Myocardial infarction shows a loss of muscle fibers with ultimate failure to regenerate muscle tissue. Cell based therapies may restore ischemic areas and adipose tissue can provide a facile source of cells for such therapy. We have previously shown that human adipose tissue contains cells which have the potential to differentiate into cardiovascular linage. One of the main disadvantages of the existing differentiation protocols is that yields of Adipose Tissue-Derived Stem Cells (ASCs) have been very low and biochemical stimulation produces random spatial organization and electrically non-synchronization cardiomyocytes colonies. Therefore there is an obvious necessity for new approaches to understand and manipulate the differentiation process in order to achieve higher yields of synchronous cardiomyocytes that can engraft effectively within the damaged heart. To approach this goal we will utilize a novel optogentics system that has been recently shown to allow tunable neuronal activation and inhibition over a range of timescales. Specifically, in our aims we propose to: 1) Identify specific sub-populations of cardiac progenitor cells within Pericardial Adipose Tissue (PTA). Based on preliminary data referred to above, our working hypothesis is that PTA contains an ample source of pluripotent cells. 2) Determine the role of opto-genetics, in regulating human adipose stem cells (hASCs) differentiation to cardiovascular cells. We postulate again on the basis of our preliminary data, that continuous membrane potential depolarization promote hASCs commitment to facilitate the generation of CMs and 3) Evaluate the contribution of transplanted electrically synchronous hASCs to ischemic myocardial regeneration. It has been shown that transplanted hASCs-CMs improve cardiac function, here we hypothesize that synchronous hASCs-CMs can show higher rate of engraftment and directly contribute to the systolic function. These experiments should help us understand the mechanisms of ASCs differentiation and provide the basis for autologous stem cell transplantation for the treatment of ischemic cardiomyopathy.

Public Health Relevance

The project is relevant to the NIH mission because patients with ischemic cardiomyopathy will benefit from therapy whereby injected differentiated cardiomyocytes can be incorporated into the heart muscle. We have already shown that perivascular adipose stromal cells have a potential in differentiating into cardiomyocytes and that using our novel approach we can stimulate cells to redirect them into cardiac linage cells. Hereby we propose to characterize and enhance the potential of these cells and explore how they can help in cardiac muscle regeneration using optogenetic stimulation. This research could provide a basis for autogenous tissue being used as a source of cells for the treatment of end-stage ischemic heart disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21EB012155-02
Application #
8240970
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Hunziker, Rosemarie
Project Start
2011-04-01
Project End
2013-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
2
Fiscal Year
2012
Total Cost
$197,623
Indirect Cost
$72,623
Name
Stanford University
Department
Surgery
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Myers, Frank B; Silver, Jason S; Zhuge, Yan et al. (2013) Robust pluripotent stem cell expansion and cardiomyocyte differentiation via geometric patterning. Integr Biol (Camb) 5:1495-506
Patlolla, Bhagat; Beygui, Ramin; Haddad, Francois (2013) Right-ventricular failure following left ventricle assist device implantation. Curr Opin Cardiol 28:223-33
Ge, Jun; Neofytou, Evgenios; Cahill 3rd, Thomas J et al. (2012) Drug release from electric-field-responsive nanoparticles. ACS Nano 6:227-33