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TISSUE-SPECIFIC STEM CELLS

Involvement of Niemann-Pick Type C2 Protein in Hematopoiesis Regulation

^a Department of Biochemistry and Molecular Biology, and
^b Division of Hematology, Department of Medicine, University of Southern California, Keck School of Medicine, Los Angeles, California, USA

Key Words. Hematopoietic stem cell • Niemann-Pick type C2 protein • Thrombopoietin

Correspondence: Yi Zhao, M.D., Division of Hematology, Department of Medicine, Keck School of Medicine, University of Southern California, 1441 Eastlake Ave., Los Angeles, California 90033, USA. Telephone: 323-865-0646; Fax: 323-865-0097; e-mail: yizhao{at}usc.edu

Received September 15, 2005; accepted for publication February 2, 2006.

Niemann-Pick type C2 (NPC2) protein has been characterized as a cholesterol-binding protein. Its loss leads to NPC2 disease, an inherited neurodegenerative disorder. When analyzing gene expression profile, we noticed high expression of both NPC2 and its receptor, mannose 6-phosphate receptor (MPR), in murine hematopoietic stem cells. NPC2 protein, in the presence of thrombopoietin (TPO), causes an increase in CFU-GEMM (colony-forming unit-granulocyte-erythroid-macrophage-megakaryocyte) and a decrease in CFU-GM (colony-forming unit-granulocyte-macrophage) colony number in colony-forming cell (CFC) assays. This effect is independent of cholesterol binding but does require the presence of MPR. With M07e cells, a TPO-dependent hematopoietic leukemia cell line, NPC2 can inhibit TPO-induced differentiation and enhance TPO-mediated anti-apoptosis effects. Strikingly, these results are not observed under the standard 20% O₂ level of the standard incubator, but rather at 7% O₂, the physiological oxygen level of bone marrow. Furthermore, NPC2 protein upregulates hypoxia inducible factor 1- protein level at 7% O₂, but not at 20% O₂. Our results demonstrate that NPC2 protein plays a role in hematopoiesis at the physiologic bone marrow level of O₂.