Contribution of PDGFRα Lineage cells in adult mouse hematopoiesis
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE159535 | GEO | 2023/10/19
REPOSITORIES: GEO
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Project description:The generation of the hematopoietic stem cells (HSCs) from human pluripotent stem cells (hPSCs) is a major goal for regenerative medicine. HSCs derive from hemogenic endothelium (HE) in a retinoic acid (RA)-dependent manner1. While a WNT-dependent (WNTd) patterning of nascent mesoderm specifies clonally multipotent definitive HE from hPSCs2,3, this HE is functionally unresponsive to RA4. Here we show that WNTd mesoderm, prior to HE specification, is comprised of two distinct KDR+CD34negT+ populations. In a TGFb-independent manner, CXCR4negCYP26A1+ mesoderm is specified, which gives rise to HOXA+ multilineage definitive HE, in an RA-independent manner. In contrast, CXCR4+ALDH1A2+ mesoderm is specified in a TGFb-dependent manner, and gives rise to multilineage definitive HE in a stage-specific, RA-dependent manner. Further, this NOTCH-dependent HE harbored HOXA expression resembling fetal HE. This model of human hematopoietic development defines the mesodermal origins of multiple waves of hematopoiesis, and that RA-dependent hematopoietic development occurs prior to HE development.
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Project description:The generation of the hematopoietic stem cells (HSCs) from human pluripotent stem cells (hPSCs) is a major goal for regenerative medicine. HSCs derive from hemogenic endothelium (HE) in a retinoic acid (RA)-dependent manner1. While a WNT-dependent (WNTd) patterning of nascent mesoderm specifies clonally multipotent definitive HE from hPSCs2,3, this HE is functionally unresponsive to RA4. Here we show that WNTd mesoderm, prior to HE specification, is comprised of two distinct KDR+CD34negT+ populations. In a TGFb-independent manner, CXCR4negCYP26A1+ mesoderm is specified, which gives rise to HOXA+ multilineage definitive HE, in an RA-independent manner. In contrast, CXCR4+ALDH1A2+ mesoderm is specified in a TGFb-dependent manner, and gives rise to multilineage definitive HE in a stage-specific, RA-dependent manner. Further, this NOTCH-dependent HE harbored HOXA expression resembling fetal HE. This model of human hematopoietic development defines the mesodermal origins of multiple waves of hematopoiesis, and that RA-dependent hematopoietic development occurs prior to HE development.
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