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Mpl and the hematopoietic stem cell

Leukemia volume 16, pages 738–739 (2002)Cite this article

Hematopoietic stem cells give rise to immature progenitors of each of the hematopoietic lineages, including megakaryocytes for which thrombopoietin (TPO) plays an important role in their development. Less is known about the role of TPO in the development of hematopoietic stem cells. Several approaches to evaluate stem cell function have been established; in some this population can be purified by sorting cells from bone marrow and cultured in the presence of one or more cytokines, monitoring for cell survival and proliferation. Using lineage depletion with antibodies, forward and side scatter in flow cytometry, and the capacity to extrude rhodamine and Hoechst dyes, we have found that in the absence of any growth factors stem cell populations die within 2–3 days. In the presence of interleukin (IL)-3 or steel factor (SF), most of these cells survive and many begin to proliferate. Surprisingly, TPO affects hematopoietic stem cells by supporting their survival, but when used alone, does not induce their proliferation. However, in combination with IL-3 or SF, TPO profoundly influences stem cell proliferation over that seen with IL-3 or SF alone. For example, after about 1 week of culture in IL-3 alone, only about 10% of the cells have entered the cell cycle; in the additional presence of TPO, 40% or 50% of the cells have begun to divide.1 Similar data can be demonstrated for steel factor with TPO. Therefore, TPO has been shown to promote survival and induce proliferation of stem cells in the presence of other proliferative growth factors.

The role of TPO and its receptor in hematopoiesis has also been demonstrated in vivo by genetically eliminating the c-Mpl receptor in mice.2 Using a competitive repopulation assay Mpl nullizygous mice display about one-seventh the number of hematopoietic stem cells as their wild-type counterparts, which appears to be insufficient to cause aplasia; other than severe thrombocytopenia, hematopoiesis is relatively normal. If the hematopoietic stem cell compartment is reduced, the hematopoietic progenitor cell compartment might also be compromised. In earlier work by Warren Alexander in Australia, the number of granulocyte–macrophage colony-forming cells in bone marrow was greatly reduced in Mpl knockout mice compared to normal. The same was true for BFU-E and mixed lineage colonies.3

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  1. Department of Medicine, Division of Hematology, University of Washington School of Medicine, Seattle, WA, USA

    K Kaushansky

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This paper is part of a series of keynote addresses to be published in Leukemia. They were presented at the Acute Leukemia Forum, San Francisco, 20 April 2001. Supported by an unrestricted educational grant from Immunex.

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Kaushansky, K. Mpl and the hematopoietic stem cell. Leukemia 16, 738–739 (2002). https://doi.org/10.1038/sj.leu.2402398

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