Due to rise in cardiovascular disease throughout the world, there is increasing demand for small diameter blood vessels as replacement grafts. Although venous grafts are currently the golden standard, the ten-year failure rate is approaching 35%. Bioengineered vascular grafts are capable of remodeling in response to host signals and offer a clear alternative to existing technologies. Recently we showed that fibrin-based small- diameter tissue engineered blood vessels (TEV) exhibited vascular reactivity and considerable mechanical strength to withstand interpositional implantation into the jugular veins of lambs. Implanted TEV remained patent for the duration of the experiment (15 weeks), supported blood flow to the same degree as native veins and exhibited remarkable matrix remodeling. Despite significant progress in design of biomaterials for vascular tissue engineering, the source of cells remains a major problem. Isolation of autologous cells from the patient requires invasive surgery and injures the donor site. Most important, the proliferative capacity and functional properties of vascular smooth muscle cells are limited, especially when they originate from older donors, the population mostly in need for vascular prostheses. To address this challenge, we propose to isolate smooth muscle cells from the bone marrow (BM) of young (6 months to 1year old) and old (aged, >6 years old) animals using a novel methodology that we developed in our laboratory. Tissue engineered vessels from young (yBM-TEV) and aged (aBM-TEV) smooth muscle progenitor cells will be studied with a series of molecular and functional assays. The response of BM-TEV to biochemical and physical stimuli will be evaluated in order to establish optimal culture conditions that improve deposition of extracellular matrix and mechanical strength. Gene expression profiles will be obtained to identify molecules that may be responsible for potential loss of function as a result of aging. In addition, fibrin hydrogels will be decorated with growth factor fusion proteins as a means of improving signaling and enhancing the functional properties of BM-TEV. Finally, we will implant aBM-TEV and yBM-TEV in the venous system of young ovine recipients and assess patency and long-term remodeling up to one year post-implantation. The proposed work will elucidate the effects of aging on the potential of BM-derived smooth muscle cells as a source for vascular tissue engineering and will determine the biochemical and biophysical factors that enhance the functional properties of BM-TEV.

Public Health Relevance

Due to rise in cardiovascular disease throughout the world, there is increasing demand for small diameter blood vessels as replacement grafts. To address this health challenge, we will evaluate the potential of bone marrow as an autologous stem cell source for engineering small diameter vascular grafts for treatment of cardiovascular disease. The same cells may also be applied in engineering other cardiac tissues such as heart valves and cardiac patches further increasing the potential clinical impact of this work.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL086582-04
Application #
8047975
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Lundberg, Martha
Project Start
2008-05-01
Project End
2013-12-15
Budget Start
2011-04-01
Budget End
2013-12-15
Support Year
4
Fiscal Year
2011
Total Cost
$387,321
Indirect Cost
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
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Shahini, Aref; Vydiam, Kalyan; Choudhury, Debanik et al. (2018) Efficient and high yield isolation of myoblasts from skeletal muscle. Stem Cell Res 30:122-129
Shahini, Aref; Mistriotis, Panagiotis; Asmani, Mohammadnabi et al. (2017) NANOG Restores Contractility of Mesenchymal Stem Cell-Based Senescent Microtissues. Tissue Eng Part A 23:535-545
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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
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
Alimperti, Stella; Andreadis, Stelios T (2015) CDH2 and CDH11 act as regulators of stem cell fate decisions. Stem Cell Res 14:270-82
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

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