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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BDA-P (90))
Program Officer
Anderson, Vernon
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Illinois at Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Tsang, Kit Man; Hyun, James S; Cheng, Kwong Tai et al. (2017) Embryonic Stem Cell Differentiation to Functional Arterial Endothelial Cells through Sequential Activation of ETV2 and NOTCH1 Signaling by HIF1?. Stem Cell Reports 9:796-806
Marsboom, Glenn; Chen, Zhenlong; Yuan, Yang et al. (2017) Aberrant caveolin-1-mediated Smad signaling and proliferation identified by analysis of adenine 474 deletion mutation (c.474delA) in patient fibroblasts: a new perspective on the mechanism of pulmonary hypertension. Mol Biol Cell 28:1177-1185
Zhang, Lianghui; Jambusaria, Ankit; Hong, Zhigang et al. (2017) SOX17 Regulates Conversion of Human Fibroblasts Into Endothelial Cells and Erythroblasts by Dedifferentiation Into CD34+Progenitor Cells. Circulation 135:2505-2523
Gong, Haixia; Liu, Menglin; Klomp, Jeff et al. (2017) Method for Dual Viral Vector Mediated CRISPR-Cas9 Gene Disruption in Primary Human Endothelial Cells. Sci Rep 7:42127
Cantelmo, Anna Rita; Conradi, Lena-Christin; Brajic, Aleksandra et al. (2016) Inhibition of the Glycolytic Activator PFKFB3 in Endothelium Induces Tumor Vessel Normalization, Impairs Metastasis, and Improves Chemotherapy. Cancer Cell 30:968-985
Gong, Haixia; An, Shejuan; Sassmann, Antonia et al. (2016) PAR1 Scaffolds TGF?RII to Downregulate TGF-? 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 16:323-332
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
Toya, Sophie P; Wary, Kishore K; Mittal, Manish et al. (2015) Integrin ?6?1 Expressed in ESCs Instructs the Differentiation to Endothelial Cells. Stem Cells 33:1719-29
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

Showing the most recent 10 out of 24 publications