Due to rise in cardiovascular disease throughout the world, there is increasing demand for small diameter blood vessels as replacement grafts. In principle, the need for large number of autologous cells to populate those tissues can be met by adult mesenchymal stem cells (MSC), which show significant proliferation and differentiation potential. However, reports from several laboratories including ours showed that MSC originating from older donors suffer from limited proliferative capacity and significantly reduced differentiation potential. This is a major concern, as the patients mostly in need for vascular grafts are elderly. The current proposal seeks to address this challenge using a highly innovative approach that is based on preliminary data from our laboratory showing that the effects of aging can be reversed by expression of a single transcription factor, namely Nanog. Based on these results we propose the following specific aims. In the new aim 1 we will examine whether transient expression of Nanog is sufficient to reverse the effects of donor aging on proliferation and myogenic differentiation of MSC.
In aim 2 we will investigate a novel hypothesis to uncover the mechanism through which Nanog enhances transcription of myogenic genes and contractile function. We will also employ oligonucleotide microarrays as well as high throughput epigenetic analysis to determine how Nanog restructures the chromatin and unravel novel genes that are differentially expressed due to Nanog expression.
In aim 3 we will develop a novel strategy to deliver the Nanog protein into MSC in order to restore their lost function. Novel hypotheses will be addressed to engineer Nanog protein variants with enhanced transcriptional activity in order to maximize their potency in reversing the effects of senescence on MSC myogenic differentiation potential. Finally, in aim 4 we will examine the potential of the Nanog-treated stem cells for engineering small-diameter, functional blood vessels that could be implanted into the arterial system of a pre-clinical ovine animal model that was developed in our laboratory. Successful completion of this project will significantly enhance the therapeutic clinical potential of MSC from adult donors without genetic modification or reprogramming to the pluripotent state.

Public Health Relevance

Mesenchymal stem cells have tremendous potential as cell source for cellular therapies for treatment of cardiovascular disease. However, the proliferation and differentiation potential of MSC declines significantly with donor age, limiting the potential f MSC for treatment of older patients, the population most likely to suffer from cardiovascular disease. Here we propose a highly innovative research plan to reverse the effects of aging and enhance the therapeutic potential of MSC.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL086582-05A1
Application #
8629183
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Lundberg, Martha
Project Start
2006-12-01
Project End
2017-11-30
Budget Start
2013-12-16
Budget End
2014-11-30
Support Year
5
Fiscal Year
2014
Total Cost
$343,126
Indirect Cost
$118,126
Name
State University of New York at Buffalo
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260
Koobatian, Maxwell T; Row, Sindhu; Smith Jr, Randall J et al. (2016) Successful endothelialization and remodeling of a cell-free small-diameter arterial graft in a large animal model. Biomaterials 76:344-58
Son, Seoyoung; Liang, Mao-Shih; Lei, Pedro et al. (2015) Magnetofection Mediated Transient NANOG Overexpression Enhances Proliferation and Myogenic Differentiation of Human Hair Follicle Derived Mesenchymal Stem Cells. Bioconjug Chem 26:1314-27
Row, Sindhu; Peng, Haofan; Schlaich, Evan M et al. (2015) Arterial grafts exhibiting unprecedented cellular infiltration and remodeling in vivo: the role of cells in the vascular wall. Biomaterials 50:115-26
Alimperti, Stella; Andreadis, Stelios T (2015) CDH2 and CDH11 act as regulators of stem cell fate decisions. Stem Cell Res 14:270-82
Koobatian, Maxwell T; Liang, Mao-Shih; Swartz, Daniel D et al. (2015) Differential effects of culture senescence and mechanical stimulation on the proliferation and leiomyogenic differentiation of MSC from different sources: implications for engineering vascular grafts. Tissue Eng Part A 21:1364-75
Koobatian, Maxwell T; Koenigsknecht, Carmon; Row, Sindhu et al. (2015) Surgical technique for the implantation of tissue engineered vascular grafts and subsequent in vivo monitoring. J Vis Exp :e52354
Smith Jr, Randall J; Koobatian, Maxwell T; Shahini, Aref et al. (2015) Capture of endothelial cells under flow using immobilized vascular endothelial growth factor. Biomaterials 51:303-12
Lu, Yu; Loh, Yuin-Han; Li, Hu et al. (2014) Alternative splicing of MBD2 supports self-renewal in human pluripotent stem cells. Cell Stem Cell 15:92-101
Alimperti, Stella; Lei, Pedro; Wen, Yuan et al. (2014) Serum-free spheroid suspension culture maintains mesenchymal stem cell proliferation and differentiation potential. Biotechnol Prog 30:974-83
Alimperti, Stella; You, Hui; George, Teresa et al. (2014) Cadherin-11 regulates both mesenchymal stem cell differentiation into smooth muscle cells and the development of contractile function in vivo. J Cell Sci 127:2627-38

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