Pleiotrophin regulates the expansion and regeneration of hematopoietic stem cells

HA Himburg, GG Muramoto, P Daher, SK Meadows… - Nature medicine, 2010 - nature.com
HA Himburg, GG Muramoto, P Daher, SK Meadows, JL Russell, P Doan, JT Chi, AB Salter…
Nature medicine, 2010nature.com
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 …
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+CDCD38Lin 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.
nature.com