Stimulating endogenous cardiac repair

Abstract

The healthy adult heart has a low turnover of cardiac myocytes. The renewal capacity, however, is augmented after cardiac injury. Participants in cardiac regeneration include cardiac myocytes themselves, cardiac progenitor cells, and peripheral stem cells, particularly from the bone marrow compartment. Cardiac progenitor cells and bone marrow stem cells are augmented after cardiac injury, migrate to the myocardium, and support regeneration. Depletion studies of these populations have demonstrated their necessary role in cardiac repair. However, the potential of these cells to completely regenerate the heart is limited. Efforts are now being focused on ways to augment these natural pathways to improve cardiac healing, primarily after ischemic injury but in other cardiac pathologies as well. Cell and gene therapy or pharmacological interventions are proposed mechanisms. Cell therapy has demonstrated modest results and has passed into clinical trials. However, the beneficial effects of cell therapy have primarily been their ability to produce paracrine effects on the cardiac tissue and recruit endogenous stem cell populations as opposed to direct cardiac regeneration. Gene therapy efforts have focused on prolonging or reactivating natural signaling pathways. Positive results have been demonstrated to activate the endogenous stem cell populations and are currently being tested in clinical trials. A potential new avenue may be to refine pharmacological treatments that are currently in place in the clinic. Evidence is mounting that drugs such as statins or beta blockers may alter endogenous stem cell activity. Understanding the effects of these drugs on stem cell repair while keeping in mind their primary function may strike a balance in myocardial healing. To maximize endogenous cardiac regeneration, a combination of these approaches could ameliorate the overall repair process to incorporate the participation of multiple cellular players.

Keywords: beta blockers; cardiac progenitor cells; cell therapy; gene therapy; regeneration; statins; stem cells.

Figure 1

Endogenous cardiac regeneration. After a cardiac insult, a significant number of cardiac mycoytes die and vessel density gets reduced. In a very limited way, the heart has the ability to regenerate but it is insufficient to compensate for the total damage. The cellular participants in the endogenous regeneration process may include cardiac myocytes (pink cells, black lines), local cardiac progenitor cells (blue cells), and recruited peripheral stem cells (red cells). These cells have the potential to proliferate and participate in the regeneration of cardiac myocytes, angiogenesis, and the release of trophic factors that may reduce cardiac cell death. Modes of the cells participation are identified by colored arrows (peripheral stem cell, red; cardiac progenitor cell, blue; cardiac myocyte, green). Methods that could be employed to improve these endogenous mechanisms include cell and/or gene therapy and pharmacologic treatments.

Figure 2

Cardiac cell therapy. After a cardiac injury, a patient's adult stem cells are isolated. These cells can be isolated from either cardiac tissue or from peripheral sites. The cells are amplified to have a sufficient number for therapeutic transplant. The cells are injected into the patient either intravenously or intracardiac, alone or in the presence of pro-survival cocktails, hydrogels, or extracellular matrix patches. The injected cells can participate themselves in cardiac regeneration or improve endogenous healing by excreting paracrine factors which reduce apoptosis and increase stem cell recruitment and activity and angiogenesis to repair the damaged cardiac tissue.

Figure 3

Cardiac gene therapy. In animal models, cardiac gene therapy has shown to be successful when delivered by direct plasmid, in a lenti- or adenovirus, or in exosomes. Growth factors, chemokines, transcription factors and miRNAs have all been tested in cardiac gene therapy. Expression of these proteins and miRNAs have the potential to improve endogenous cardiac regeneration through the recruitment, activation and differentiation of local and peripheral stem cells, improved vascular density, or by proliferation of cardiac myocytes. Additional cardiac “rescuing” gene therapy targets (e.g., Serca2a) can improve cardiac function but it has yet to been investigated if these approaches can alter endogenous cardiac regeneration.