Cell-based therapies for myocardial repair or regeneration have shown great potential;however, debate as to the efficacy of specific cell populations, the logistics of cell harvesting and expansion, the mechanisms of cell- based myocardial repair/regeneration remain to be elucidated. Most importantly difficulties over cell isolation, immune tolerance, cellular engraftment and integration remain. Therefore strategies to augment cell delivery, cell function/survival are crucial in permitting successful myocardial repair/regeneration through cellular therapy. Recently, we have demonstrated that autogeneic mitochondria isolated from the patient's own body, from skeletal tissue, unaffected by ischemia and then injected into the ischemic zone during early reperfusion significantly decreases myonecrosis (necrosis and apoptosis) and significantly enhance post-ischemic function. The transplanted mitochondria are viable, respiration competent, maintain membrane potential, are present in the myocardium for at least 21 days after injection and are distributed from the epi- to the sub- endocardium at significant distance from the site of injection. The isolation and preparation of autogeneic mitochondria from remote skeletal muscle is rapid and can be performed in <90 min. - a time frame reasonable within the clinical interventions of both coronary artery bypass grafting (CABG) and percutaneous coronary intervention for coronary revascularization for ST segment elevation myocardial infarction (PCI-STEMI). Autogeneic mitochondrial transplantation provides immunological advantages for practical application without the use of anti-rejection drug therapy and could be used either as an exclusive intervention or as a primary intervention prior to subsequent auto-, allo- or xeno-geneic cellular regenerative interventions to ameliorate myonecrosis and enhance myocardial function. We propose to optimize the use of autogeneic mitochondrial transplantation for the amelioration of myonecrosis and enhancement of myocardial function in the clinically relevant in situ CABG and PCI-STEMI model;and to identify the specific mechanism(s) through which autogenic mitochondrial transplantation significantly enhances surgical cardioprotection using biochemical /immunohistochemical, NMR and integrated transcriptomic and proteomic analysis.

Public Health Relevance

Recently, we have demonstrated that autogeneic mitochondria isolated from the patient's own body, from remote skeletal tissue unaffected by ischemia, and then directly injected into the ischemic zone of the myocardium during early reperfusion, significantly decrease myonecrosis (necrosis and apoptosis) and significantly enhance post-ischemic functional recovery. In this application we propose to optimize the use of autogeneic mitochondrial transplantation for the amelioration of myonecrosis and enhancement of myocardial function in the clinically relevant in situ coronary artery bypass grafting (CABG) and percutaneous coronary intervention for coronary revascularization for ST segment elevation myocardial infarction (PCI-STEMI) model;and to identify the specific mechanism(s) through which autogenic mitochondrial transplantation significantly enhances surgical cardioprotection using biochemical /immunohistochemical, NMR and integrated transcriptomic and proteomic analysis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL103642-03
Application #
8284454
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Wong, Renee P
Project Start
2010-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
3
Fiscal Year
2012
Total Cost
$430,650
Indirect Cost
$183,150
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Preble, Janine M; Pacak, Christina A; Kondo, Hiroshi et al. (2014) Rapid isolation and purification of mitochondria for transplantation by tissue dissociation and differential filtration. J Vis Exp :e51682
Masuzawa, Akihiro; Black, Kendra M; Pacak, Christina A et al. (2013) Transplantation of autologously derived mitochondria protects the heart from ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 304:H966-82