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Pleiotrophin regulates the expansion and regeneration of hematopoietic stem cells

Nature Medicine volume 16, pages 475–482 (2010)Cite this article

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Abstract

Hematopoietic stem cell (HSC) self-renewal is regulated by both intrinsic and extrinsic signals. Although some of the pathways that regulate HSC self-renewal have been uncovered, it remains largely unknown whether these pathways can be triggered by deliverable growth factors to induce HSC growth or regeneration. Here we show that pleiotrophin, a neurite outgrowth factor with no known function in hematopoiesis, efficiently promotes HSC expansion in vitro and HSC regeneration in vivo. Treatment of mouse bone marrow HSCs with pleiotrophin caused a marked increase in long-term repopulating HSC numbers in culture, as measured in competitive repopulating assays. Treatment of human cord blood CD34+CDCD38−Lin− cells with pleiotrophin also substantially increased severe combined immunodeficient (SCID)-repopulating cell counts in culture, compared to input and cytokine-treated cultures. Systemic administration of pleiotrophin to irradiated mice caused a pronounced expansion of bone marrow stem and progenitor cells in vivo, indicating that pleiotrophin is a regenerative growth factor for HSCs. Mechanistically, pleiotrophin activated phosphoinositide 3-kinase (PI3K) signaling in HSCs; antagonism of PI3K or Notch signaling inhibited pleiotrophin-mediated expansion of HSCs in culture. We identify the secreted growth factor pleiotrophin as a new regulator of both HSC expansion and regeneration.

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Figure 1: Pleiotrophin is overexpressed by HUBECs, and treatment with pleiotrophin induces the expansion of phenotypic HSCs in culture.
Figure 2: Treatment with pleiotrophin induces the expansion of mouse short- and long-term HSCs.
Figure 3: Treatment with pleiotrophin induces the expansion of human HSCs.
Figure 4: Pleiotrophin mediates bone marrow progenitor cell expansion via activation of PI3K and Notch signaling.
Figure 5: Pleiotrophin induces bone marrow stem and progenitor cell regeneration in vivo.

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Acknowledgements

We acknowledge J. Whitesides for assistance with cell sorting procedures. This work was supported in part by US National Institutes of Health grant AI067798 to J.P.C., H.A.H. is supported by a post-doctoral training grant from the Center for Biomolecular and Tissue Engineering, US National Institute of Biomedical Imaging and Bioengineering.

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Author notes

  1. Garrett G Muramoto and Pamela Daher: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Cellular Therapy, Department of Medicine, Duke University, Durham, North Carolina, USA

    Heather A Himburg, Garrett G Muramoto, Pamela Daher, Sarah K Meadows, J Lauren Russell, Phuong Doan, Jen-Tsan Chi, Alice B Salter, Nelson J Chao & John P Chute

  2. Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina, USA

    Jen-Tsan Chi

  3. Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, USA

    William E Lento, Tannishtha Reya & John P Chute

  4. Department of Immunology, Duke University, Durham, North Carolina, USA

    Nelson J Chao

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  1. Heather A Himburg
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Contributions

H.A.H. designed and performed experiments, analyzed data and wrote the paper; G.G.M., P.D., S.K.M., J.L.R., P.D., A.B.S. and W.E.L. performed experiments; J.-T.C. guided the microarray analysis; T.R. and N.J.C. analyzed data and wrote the paper; J.P.C. designed the experiments, analyzed the data and wrote the paper.

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Correspondence to John P Chute.

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The authors declare no competing financial interests.

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Supplementary Figs. 1–5, Supplementary Tables 1 and 2 and Supplementary Methods (PDF 799 kb)

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Himburg, H., Muramoto, G., Daher, P. et al. Pleiotrophin regulates the expansion and regeneration of hematopoietic stem cells. Nat Med 16, 475–482 (2010). https://doi.org/10.1038/nm.2119

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