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.
Subscribe to Journal
Get full journal access for 1 year
only $41.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Kohli L, Passegue E. Surviving change: the metabolic journey of hematopoietic stem cells. Trends Cell Biol. 2014;24:479–87.
Morrison SJ, Scadden DT. The bone marrow niche for haematopoietic stem cells. Nature. 2014;505:327–34.
Mantel CR, O’Leary HA, Chitteti BR, Huang X, Cooper S, Hangoc G, et al. Enhancing hematopoietic stem cell transplantation efficacy by mitigating oxygen shock. Cell. 2015;161:1553–65.
Ito K, Hirao A, Arai F, Takubo K, Matsuoka S, Miyamoto K, et al. Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nat Med. 2006;12:446–51.
Ludin A, Gur-Cohen S, Golan K, Kaufmann KB, Itkin T, Medaglia C, et al. Reactive oxygen species regulate hematopoietic stem cell self-renewal, migration and development, as well as their bone marrow microenvironment. Antioxid Redox Signal. 2014;21:1605–19.
Jang YY, Sharkis SJ. A low level of reactive oxygen species selects for primitive hematopoietic stem cells that may reside in the low-oxygenic niche. Blood. 2007;110:3056–63.
Bowman RL, Busque L, Levine RL. Clonal hematopoiesis and evolution to hematopoietic malignancies. Cell Stem Cell. 2018;22:157–70.
Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372:425–32.
La Cava A, Matarese G. The weight of leptin in immunity. Nat Rev Immunol. 2004;4:371–9.
Lee GH, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI, et al. Abnormal splicing of the leptin receptor in diabetic mice. Nature. 1996;379:632–5.
Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, et al. Identification and expression cloning of a leptin receptor, OB-R. Cell. 1995;83:1263–71.
Bahary N, Leibel RL, Joseph L, Friedman JM. Molecular mapping of the mouse db mutation. Proc Natl Acad Sci USA. 1990;87:8642–6.
Zhou BO, Yue R, Murphy MM, Peyer JG, Morrison SJ. Leptin-receptor-expressing mesenchymal stromal cells represent the main source of bone formed by adult bone marrow. Cell Stem Cell. 2014;15:154–68.
Bennett BD, Solar GP, Yuan JQ, Mathias J, Thomas GR, Matthews W. A role for leptin and its cognate receptor in hematopoiesis. Curr Biol. 1996;6:1170–80.
Cioffi JA, Shafer AW, Zupancic TJ, Smith-Gbur J, Mikhail A, Platika D, et al. Novel B219/OB receptor isoforms: possible role of leptin in hematopoiesis and reproduction. Nat Med. 1996;2:585–9.
Gainsford T, Willson TA, Metcalf D, Handman E, McFarlane C, Ng A, et al. Leptin can induce proliferation, differentiation, and functional activation of hemopoietic cells. Proc Natl Acad Sci USA. 1996;93:14564–8.
Umemoto Y, Tsuji K, Yang FC, Ebihara Y, Kaneko A, Furukawa S, et al. Leptin stimulates the proliferation of murine myelocytic and primitive hematopoietic progenitor cells. Blood. 1997;90:3438–43.
Claycombe K, King LE, Fraker PJ. A role for leptin in sustaining lymphopoiesis and myelopoiesis. Proc Natl Acad Sci USA. 2008;105:2017–21.
Ding L, Saunders TL, Enikolopov G, Morrison SJ. Endothelial and perivascular cells maintain haematopoietic stem cells. Nature. 2012;481:457–62.
Zhou BO, Yu H, Yue R, Zhao Z, Rios JJ, Naveiras O, et al. Bone marrow adipocytes promote the regeneration of stem cells and haematopoiesis by secreting SCF. Nat Cell Biol. 2017;19:891–903.
Himburg HA, Termini CM, Schlussel L, Kan J, Li M, Zhao L, et al. Distinct bone marrow sources of pleiotrophin control hematopoietic stem cell maintenance and regeneration. Cell Stem Cell. 2018;23:370–81.e5.
Comazzetto S, Murphy MM, Berto S, Jeffery E, Zhao Z, Morrison SJ. Restricted hematopoietic progenitors and erythropoiesis require SCF from leptin receptor+ niche cells in the bone marrow. Cell Stem Cell. 2019;24:477–86.e6.
Galvin A, Weglarz M, Folz-Donahue K, Handley M, Baum M, Mazzola M, et al. Cell cycle analysis of hematopoietic stem and progenitor cells by multicolor flow cytometry. Curr Protoc Cytom. 2019;87:e50.
