Stem cell transplantation

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 LeprHSCs in primary transplant. Compared to LeprLSK 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.

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Fig. 1: Lepr+ LSK cells are significantly enriched for phenotypically-defined HSCs, but Lepr+HSCs represent a minor subset out of the total HSC population.
Fig. 2: Compared to LeprLSK cells, Lepr+LSK cells contained significantly higher numbers of both colony-forming progenitor cells and functional long-term self-renewing HSCs.
Fig. 3: Lepr+HSCs exhibited more robust repopulating capacity, but showed similar lineage output and homing capacity compared to LeprHSCs.
Fig. 4: Lepr+HSCs constitute a subset of functional long-term repopulating HSCs that is characterized by a pro-inflammatory transcriptomic signature.
Fig. 5: Human CB LEPR+CD34+ cells, a minor subset of total CD34+ cells, are more highly enriched for phenotypically-defined HSCs and MPPs but have fewer colony-forming progenitor cells.
Fig. 6: LEPR+CD34+ cells show a trend to enhanced engraftment compared to LEPRCD34+ cell in NSG mice.

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Acknowledgements

These studies were supported by US Public Health Service grants from the National Institutes of Health to HEB: R35 HL139599, R01 DK109188, T32 DK007519, the IU Simon Comprehensive Cancer Center Support Grant P30CA082709 and U54 DK106846 (to HEB and EFS). TT, JR, and AA were supported by Training grant T32 DK007519.

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TT, EFS, and HEB designed experiments and interpreted data. TT, AA, AS, SC, and HEB performed experiments. TT and JR analyzed data. TT, JR, and HEB wrote the paper.

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Correspondence to Hal E. Broxmeyer.

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All animal studies were approved by the Indiana University Committees on Use and Care of Animals. All CB studies were approved by the Indiana University Institutional Review Board.

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Trinh, T., Ropa, J., Aljoufi, A. et al. Leptin receptor, a surface marker for a subset of highly engrafting long-term functional hematopoietic stem cells. Leukemia (2020). https://doi.org/10.1038/s41375-020-01079-z

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