Induced pluripotent stem cells (iPSCs) are a novel source for cardiovascular regenerative medicine. Because iPSCs are derived from the tissues of recipient patients, they obviate two major problems in the field of human embryonic stem cells (hESCs), namely immune rejection and the political/ethical concerns regarding the destruction of embryos. However, at present the field is in its infancy, and issues surrounding the efficiency, safety, and efficacy of iPSC-based derivatives require resolution before reduction to clinical practice occurs. This multi-disciplinary project will investigate the epigenomics of iPSC-derived endothelial cells (iPSC-ECs) for use in a murine myocardial infarction model. First, endothelial cells and fibroblasts will be de-differentiated into iPSCs. These two lines, as well as hESCs, will then be differentiating into endothelial cells. The stem cells, their tissues of origin (for the two iPSCs), and their endothelial derived tissues will be subjected to second-generation sequencing to determine their epigenomic states. Finally, the three stem cell-derived endothelial cell lines will be injected into a murine myocardial infarction system. Their effects on myocardial function will be observed over time. These experiments are anticipated to reveal the epigenomic features underlying more efficient somatic cell reprogramming, more robust stem cell differentiation, and greater therapeutic capacity for myocardial ischemia. These studies should pave the way to identifying molecular interventions which can be integrated into iPSC-EC preparation, so that eventually, these stem cell derivatives may be effective in the clinical setting for cardiovascular disease patients

Public Health Relevance

Studying the epigenomics of stem-cell reprogramming and differentiation should allow for greater efficiency in their preparation. Tracking their subsequent behavior in a myocardial ischemia model will lead to molecular manipulations of the epigenome to make them more beneficial to patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32HL110473-02
Application #
8311991
Study Section
Special Emphasis Panel (ZRG1-F10A-S (20))
Program Officer
Meadows, Tawanna
Project Start
2011-07-20
Project End
2014-07-19
Budget Start
2012-07-20
Budget End
2013-07-19
Support Year
2
Fiscal Year
2012
Total Cost
$59,432
Indirect Cost
Name
Stanford University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Martin-Almedina, Silvia; Martinez-Corral, Ines; Holdhus, Rita et al. (2016) EPHB4 kinase-inactivating mutations cause autosomal dominant lymphatic-related hydrops fetalis. J Clin Invest 126:3080-8
Xiao, Zhenyu; Chung, Haniee; Banan, Babak et al. (2015) Antibody mediated therapy targeting CD47 inhibits tumor progression of hepatocellular carcinoma. Cancer Lett 360:302-9
Schultz, Matthew D; He, Yupeng; Whitaker, John W et al. (2015) Human body epigenome maps reveal noncanonical DNA methylation variation. Nature 523:212-6
Lin, Yiing; Lin, Shin; Baxter, Melanie D et al. (2015) Novel APC promoter and exon 1B deletion and allelic silencing in three mutation-negative classic familial adenomatous polyposis families. Genome Med 7:42
Leung, Danny; Jung, Inkyung; Rajagopal, Nisha et al. (2015) Integrative analysis of haplotype-resolved epigenomes across human tissues. Nature 518:350-4
Fotiou, Elisavet; Martin-Almedina, Silvia; Simpson, Michael A et al. (2015) Novel mutations in PIEZO1 cause an autosomal recessive generalized lymphatic dysplasia with non-immune hydrops fetalis. Nat Commun 6:8085
Roadmap Epigenomics Consortium; Kundaje, Anshul; Meuleman, Wouter et al. (2015) Integrative analysis of 111 reference human epigenomes. Nature 518:317-30
Yue, Feng; Cheng, Yong; Breschi, Alessandra et al. (2014) A comparative encyclopedia of DNA elements in the mouse genome. Nature 515:355-64
Lin, Shin; Lin, Yiing; Nery, Joseph R et al. (2014) Comparison of the transcriptional landscapes between human and mouse tissues. Proc Natl Acad Sci U S A 111:17224-9
Lin, Shin; Tremmel, Jennifer A; Yamada, Ryotaro et al. (2013) A novel stress echocardiography pattern for myocardial bridge with invasive structural and hemodynamic correlation. J Am Heart Assoc 2:e000097

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