SDF-1 in myocardial repair

Abstract

Stem cell therapy for the prevention and treatment of cardiac dysfunction holds significant promise for patients with ischemic heart disease. Excitingly early clinical studies have demonstrated safety and some clinical feasibility, while at the same time studies in the laboratory have investigated mechanisms of action and strategies to optimize the effects of regenerative cardiac therapies. One of the key pathways that has been demonstrated critical in stem cell-based cardiac repair is (stromal cell-derived factor-1) SDF-1:CXCR4. SDF-1:CXCR4 has been shown to affect stem cell homing, cardiac myocyte survival and ventricular remodeling in animal studies of acute myocardial infarction and chronic heart failure. Recently released clinical data suggest that SDF-1 alone is sufficient to induce cardiac repair. Most importantly, studies like those on the SDF-1:CXCR4 axis have suggested mechanisms critical for cardiac regenerative therapies that if clinical investigators continue to ignore will result in poorly designed studies that will continue to yield negative results. Gene Therapy (2012) 19, 583-587; doi:10.1038/gt.2012.32Keywords: acute myocordial infarction; regenerative medicine; stem cells; chemokines INTRODUCTIONOver a decade ago we hypothesized that stem cell-based repair of ischemic tissue is a natural response to tissue injury but that it is clinically inefficient because of the short-lived nature of the molecular signals regulating the process, not a lack of stem cells. At that time it was of great interest to us that stem cells in the blood stream homed to the myocardium in animal models of acute myocardial infarction (AMI), but not in models of chronic ischemic cardiomyopathy. These observations led us to investigate potential regulators of stem cell homing. We eventually identified stromal cell-derived factor-1 (SDF-1, aka CXCL12) as the key regulator of stem cell migration to sites of tissue injury. 1 More recently studies have extended the relevance of the SDF-1:CXCR4 axis by demonstrating its critical importance in cardiogenic specification during development. 2 As that initial observation we have demonstrated that transient engineered-cell-based 3 or plasmid-based 4 overexpression of SDF-1 in ischemic cardiomyopathy improved cardiac function. Furthermore, we have demonstrated that delivery of mesenchymal stem cells engineered to overexpress SDF-1 at the time of AMI leads to improvement in cardiac function. 5 Research by our laboratory and others have demonstrated that mechanism of action of SDF-1 overexpression in AMI and chronic heart failure (CHF) are clearly multifactorial including both systemic and direct trophic effects. [4][5][6] The initiation of endogenous stem cell-based repair appears blunted because of the natural short-term expression of SDF-1 at the time of AMI. 1 Furthermore, there appears to be commonalities associated with the mechanisms of action of SDF-1 in AMI and CHF as well as some distinct differences. We were the first to show that SDF-1 leads to the recruitment of cardiac st...

Hypoxia Induces Myocardial Regeneration in Zebrafish

“…6,32-40 Furthermore, we were able to identify genes within the upregulated group that have a heart-associated function (the Table) such as thbs4b, jak2a, txnipa, pim1, slc4a1a, and cxcr4b. 39,[41][42][43][44][45] A number of proproliferative genes were also shown to be upregulated in the wild-type sample compared with the dnHIF1␣ sample (the Table). 46 -51 Although the positive aspects of dedifferentiation have not been intensely investigated, we were able to identify a couple of genes that have been linked to this phenomenon, namely jak2a and cxcr4b, albeit these are most commonly associated with cancer cell dedifferentiation.…”

Cardiovascular Actions of Incretin-Based Therapies

“…90 The majority of studies in young healthy rodents demonstrate that DPP-4 inhibition leads to cardioprotection, often in association with increased stem cell mobilization, thought to be secondary to enhanced levels of stromal cell-derived factor-1. 91 Stromal cell-derived factor-1, also designated chemokine (CXC motif) ligand 12 (CXCL12), regulates stem cell homing, angiogenesis, and cardiomyocyte repair and survival [92][93][94] through the CXC chemokine receptor type-4 . CXCL12 also binds to a second receptor, CXC chemokine receptor type-7; however, the importance, if any, of CXC chemokine receptor type-7 for CXCL12 action in the injured heart remains uncertain.…”

“…96 Enhancing CXCL12 activity, by administration of CXCL12, by viral, cellular, or plasmid-mediated overexpression of CXCL12, or through inhibition of DPP-4 activity, resulted in cardioprotective actions in the setting of acute ischemic cardiac injury. 93,97,98 Experimental and clinical diabetes mellitus may be associated with a reduced endothelial progenitor response to hypoxic injury 99 ; however, this defect is reversible on administration of CXCL12. 99,100 Furthermore, plasma levels of CXCL12 and circulating levels of progenitor cells are increased in human diabetic subjects treated with DPP-4 inhibitor, sitagliptin.…”

“…99,100 Furthermore, plasma levels of CXCL12 and circulating levels of progenitor cells are increased in human diabetic subjects treated with DPP-4 inhibitor, sitagliptin. 101 Given the extensive preclinical data linking CXCL12 activity to DPP-4 inhibitor-mediated cardioprotection, 91,93,97,98,102,103 CXCL12 is widely viewed as a putative mediator of DPP-4 action in the heart.…”

Novel stable cytokine delivery system in physiological pH solution: chitosan oligosaccharide/heparin nanoparticles

“…5,6 Various cytokines are essential for homing, proliferation, and differentiation of stem/progenitor cells in the process of tissue regeneration. 7,8 Cytokines have been widely studied in tissue regeneration, but their short half-lives and the low local concentrations render their application limited. 9,10 Therefore, a reliable delivery system able to localize cytokines to specific tissues for an extended period of time and maintain their bioactivity could improve the homing, differentiation, and proliferation of stem/progenitor cells at their target tissue.…”