Stem cells are characterized by their multi-lineage differentiation potential (pluripotency) and their ability for self-renewal, which permits them to proliferate while avoiding lineage commitment and senescence. There has been much interest in identifying the pathways by which stem cells choose between the cell fates of lineage commitment versus self-renewal. A better understanding of this process would allow for the development of specific modulators that direct stem cell fate and improve their utility for regenerative therapies. Recent studies have demonstrated that mitochondrial function regulates gene expression and self-renewal in multiple cell types but little is known about the role of mitochondrial function in embryonic stem cells. We therefore studied the mitochondrial function and activity in human embryonic stem cells (hESCs). Our novel preliminary data suggest that when compared to differentiated cells, undifferentiated hESCs have high mitochondrial biogenesis, but exhibit low levels of mitochondrial glucose oxidation. Based on our data and recent published findings, we have formulated the central hypothesis of the proposal glucose oxidation regulates self-renewal and differentiation of human embryonic stem cells (hESCs). We propose to evaluate this by testing the following three hypotheses:
In Aim 1, we will assess the effect of modulating glucose oxidation on the metabolic activity of hESCs.
In Aim 2, we will evaluate the effect of modulating glucose oxidation on the self-renewal and differentiation of hESCs.
In Aim 3, we will assess how enhancing mitochondrial glucose oxidation affects the therapeutic use of hESC by using in vivo models of teratoma formation and angiogenesis. This proposal investigates a new paradigm, since there is no clearly established link yet between mitochondrial glucose oxidation and human ESC fate. The results from our study of are likely to yield major insights into cellular metabolic and regenerative processes. Since multiple pharmacological modulators of metabolism are currently available and have been approved for use in patients, we believe that our findings on metabolic processes in stem biology could be readily translated into the clinical setting to improve regenerative stem cell therapies.

Public Health Relevance

Stem cell therapies are likely to be the cornerstone of future medicine, since stem cells are able to regenerate damaged or injured tissue. Our proposal explores the novel idea whether stem cell survival and differentiation are linked to the metabolism of stem cells. Such a link would enable us to significantly improve stem cell therapies in patients by regulating the metabolism of stem cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM094220-04
Application #
8653967
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Anderson, Vernon
Project Start
2011-09-01
Project End
2016-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Chicago
State
IL
Country
United States
Zip Code
60612
Gong, Haixia; An, Shejuan; Sassmann, Antonia et al. (2016) PAR1 Scaffolds TGFβRII to Downregulate TGF-β Signaling and Activate ESC Differentiation to Endothelial Cells. Stem Cell Reports 7:1050-1058
Marsboom, Glenn; Zhang, Guo-Fang; Pohl-Avila, Nicole et al. (2016) Glutamine Metabolism Regulates the Pluripotency Transcription Factor OCT4. Cell Rep 16:323-32
Wu, Liangtang; Wary, Kishore K; Revskoy, Sergei et al. (2015) Histone Demethylases KDM4A and KDM4C Regulate Differentiation of Embryonic Stem Cells to Endothelial Cells. Stem Cell Reports 5:10-21
Liu, Yuru; Kumar, Varsha Suresh; Zhang, Wei et al. (2015) Activation of type II cells into regenerative stem cell antigen-1(+) cells during alveolar repair. Am J Respir Cell Mol Biol 53:113-24
Váraljai, Renáta; Islam, Abul B M M K; Beshiri, Michael L et al. (2015) Increased mitochondrial function downstream from KDM5A histone demethylase rescues differentiation in pRB-deficient cells. Genes Dev 29:1817-34
Gong, Haixia; Rehman, Jalees; Tang, Haiyang et al. (2015) HIF2α signaling inhibits adherens junctional disruption in acute lung injury. J Clin Invest 125:652-64
Toya, Sophie P; Wary, Kishore K; Mittal, Manish et al. (2015) Integrin α6β1 Expressed in ESCs Instructs the Differentiation to Endothelial Cells. Stem Cells 33:1719-29
Zhang, Min; Malik, Asrar B; Rehman, Jalees (2014) Endothelial progenitor cells and vascular repair. Curr Opin Hematol 21:224-8
Ushio-Fukai, Masuko; Rehman, Jalees (2014) Redox and metabolic regulation of stem/progenitor cells and their niche. Antioxid Redox Signal 21:1587-90
Zhang, Lianghui; Malik, Asrar B; Rehman, Jalees (2014) Reprogramming fibroblasts to endothelial cells: converted or born again? Circulation 130:1136-8

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