Submitted on September 15, 2005
Accepted on February 2, 2006
Tissue-Specific Stem Cells
|
Involvement of Niemann-Pick Type C2 Protein in Hematopoiesis Regulation
Kyu Heo 1,
Unnati Jariwala 1,
Jeongim Woo 1,
Yuxia Zhan 1,
Kathleen A. Burke 1,
Lunjian Zhu 1,
W. French Anderson 1,
Yi Zhao 2*
1 Department of Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine, Los Angeles, California
2 Division of Hematology, Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, California
* To whom correspondence should be addressed. E-mail: yizhao{at}usc.edu.
 |
Abstract |
|---|
NPC2 protein has been characterized as a cholesterol-binding protein. Its loss leads to Niemann-Pick Type C2 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 and a decrease in CFU-GM colony number in colony forming cell (CFC) assays. This effect isindependent of cholesterol binding, but does require the presence of the 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 up-regulates hypoxia inducible factor 1
(HIF-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.
