Cardiac mesenchymal stem cells (C-MSC) are a unique pool of stem cells residing in the heart that play an important role in vascular homeostasis and physiological vascular cell turnover. Transplanting C-MSC into the heart has shown promise for vessel repair and angiogenesis, but poor survival of transplanted cells poses a major technical challenge. We reported that hypoxic preconditioning (HP) improves donor stem cell survival and angiogenesis in a HIF-1?- dependent manner. Mechanistically, C-MSC responses to HP correlate with the level of activation of Notch signaling, a cell-cell contact and pathway in stem cells that also mediates vascular smooth muscle cell (VSMC) differentiation of C-MSC. Moreover, we have identified a Notch-regulated microRNA, miR-322, the rodent homolog of human miR-424, which was reported to promote angiogenesis by blocking degradation of HIF-1? isoforms in human endothelial cells during hypoxia, suggesting a novel mechanism of crosstalk between Notch- regulated miR-322 and HIF-1?. We propose to investigate how Notch-1 and the newly identified Notch-1 target miR-322 sustain and potentiate the beneficial effects of HP on the vascular cell survival and angiogenic activity of stem cells. We will also determine whether harnessing these regulatory mechanisms in stem cells can enhance vessel protection and repair in a mouse model of myocardial infarction (MI). There are three aims:
Aim 1 : Test the hypothesis that Notch signaling regulates the beneficial effects of HP in stem cell-mediated vascular repair.
Aim 2 : Test the hypothesis that miR-322 mediates crosstalk between Notch1 and HIF-1? signaling in stem cells to enhance their activity.
Aim 3 : Test the therapeutic potential of targeting the Notch1/miR-322 axis to enhance stem cell-mediated vascular repair and angiogenesis in a mouse model of MI. Successful completion of the proposed studies will elucidate novel mechanisms associated with C-MSC mediated vascular repair and angiogenesis and enhance the efficacy of C-MSC therapy.

Public Health Relevance

Stem cells can be used to repair damaged vessels in hearts, but the beneficial effects thus far have been limited. We have discovered that stem cells lose an important pathway of communication, called Notch, which may limit their therapeutic potential. We will investigate how Notch helps stem cells work properly and determine whether we can use this information to improve stem cell repair.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wong, Renee P
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Augusta University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Dou, Huijuan; Feher, Attila; Davila, Alec C et al. (2017) Role of Adipose Tissue Endothelial ADAM17 in Age-Related Coronary Microvascular Dysfunction. Arterioscler Thromb Vasc Biol 37:1180-1193
Gao, Lixia; Wang, Xuli; Tang, Yaoliang et al. (2017) FGF19/FGFR4 signaling contributes to the resistance of hepatocellular carcinoma to sorafenib. J Exp Clin Cancer Res 36:8
Li, Jie; Ma, Wenxia; Yue, Guihua et al. (2017) Cardiac proteasome functional insufficiency plays a pathogenic role in diabetic cardiomyopathy. J Mol Cell Cardiol 102:53-60
Yiew, Nicole K H; Chatterjee, Tapan K; Tang, Yao Liang et al. (2017) A novel role for the Wnt inhibitor APCDD1 in adipocyte differentiation: Implications for diet-induced obesity. J Biol Chem 292:6312-6324
Cuomo, Jason R; Sharma, Gyanendra K; Conger, Preston D et al. (2016) Novel concepts in radiation-induced cardiovascular disease. World J Cardiol 8:504-519
Park, Kyoung-Mi; Teoh, Jian-Peng; Wang, Yongchao et al. (2016) Carvedilol-responsive microRNAs, miR-199a-3p and -214 protect cardiomyocytes from simulated ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 311:H371-83
Kim, Ha Won; Weintraub, Neal L (2016) Aortic Aneurysm: In Defense of the Vascular Smooth Muscle Cell. Arterioscler Thromb Vasc Biol 36:2138-2140
Omar, Abdullah; Zhou, Mi; Berman, Adam et al. (2016) Genomic-based diagnosis of arrhythmia disease in a personalized medicine era. Expert Rev Precis Med Drug Dev 1:497-504
Bayoumi, Ahmed S; Sayed, Amer; Broskova, Zuzana et al. (2016) Crosstalk between Long Noncoding RNAs and MicroRNAs in Health and Disease. Int J Mol Sci 17:356
Chen, Yanfang; Tang, Yaoliang; Long, Weiwen et al. (2016) Stem Cell-Released Microvesicles and Exosomes as Novel Biomarkers and Treatments of Diseases. Stem Cells Int 2016:2417268

Showing the most recent 10 out of 12 publications