Pietras EM, Lakshminarasimhan R, Techner JM, Fong S, Flach J, Binnewies M, et al. Re-entry into quiescence protects hematopoietic stem cells from the killing effect of chronic exposure to type I interferons. J Exp Med. 2014;211:245–62.
Broxmeyer HE, Hoggatt J, O’Leary HA, Mantel C, Chitteti BR, Cooper S, et al. Dipeptidylpeptidase 4 negatively regulates colony-stimulating factor activity and stress hematopoiesis. Nat Med. 2012;18:1786–96.
Chen Y, Yao C, Teng Y, Jiang R, Huang X, Liu S, et al. Phorbol ester induced ex vivo expansion of rigorously-defined phenotypic but not functional human cord blood hematopoietic stem cells: a cautionary tale demonstrating that phenotype does not always recapitulate stem cell function. Leukemia. 2019;33:2962–6.
Pietras EM, Reynaud D, Kang YA, Carlin D, Calero-Nieto FJ, Leavitt AD, et al. Functionally distinct subsets of lineage-biased multipotent progenitors control blood production in normal and regenerative conditions. Cell Stem Cell. 2015;17:35–46.
Doulatov S, Notta F, Laurenti E, Dick JE. Hematopoiesis: a human perspective. Cell Stem Cell. 2012;10:120–36.
Naylor C, Petri WA Jr. Leptin regulation of immune responses. Trends Mol Med. 2016;22:88–98.
Sawamiphak S, Kontarakis Z, Stainier DY. Interferon gamma signaling positively regulates hematopoietic stem cell emergence. Dev Cell. 2014;31:640–53.
Espin-Palazon R, Traver D. The NF-kappaB family: key players during embryonic development and HSC emergence. Exp Hematol. 2016;44:519–27.
Zhao C, Xiu Y, Ashton J, Xing L, Morita Y, Jordan CT, et al. Noncanonical NF-kappaB signaling regulates hematopoietic stem cell self-renewal and microenvironment interactions. Stem Cells. 2012;30:709–18.
Espin-Palazon R, Stachura DL, Campbell CA, Garcia-Moreno D, Del Cid N, Kim AD, et al. Proinflammatory signaling regulates hematopoietic stem cell emergence. Cell. 2014;159:1070–85.
Stein SJ, Baldwin AS. Deletion of the NF-kappaB subunit p65/RelA in the hematopoietic compartment leads to defects in hematopoietic stem cell function. Blood. 2013;121:5015–24.
Mayani H, Wagner JE, Broxmeyer HE. Cord blood research, banking, and transplantation: achievements, challenges, and perspectives. Bone Marrow Transplant. 2020;55:48–61.
Ballen KK, Gluckman E, Broxmeyer HE. Umbilical cord blood transplantation: the first 25 years and beyond. Blood. 2013;122:491–8.
Talib S, Shepard KA. Unleashing the cure: overcoming persistent obstacles in the translation and expanded use of hematopoietic stem cell-based therapies. Stem Cells Transl Med. 2020;9:420–6.
Nakao T, Hino M, Yamane T, Nishizawa Y, Morii H, Tatsumi N. Expression of the leptin receptor in human leukaemic blast cells. Br J Haematol. 1998;102:740–5.
Lu Z, Xie J, Wu G, Shen J, Collins R, Chen W, et al. Fasting selectively blocks development of acute lymphoblastic leukemia via leptin-receptor upregulation. Nat Med. 2017;23:79–90.
Konopleva M, Mikhail A, Estrov Z, Zhao S, Harris D, Sanchez-Williams G, et al. Expression and function of leptin receptor isoforms in myeloid leukemia and myelodysplastic syndromes: proliferative and anti-apoptotic activities. Blood. 1999;93:1668–76.
Ozturk K, Avcu F, Ural AU. Aberrant expressions of leptin and adiponectin receptor isoforms in chronic myeloid leukemia patients. Cytokine. 2012;57:61–7.
Gorska E, Popko K, Wasik M. Leptin receptor in childhood acute leukemias. Adv Exp Med Biol. 2013;756:155–61.
Park HY, Kwon HM, Lim HJ, Hong BK, Lee JY, Park BE, et al. Potential role of leptin in angiogenesis: leptin induces endothelial cell proliferation and expression of matrix metalloproteinases in vivo and in vitro. Exp Mol Med. 2001;33:95–102.
Sierra-Honigmann MR, Nath AK, Murakami C, Garcia-Cardena G, Papapetropoulos A, Sessa WC, et al. Biological action of leptin as an angiogenic factor. Science. 1998;281:1683–6.
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.
Conflict of interest
The authors declare that they have no conflict of interest.
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.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
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
Stem Cell Reviews and Reports (2020)