Haematopoietic stem and progenitor cell heterogeneity is inherited from the embryonic endothelium


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Joey J Ghersi , Gabriel Baldissera , Jared Hintzen, Stephanie A Luff, Siyuan Cheng , Ivan Fan Xia , Christopher M Sturgeon , Stefania Nicoli Nat Cell Biol 2023 Jul 17. doi: 10.1038/s41556-023-01187-9. Online ahead of print. PMID: 37460694


Definitive haematopoietic stem and progenitor cells (HSPCs) generate erythroid, lymphoid and myeloid lineages. HSPCs are produced in the embryo via transdifferentiation of haemogenic endothelial cells in the aorta-gonad-mesonephros (AGM). HSPCs in the AGM are heterogeneous in differentiation and proliferative output, but how these intrinsic differences are acquired remains unanswered. Here we discovered that loss of microRNA (miR)-128 in zebrafish leads to an expansion of HSPCs in the AGM with different cell cycle states and a skew towards erythroid and lymphoid progenitors. Manipulating miR-128 in differentiating haemogenic endothelial cells, before their transition to HSPCs, recapitulated the lineage skewing in both zebrafish and human pluripotent stem cells. miR-128 promotes Wnt and Notch signalling in the AGM via post-transcriptional repression of the Wnt inhibitor csnk1a1 and the Notch ligand jag1b. De-repression of cskn1a1 resulted in replicative and erythroid-biased HSPCs, whereas de-repression of jag1b resulted in G2/M and lymphoid-biased HSPCs with long-term consequence on the respective blood lineages. We propose that HSPC heterogeneity arises in the AGM endothelium and is programmed in part by Wnt and Notch signalling.


Cells utilized in this study were obtained from the Cell Prep & Analysis Core at the Yale Cooperative Center of Excellence in Hematology (NIH/NIDDK U54 DK106857).




Publication: 2023-08-07