads-mesonephros (AGM) region via {beta}2-adrenergic receptor signalling. This regulation occurs at the SNS progenitor level and is in contrast to the cell-intrinsic function of p57Kip2 in maintaining adult HSCs. Using single-cell RNA-Seq we dissect the differentiation pathway of neural crest cells into SNS cells in the AGM and reveal that they are able to take an alternative differentiation pathway, giving rise to a subset of mesenchymal cells expressing HSC-supportive factors. Neural crest cells thus appear to contribute to the AGM HSC niche via two different mechanisms: SNS-mediated catecholamine secretion and HSC-supportive mesenchymal cell production.