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Identification of a retinoic acid-dependent definitive hematopoietic progenitor from human pluripotent stem cells

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE139853 | GEO | 2022/02/14

REPOSITORIES: GEO

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Identification of a retinoic acid-dependent definitive hematopoietic progenitor from human pluripotent stem cells [HE]

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.

2022-02-14 | GSE139843 | GEO

Identification of a retinoic acid-dependent definitive hematopoietic progenitor from human pluripotent stem cells [CXCR4]

2022-02-14 | GSE139838 | GEO

Identification of a retinoic acid-dependent definitive hematopoietic progenitor from human pluripotent stem cells [scRNA-seq]

2022-02-14 | GSE139850 | GEO

Identification of a retinoic acid-dependent haemogenic endothelial progenitor from human pluripotent stem cells.

Project description: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.

| S-EPMC9109599 | biostudies-literature

Identification of a retinoic acid-dependent definitive hematopoietic progenitor from human pluripotent stem cells

Project description:Identification of a retinoic acid-dependent definitive hematopoietic progenitor from human pluripotent stem cells

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Identification of a retinoic acid-dependent definitive hematopoietic progenitor from human pluripotent stem cells [CXCR4]

Project description:Identification of a retinoic acid-dependent definitive hematopoietic progenitor from human pluripotent stem cells [CXCR4]

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Identification of a retinoic acid-dependent definitive hematopoietic progenitor from human pluripotent stem cells [HE]

Project description:Identification of a retinoic acid-dependent definitive hematopoietic progenitor from human pluripotent stem cells [HE]

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Retinoic acid regulates hematopoietic development from human pluripotent stem cells.

Project description:The functions of retinoic acid (RA), a potent morphogen with crucial roles in embryogenesis including developmental hematopoiesis, have not been thoroughly investigated in the human setting. Using an in vitro model of human hematopoietic development, we evaluated the effects of RA signaling on the development of blood and on generated hematopoietic progenitors. Decreased RA signaling increases the generation of cells with a hematopoietic stem cell (HSC)-like phenotype, capable of differentiation into myeloid and lymphoid lineages, through two separate mechanisms: by increasing the commitment of pluripotent stem cells toward the hematopoietic lineage during the developmental process and by decreasing the differentiation of generated blood progenitors. Our results demonstrate that controlled low-level RA signaling is a requirement in human blood development, and we propose a new interpretation of RA as a regulatory factor, where appropriate control of RA signaling enables increased generation of hematopoietic progenitor cells from pluripotent stem cells in vitro.

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Identification of a retinoic acid-dependent definitive hematopoietic progenitor from human pluripotent stem cells [scRNA-seq]

Project description:Identification of a retinoic acid-dependent definitive hematopoietic progenitor from human pluripotent stem cells [scRNA-seq]

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Definitive Hematopoietic Multipotent Progenitor Cells Are Transiently Generated From Hemogenic Endothelial Cells in Human Pluripotent Stem Cells.

Project description:Generation of fully functional hematopoietic multipotent progenitor (MPP) cells from human pluripotent stem cells (hPSCs) has a great therapeutic potential to provide an unlimited cell source for treatment of hematological disorders. We previously demonstrated that CD34(+) CD31(+) CD144(+) population derived from hPSCs contain hemato-endothelial progenitors (HEPs) that give rise to hematopoietic and endothelial cells. Here, we report a differentiation system to generate definitive hematopoietic MPP cells from HEPs via endothelial monolayer. In the presence of angiogenic factors, HEPs formed an endothelial monolayer, from which hematopoietic clusters emerged through the process of endothelial-to-hematopoietic transition (EHT). EHT was significantly enhanced by hematopoietic growth factors. The definitive MPP cells generated from endothelial monolayer were capable of forming multilineage hematopoietic colonies, giving rise to T lymphoid cells, and differentiating into enucleated erythrocytes. Emergence of hematopoietic cells from endothelial monolayer occurred transiently. Hematopoietic potential was lost during prolonged culture of HEPs in endothelial growth conditions. Our study demonstrated that CD34(+) CD31(+) CD144(+) HEPs gave rise to hematopoietic MPP cells via hemogenic endothelial cells that exist transiently. The established differentiation system provides a platform for future investigation of regulatory factors involved in de novo generation of hematopoietic MPP cells and their applications in transplantation.

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