Pleiotrophin regulates the expansion and regeneration of hematopoietic stem cells

Nat Med. 2010 Apr;16(4):475-82. doi: 10.1038/nm.2119. Epub 2010 Mar 21.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / physiology
  • Carrier Proteins / pharmacology
  • Carrier Proteins / physiology*
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Cytokines / pharmacology
  • Cytokines / physiology*
  • Dose-Response Relationship, Drug
  • Hematopoietic Stem Cells / drug effects
  • Hematopoietic Stem Cells / physiology*
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, SCID
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphatidylinositol 3-Kinases / physiology
  • Receptors, Notch / physiology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Stem Cell Factor / pharmacology
  • Thrombopoietin / pharmacology


  • Carrier Proteins
  • Cytokines
  • Receptors, Notch
  • Stem Cell Factor
  • pleiotrophin
  • Thrombopoietin
  • Phosphatidylinositol 3-Kinases

Associated data

  • OMIM/GSE20243