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Leptin receptor, a surface marker for a subset of highly engrafting long-term functional hematopoietic stem cells.

ABSTRACT: The hematopoietic system is sustained by a rare population of hematopoietic stem cells (HSCs), which emerge during early embryonic development and then reside in the hypoxic niche of the adult bone marrow microenvironment. Although leptin receptor (Lepr)-expressing stromal cells are well-studied as critical regulators of murine hematopoiesis, the biological implications of Lepr expression on HSCs remain largely unexplored. We hypothesized that Lepr⁺HSCs are functionally different from other HSCs. Using in vitro and in vivo experimental approaches, we demonstrated that Lepr further differentiates SLAM HSCs into two distinct populations; Lepr⁺HSCs engrafted better than Lepr^-HSCs in primary transplant. Compared to Lepr^-LSK cells, Lepr⁺LSK cells were highly enriched for extensively repopulating and self-renewing HSCs. Molecularly, Lepr⁺HSCs were characterized by a pro-inflammatory transcriptomic profile enriched for Type-I Interferon and Interferon-gamma (IFN-γ) response pathways, which are known to be critical for the emergence of HSCs in the embryo. We conclude that although Lepr⁺HSCs represent a minor subset of HSCs, they are highly engrafting cells that possess embryonic-like transcriptomic characteristics, and that Lepr can serve as a reliable marker for functional long-term HSCs, which may have potential clinical applicability.

SUBMITTER: Trinh T

PROVIDER: S-EPMC8102644 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Leptin Receptor, a Surface Marker for a Subset of Highly Engrafting Long-term Functional Hematopoietic Stem Cells

Project description:The hematopoietic system is sustained by a rare population of hematopoietic stem cells (HSCs), which emerge during early fetal development and then reside in the hypoxic niche of the adult bone marrow microenvironment. Although leptin receptor (Lepr)-expressing stromal cells are well-studied as critical regulators of murine hematopoiesis, the biological implications of Lepr expression on HSCs remain largely unexplored. We hypothesized that Lepr+HSCs are functionally different from other HSCs. Using in vitro and in vivo experimental approaches, we demonstrated that Lepr further differentiates SLAM HSCs into two distinct populations; Lepr+HSCs engrafted significantly higher than Lepr-HSCs and self-renewed more extensively as noted in secondary transplants. To determine how molecular pathways and gene expression profiles affect their functional differences, we performed bulk RNA-sequencing on purified Lepr+HSC/MPP and Lepr-HSC/MPP cells. Our results showed that Lepr+HSCs were characterized by a proinflammatory transcriptomic profile enriched for Type-I Interferon and Interferon-gamma (IFN-γ) response pathways, which are known to be critical for the emergence of HSCs in fetal life. Gene set analyses indicated that Lepr+HSCs were more highly enriched for genes associated with long-term HSCs whereas Lepr-HSCs’ expression profiles were more closely related to progenitors. We conclude that although Lepr+HSCs represent a minor subset of HSCs, they are highly engrafting cells that possess embryonic-like transcriptomic characteristics, and that Lepr can serve as a useful marker for functional long term HSCs, which may have potential clinical applicability.

2020-10-30 | GSE158393 | GEO

Leptin Receptor, a Surface Marker for a Subset of Highly Engrafting Long-term Functional Hematopoietic Stem Cells

Project description:Leptin Receptor, a Surface Marker for a Subset of Highly Engrafting Long-term Functional Hematopoietic Stem Cells

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Endothelial Cells Promote Expansion of Long-Term Engrafting Marrow Hematopoietic Stem and Progenitor Cells in Primates.

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