| Popis: |
In 2001 it was noted that stem cells infused into the bloodstream within days of a myocardial infarction homed to the infarct zone. This led to the hypothesis that stem cell-based repair of injured tissue is a natural process that does not lead to significant clinical benefit due to dysregulation of the reparative system, not the lack of stem cells. At that time there was interest in defining the molecular regulators of endogenous stem cell repair of injured tissue. Stromal cell-derived factor-1 (SDF-1) was identified as a key regulator of stem cell recruitment to the heart following AMI. The overexpression of SDF-1 has been shown to recruit stem cells to the heart, inhibit cardiac myocyte death, and remodel scar, which leads to improvements in cardiac dimensions and function. It recruits both cardiac stem cells and bone marrow-derived stem cells to the infarct zone. Recently using mice that lack cardiac myocyte and cardiac stem cell CXCR4 expression, it was demonstrated that the release of SDF-1 by MSC is critical for MSC-induced inhibition of cardiac myocyte death and enhancement of cardiac stem cell recruitment. These data demonstrate that an important mechanism of effect of adult stem cell therapy is activation of endogenous stem cell repair and that one benefit of adult stem cell therapy is the temporal realignment of SDF-1 secretion with CXCR4 receptor expression by end-organ cells (cardiac myocytes) and endogenous tissue-specific stem cells (cardiac stem cells). SDF-1 overexpression was evaluated in a Phase I clinical trial that sought to re-establish SDF-1 expression in the myocardium of patients with NYHA Class III chronic heart failure due to a history of myocardial infarction (NCT01082094), and subsequently enrollment has been completed in three Phase II trials in chronic heart failure (NCT01643590, NCT01961726) and critical limb ischemia (NCT01410331). The results of these trials to date demonstrate the safety and efficacy of SDF-1 therapy to induce cardiac repair. Just as important as developing therapies that can lead to improved clinical outcomes is the potential to simultaneously expand our understanding of pathophysiology of ventricular dysfunction and is the goal of defining the molecular mechanisms associated with stem cell-based tissue repair strategies to optimize cardiac function. |
