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Identification of Adiponectin as a Novel Hemopoietic Stem Cell Growth Factor¹

Leah DiMascio^*, Carlijn Voermans^*, Mweia Uqoezwa^*, Andrew Duncan^*, Danhong Lu, Judy Wu^*, Uma Sankar^* and Tannishtha Reya^2,*

^* Department of Pharmacology and Cancer Biology; and Sarah Stedman Center for Nutrition and Diabetes Research, Duke University Medical Center; Durham, NC 27710

The hemopoietic microenvironment consists of a diverse repertoire of cells capable of providing signals that influence hemopoietic stem cell function. Although the role of osteoblasts and vascular endothelial cells has recently been characterized, the function of the most abundant cell type in the bone marrow, the adipocyte, is less defined. Given the emergence of a growing number of adipokines, it is possible that these factors may also play a role in regulating hematopoiesis. Here, we investigated the role of adiponectin, a secreted molecule derived from adipocytes, in hemopoietic stem cell (HSC) function. We show that adiponectin is expressed by components of the HSC niche and its’ receptors AdipoR1 and AdipoR2 are expressed by HSCs. At a functional level, adiponectin influences HSCs by increasing their proliferation, while retaining the cells in a functionally immature state as determined by in vitro and in vivo assays. We also demonstrate that adiponectin signaling is required for optimal HSC proliferation both in vitro and in long term hemopoietic reconstitution in vivo. Finally we show that adiponectin stimulation activates p38 MAPK, and that inhibition of this pathway abrogates adiponectin’s proliferative effect on HSCs. These studies collectively identify adiponectin as a novel regulator of HSC function and suggest that it acts through a p38 dependent pathway.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ L.D. and A.D. are recipients of American Heart Association predoctoral awards. C.V. is the recipient of a Netherlands Organization for Scientific Research Talent postdoctoral fellowship. U.S. is a recipient of an American Cancer Society postdoctoral fellowship. T.R. is the recipient of a Cancer Research Institute Investigator Award and an Ellison Medical Foundation New Scholar Award. This work was also supported by the Lisa Stafford Memorial Prize, Research Discovery Group Award (Duke University), and National Institutes of Health Grants DK63031 and DK072234 (to T.R.).

² Address correspondence and reprint requests to Dr. Tannishtha Reya, Duke University, Pharmacology and Cancer Biology, C333 LSRC, Research Drive, Durham, NC 27710. E-mail address: t.reya{at}duke.edu

³ Abbreviations used in this paper: HSC, hemopoietic stem cell; AMPK, AMP-activated protein kinase; DAPI, 4',6'-diamidino-2-phenylindole.

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