Details

Autor(en) / Beteiligte

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

Titel

Pleiotrophin regulates the expansion and regeneration of hematopoietic stem cells

Ist Teil von

• Nature medicine, 2010-04, Vol.16 (4), p.475-482

Ort / Verlag

New York: Nature Publishing Group US

Erscheinungsjahr

2010

Quelle

MEDLINE

Beschreibungen/Notizen

• A technique for expanding hematopoietic stem cell numbers could have many clinical applications, including improving bone marrow transplantation and recovery from myelotoxic chemotherapy. In this report, Heather Himburg et al . suggest a new strategy to accomplish this by identifying pleiotrophin, a growth factor not previously known to affect hematopoiesis, as an inducer of both mouse and human hematopoietic stem cell expansion ex vivo and of hematopoietic stem cell regeneration in vivo . 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.