| Literature DB >> 35484246 |
Stephanie A Luff1,2,3, J Philip Creamer3, Sara Valsoni4, Carissa Dege3, Rebecca Scarfò4, Analisa Dacunto1,2, Sara Cascione4, Lauren N Randolph4, Eleonora Cavalca4, Ivan Merelli4,5, Samantha A Morris6,7, Andrea Ditadi8, Christopher M Sturgeon9,10,11.
Abstract
The generation of haematopoietic stem cells (HSCs) from human pluripotent stem cells (hPSCs) is a major goal for regenerative medicine. During embryonic development, HSCs derive from haemogenic endothelium (HE) in a NOTCH- and retinoic acid (RA)-dependent manner. Although a WNT-dependent (WNTd) patterning of nascent hPSC mesoderm specifies clonally multipotent intra-embryonic-like HOXA+ definitive HE, this HE is functionally unresponsive to RA. Here we show that WNTd mesoderm, before HE specification, is actually composed of two distinct KDR+ CD34neg populations. CXCR4negCYP26A1+ mesoderm gives rise to HOXA+ multilineage definitive HE in an RA-independent manner, whereas CXCR4+ ALDH1A2+ mesoderm gives rise to HOXA+ multilineage definitive HE in a stage-specific, RA-dependent manner. Furthermore, both RA-independent (RAi) and RA-dependent (RAd) HE harbour transcriptional similarity to distinct populations found in the early human embryo, including HSC-competent HE. This revised model of human haematopoietic development provides essential resolution to the regulation and origins of the multiple waves of haematopoiesis. These insights provide the basis for the generation of specific haematopoietic populations, including the de novo specification of HSCs.Entities:
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Year: 2022 PMID： 35484246 PMCID： PMC9109599 DOI： 10.1038/s41556-022-00898-9
Source DB: PubMed Journal: Nat Cell Biol ISSN： 1465-7392 Impact factor: 28.213