PUBLICATION
Haematopoietic stem and progenitor cell heterogeneity is inherited from the embryonic endothelium
- Authors
- Ghersi, J.J., Baldissera, G., Hintzen, J., Luff, S.A., Cheng, S., Xia, I.F., Sturgeon, C.M., Nicoli, S.
- ID
- ZDB-PUB-230718-35
- Date
- 2023
- Source
- Nature cell biology 25(8): 1135-1145 (Journal)
- Registered Authors
- Ghersi, Joey, Hintzen, Jared, Nicoli, Stefania
- Keywords
- none
- Datasets
- GEO:GSE210942, GEO:GSE210941, GEO:GSE210940
- MeSH Terms
-
- Animals
- Cell Differentiation/genetics
- Endothelium
- Hemangioblasts*
- Hematopoiesis/genetics
- Hematopoietic Stem Cells/metabolism
- Humans
- MicroRNAs*/metabolism
- Zebrafish/genetics
- PubMed
- 37460694 Full text @ Nat. Cell Biol.
Citation
Ghersi, J.J., Baldissera, G., Hintzen, J., Luff, S.A., Cheng, S., Xia, I.F., Sturgeon, C.M., Nicoli, S. (2023) Haematopoietic stem and progenitor cell heterogeneity is inherited from the embryonic endothelium. Nature cell biology. 25(8):1135-1145.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping