It remains largely unknown how energy metabolism coordinates hematopoietic stem cell (HSC) maintenance and lineage differentiation. The hypoxic microenvironment in stem cell niches limits mitochondrial aerobic metabolism (respiration/oxidative phosphorylation) in HSCs, which preserves this essential cell reservoir from oxidative damage by attenuating the production of reactive oxygen species (ROS), a byproduct of mitochondrial respiration. However, cell intrinsic mechanisms regulating HSC metabolic activities are poorly defined. Furthermore, how energy metabolism orchestrates HSC differentiation in concert with other regulatory networks has not been characterized. Lack of such knowledge impedes the understanding of the pathogenesis of blood diseases associated with mitochondrial dysfunction and metabolic conditions. PTPMT1, an evolutionarily conserved PTEN-like phosphatidylinositol phosphate (PIP) phosphatase, is localized to the mitochondrial inner membrane where ion channels and transporters, important for mitochondrial ion homeostasis and thus metabolism, reside. Our preliminary studies have shown that targeted disruption of PTPMT1 in mice results in post-implantation embryonic lethality. Deletion of PTPMT1 from adult bone marrow (BM) cells of inducible knockout (PTPMT1fl/fl/Mx1-Cre+) mice impairs myeloid and lymphoid cell development. Moreover, postnatal hematopoiesis in hematopoietic cell-specific knockout (PTPMT1fl/fl/Vav1-Cre+) mice is completely blocked. These mice succumb to pancytopenia within 3-6 days of birth. Strikingly, HSCs in the BM are increased by ~30-fold and ~10-fold in PTPMT1fl/fl/Mx1-Cre+ mice and PTPMT1fl/fl/Vav1-Cre+ neonates, respectively. Preliminary mechanistic studies show that cellular respiration of PTPMT1-depleted cells is decreased while glycolysis is enhanced. The objective of this application is to extend these studies to further determine the role and signaling mechanism of mitochondrial phosphatase PTPMT1 in HSCs. We hypothesize that PTPMT1 coordinates HSC homeostasis and lineage commitment by modulating mitochondrial metabolism. We plan to test our hypothesis and accomplish the objective of this application by pursuing the following two aims. (i) To define the role of PTPMT1 in hematopoiesis. (ii) To determine the mechanisms by which PTPMT1 modulates HSC function. The proposed work is innovative, because it explores the significance of finely controlled mitochondrial metabolism for HSC maintenance and lineage differentiation. The combination of the work proposed is collectively expected to yield novel insights into the bioenergetic regulation of hematopoietic cell development. In addition, the information gathered will lead to a better understanding of the pathophysiology of blood disorders resulting from mitochondrial dysfunction and metabolic conditions.

Public Health Relevance

The project proposed seeks to understand the role and signaling mechanisms of the newly identified mitochondria-based phosphatase PTPMT1 in blood cell development. It is anticipated that the proposed studies will yield conceptual insights into metabolic modulation of hematopoietic stem cell function. Also, the information gathered will lead to a better understanding of the pathophysiology of blood diseases associated with mitochondrial dysfunction and metabolic conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK092722-02S1
Application #
8541519
Study Section
Molecular and Cellular Hematology (MCH)
Program Officer
Wright, Daniel G
Project Start
2011-09-15
Project End
2015-07-31
Budget Start
2012-09-25
Budget End
2013-07-31
Support Year
2
Fiscal Year
2012
Total Cost
$12,560
Indirect Cost
$4,560
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Zheng, Hong; Yu, Wen-Mei; Waclaw, Ronald R et al. (2018) Gain-of-function mutations in the gene encoding the tyrosine phosphatase SHP2 induce hydrocephalus in a catalytically dependent manner. Sci Signal 11:
Liu, W; Yu, W-M; Zhang, J et al. (2017) Inhibition of the Gab2/PI3K/mTOR signaling ameliorates myeloid malignancy caused by Ptpn11 (Shp2) gain-of-function mutations. Leukemia 31:1415-1422
Dong, Lei; Zheng, Hong; Qu, Cheng-Kui (2017) CCL3 is a key mediator for the leukemogenic effect of Ptpn11-activating mutations in the stem-cell microenvironment. Blood 130:1471-1474
Ni, Fang; Qu, Cheng-Kui (2016) A metabolic stress-induced cell cycle checkpoint in stem cells. Cell Cycle 15:2539-2540
Dong, Lei; Yu, Wen-Mei; Zheng, Hong et al. (2016) Leukaemogenic effects of Ptpn11 activating mutations in the stem cell microenvironment. Nature 539:304-308
Liu, Xia; Zheng, Hong; Li, Xiaobo et al. (2016) Gain-of-function mutations of Ptpn11 (Shp2) cause aberrant mitosis and increase susceptibility to DNA damage-induced malignancies. Proc Natl Acad Sci U S A 113:984-9
Liu, Xia; Zheng, Hong; Yu, Wen-Mei et al. (2015) Maintenance of mouse hematopoietic stem cells ex vivo by reprogramming cellular metabolism. Blood 125:1562-5
Dong, Lei; Qu, Cheng-Kui (2014) Flow cytometric analysis of signaling and apoptosis in hematopoietic stem cells. Methods Mol Biol 1185:79-87
Xu, Dan; Zheng, Hong; Yu, Wen-Mei et al. (2013) Activating mutations in protein tyrosine phosphatase Ptpn11 (Shp2) enhance reactive oxygen species production that contributes to myeloproliferative disorder. PLoS One 8:e63152
Yu, Wen-Mei; Liu, Xia; Shen, Jinhua et al. (2013) Metabolic regulation by the mitochondrial phosphatase PTPMT1 is required for hematopoietic stem cell differentiation. Cell Stem Cell 12:62-74

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