The McCully Lab

Cell-based therapies for myocardial repair or regeneration have shown great potential; however, the efficacy of specific cell populations, the logistics of cell harvesting and expansion, and the mechanisms of cell-based myocardial repair or regeneration have yet to be established. Most importantly, difficulties over cell purification, immune tolerance, as well as cell engraftment, integration and function remain. Therefore, strategies to augment cell delivery, function and survival are crucial for successful myocardial repair or regeneration through cell-based therapies.

We have demonstrated that autogeneic (autologously-derived) mitochondria isolated from the patient’s own body, from remote tissue unaffected by ischemia and then directly injected into the ischemic zone of the myocardium during early reperfusion, significantly decreases myonecrosis and significantly enhances post-ischemic functional recovery in vivo. Our studies show that transplanted mitochondria initially act extracellularly to enhance energy production in the target organ. Subsequently, the transplanted mitochondria are taken up by cells and further increase oxygen consumption rates and ATP content. The transplanted mitochondria cause no electrical abnormalities or immune or auto-immune reactions. The transplanted mitochondria act to increase tissue protective cytokine production and up-regulate the signaling pathways associated with mitochondrial function and energy metabolism.

Autogeneic mitochondrial transplantation provides immunological advantages for practical application without the use of anti-rejection drug therapy. The transplantation of autogenic mitochondria could be used either as an exclusive intervention to ameliorate myonecrosis and enhance myocardial function or could be used as a primary intervention prior to subsequent auto-, allo- or xeno-geneic cellular regenerative interventions.

We have now demonstrated that transplanted mitochondria are internalized by a variety of cell types including cardiomyocytes, fibroblasts, skeletal myoblasts, cortical neurons, microglial cells, and astrocytes. These studies demonstrate that transplantation of autogeneic mitochondria offers a unique therapeutic opportunity that extends beyond their use for myocardial ischemia/reperfusion injury.

We have conducted clinically relevant, long-term survival, large animal studies to demonstrate the efficacy of mitochondrial transplantation in ischemia re-perfusion injuries of the heart, lungs, kidneys and limbs.