Bone Marrow Adipocytes Promote the Regeneration of Stem Cells and Haematopoiesis by Secreting SCF

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2017 Jul 18

PMID 28714970

Citations 274

Authors

Bo O Zhou

Hua Yu

Rui Yue

Zhiyu Zhao

Jonathan J Rios

Olaia Naveiras

Sean J Morrison

Affiliations

Soon will be listed here.

Abstract

Endothelial cells and leptin receptor (LepR) stromal cells are critical sources of haematopoietic stem cell (HSC) niche factors, including stem cell factor (SCF), in bone marrow. After irradiation or chemotherapy, these cells are depleted while adipocytes become abundant. We discovered that bone marrow adipocytes synthesize SCF. They arise from Adipoq-Cre/ER progenitors, which represent ∼5% of LepR cells, and proliferate after irradiation. Scf deletion using Adipoq-Cre/ER inhibited haematopoietic regeneration after irradiation or 5-fluorouracil treatment, depleting HSCs and reducing mouse survival. Scf from LepR cells, but not endothelial, haematopoietic or osteoblastic cells, also promoted regeneration. In non-irradiated mice, Scf deletion using Adipoq-Cre/ER did not affect HSC frequency in long bones, which have few adipocytes, but depleted HSCs in tail vertebrae, which have abundant adipocytes. A-ZIP/F1 'fatless' mice exhibited delayed haematopoietic regeneration in long bones but not in tail vertebrae, where adipocytes inhibited vascularization. Adipocytes are a niche component that promotes haematopoietic regeneration.

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References

Jeffery E, Berry R, Church C, Yu S, Shook B, Horsley V . Characterization of Cre recombinase models for the study of adipose tissue. Adipocyte. 2014; 3(3):206-11. PMC: 4110097. DOI: 10.4161/adip.29674. View

Kalajzic Z, Liu P, Kalajzic I, Du Z, Braut A, Mina M . Directing the expression of a green fluorescent protein transgene in differentiated osteoblasts: comparison between rat type I collagen and rat osteocalcin promoters. Bone. 2003; 31(6):654-60. DOI: 10.1016/s8756-3282(02)00912-2. View

Park D, Spencer J, Koh B, Kobayashi T, Fujisaki J, Clemens T . Endogenous bone marrow MSCs are dynamic, fate-restricted participants in bone maintenance and regeneration. Cell Stem Cell. 2012; 10(3):259-72. PMC: 3652251. DOI: 10.1016/j.stem.2012.02.003. View

Gimble J, ROBINSON C, Wu X, Kelly K . The function of adipocytes in the bone marrow stroma: an update. Bone. 1996; 19(5):421-8. DOI: 10.1016/s8756-3282(96)00258-x. View

Belaid-Choucair Z, Lepelletier Y, Poncin G, Thiry A, Humblet C, Maachi M . Human bone marrow adipocytes block granulopoiesis through neuropilin-1-induced granulocyte colony-stimulating factor inhibition. Stem Cells. 2008; 26(6):1556-64. DOI: 10.1634/stemcells.2008-0068. View

Naveiras O, Nardi V, Wenzel P, Hauschka P, Fahey F, Daley G . Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature. 2009; 460(7252):259-63. PMC: 2831539. DOI: 10.1038/nature08099. View

Mizoguchi T, Pinho S, Ahmed J, Kunisaki Y, Hanoun M, Mendelson A . Osterix marks distinct waves of primitive and definitive stromal progenitors during bone marrow development. Dev Cell. 2014; 29(3):340-9. PMC: 4051418. DOI: 10.1016/j.devcel.2014.03.013. View

Morrison S, Perez S, Qiao Z, Verdi J, Hicks C, Weinmaster G . Transient Notch activation initiates an irreversible switch from neurogenesis to gliogenesis by neural crest stem cells. Cell. 2000; 101(5):499-510. DOI: 10.1016/s0092-8674(00)80860-0. View

Glettig D, Kaplan D . Extending human hematopoietic stem cell survival in vitro with adipocytes. Biores Open Access. 2013; 2(3):179-85. PMC: 3666264. DOI: 10.1089/biores.2013.0006. View

10.

CALVO W, FLIEDNER T, Herbst E, Hugl E, Bruch C . Regeneration of blood-forming organs after autologous leukocyte transfusion in lethally irradiated dogs. II. Distribution and cellularity of the marrow in irradiated and transfused animals. Blood. 1976; 47(4):593-601. View

11.

DeFalco J, Tomishima M, Liu H, Zhao C, Cai X, Marth J . Virus-assisted mapping of neural inputs to a feeding center in the hypothalamus. Science. 2001; 291(5513):2608-13. DOI: 10.1126/science.1056602. View

12.

Ding L, Saunders T, Enikolopov G, Morrison S . Endothelial and perivascular cells maintain haematopoietic stem cells. Nature. 2012; 481(7382):457-62. PMC: 3270376. DOI: 10.1038/nature10783. View

13.

Koni P, Joshi S, Temann U, Olson D, Burkly L, Flavell R . Conditional vascular cell adhesion molecule 1 deletion in mice: impaired lymphocyte migration to bone marrow. J Exp Med. 2001; 193(6):741-54. PMC: 2193418. DOI: 10.1084/jem.193.6.741. View

14.

Zhang C, Lodish H . Cytokines regulating hematopoietic stem cell function. Curr Opin Hematol. 2008; 15(4):307-11. PMC: 2677548. DOI: 10.1097/MOH.0b013e3283007db5. View

15.

Knospe W, Blom J, CROSBY W . Regeneration of locally irradiated bone marrow. I. Dose dependent, long-term changes in the rat, with particular emphasis upon vascular and stromal reaction. Blood. 1966; 28(3):398-415. View

16.

Kfoury Y, Scadden D . Mesenchymal cell contributions to the stem cell niche. Cell Stem Cell. 2015; 16(3):239-53. DOI: 10.1016/j.stem.2015.02.019. View

17.

Greenbaum A, Hsu Y, Day R, Schuettpelz L, Christopher M, Borgerding J . CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance. Nature. 2013; 495(7440):227-30. PMC: 3600148. DOI: 10.1038/nature11926. View

18.

Randall T, Weissman I . Phenotypic and functional changes induced at the clonal level in hematopoietic stem cells after 5-fluorouracil treatment. Blood. 1997; 89(10):3596-606. View

19.

Liu F, Woitge H, Braut A, Kronenberg M, Lichtler A, Mina M . Expression and activity of osteoblast-targeted Cre recombinase transgenes in murine skeletal tissues. Int J Dev Biol. 2004; 48(7):645-53. DOI: 10.1387/ijdb.041816fl. View

20.

Bruns I, Lucas D, Pinho S, Ahmed J, Lambert M, Kunisaki Y . Megakaryocytes regulate hematopoietic stem cell quiescence through CXCL4 secretion. Nat Med. 2014; 20(11):1315-20. PMC: 4258871. DOI: 10.1038/nm.3707. View