The promise of stromal cell-derived factor-1 in novel heart disease treatments

Journal of Molecular Medicine, Jul 2017

Friedrich C. Luft

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

https://link.springer.com/content/pdf/10.1007%2Fs00109-017-1569-6.pdf

The promise of stromal cell-derived factor-1 in novel heart disease treatments

The promise of stromal cell-derived factor-1 in novel heart disease treatments Friedrich C. Luft 0 0 Experimental and Clinical Research Center, Max-Delbrück Center for Molecular Medicine and Charité Medical Faculty , Lindenberger Weg 80, 13125 Berlin , Germany 1 Friedrich C. Luft - The stromal cell-derived factor 1 (SDF-1), also known as CX-C motif chemokine 12 (CXCL12), is a chemokine that is ubiquitously expressed in many tissues and cell types [ 1 ]. Chemokines activate leukocytes and are induced by proinflammatory stimuli such as lipopolysaccharide, tumor necrosis factor-α (TNF-α), or interleukin-1 (IL-1). SDF-1 is important in hematopoietic stem cell homing to the bone marrow as well as in hematopoietic stem cell quiescence. The CXCL12 gene encoding SDF-1 contains a single-nucleotide polymorphism (SNP) associated with coronary disease [ 2 ]. CXCR-4 is an alpha-chemokine receptor specific for SDF-1. The two molecules represent an axis that plays a role in stem cell homing during embryogenesis and in adulthood especially after tissues are exposed to ischemia [ 3 ]. Thus, the idea that SDF-1 could be relevant to human disease has great appeal. Cardiovascular disease is the commonest cause of death worldwide, and ischemic heart disease with resultant ischemic cardiomyopathy and heart failure are major contributors to this grim statistic. Stem cell-based approaches to alleviate ischemic heart failure have generated much excitement; however, results to date are unconvincing and disappointing [ 4 ]. CD34-expressing bone marrow-derived cells seemed to improve cardiac function even in initial human trials, but subsequent more rigorous studies could not duplicate the initial results [ 5 ]. The original idea in these studies was the hope that bone marrow-derived cells would trans-differentiate into cardiomyocytes [ 6 ]. Insufficient homing and engraftment could have contributed to the eventual lack of success. Another approach could be recruitment of cells in cardiac tissue that specifically express the surface tyrosine receptor kinase, cKit. Mesenchymal stem cells (MSCs) enhance the efficacy of cardiac cKit+ cells. Hatzistergos et al. recently tested the hypothesis that MSCs stimulate endogenous cardiac cKit+ cells via the SDF-1/CXCR4 pathway [ 7 ]. The endothelial expression of SDF-1 acts as a signal indicating the presence of tissue ischemia. The hypoxia-inducible factor-1 (HIF-1) directly regulates SDF-1 expression [ 8 ]. Subsequent events, including proliferation, patterning, and assembly of recruited progenitors, are also influenced by tissue oxygen tension and hypoxia. Furthermore, both SDF-1 and hypoxia are present in the bone marrow niche. This finding suggests that hypoxia may be a fundamental requirement for progenitor cell trafficking and function. Thus, ischemic tissue may represent a conditional stem cell niche with the recruitment and retention of circulating progenitors regulated by hypoxia through differential expression of SDF-1. In this issue of J Mol Med, Ghadge et al. took advantage of these interrelationships to address the issue of cardiac repair after experimental myocardial infarction [ 9 ]. They used transgenic CXCR4-EGFP reporter mice that contain a modified bacterial artificial chromosome (BAC) vector harboring an enhanced green fluorescent protein (EGFP) reporter gene. Mononuclear bone marrow-derived cells from these mice could be visually followed. Groups of mice were subjected to left anterior-descending (LAD) coronary artery ligationinduced myocardial infarction. Fluorescent antibody cellsorting analysis of CXCR4-EGFP reporter mice display enhanced numbers of CD45+/CXCR4+/CD11b+ cells in the bone marrow and within the ischemic hearts. In the ischemic hearts, cells expressing CD4+,CD20+, and other markers including cKit+ were increased. In the bone marrow and heart, CXCR4-EGFP was predominantly expressed in CD45+/ CD11b+ leukocytes, which significantly increased after myocardial ischemia. The authors next aimed to augment CXCR4+ cell recruitment and myocardial repair by activating HIF-1α target genes, including SDF-1 and CXCR4. They administered dimethyloxalylglycine (DMOG), a compound inhibiting prolyl-hydroxylase (PH). DMOG treatment caused upregulation of HIF-1α. Furthermore, DMOG increased SDF-1 and CXCR4 mRNA expression time and dose dependently. SDF-1 was increased in both cytosol and nuclear fraction of non-infarcted and infarcted hearts. Other HIF-1α target genes such as vascular endothelial growth factor (VEGF), phosphoinositidedependent kinase-1, and lactate dehydrogenase-A were also increased. Finally, reporter mice treated with DMOG showed a robust CXCR4-EGFP activity induction in coronary artery vessels and cardiac capillary networks. The authors also found that DMOG treatment decreased apoptosis and increased neovascularization in the heart. But more impressively, DMOG reduced myocardial scar size and improved cardiac function. For the func (...truncated)


This is a preview of a remote PDF: https://link.springer.com/content/pdf/10.1007%2Fs00109-017-1569-6.pdf

Friedrich C. Luft. The promise of stromal cell-derived factor-1 in novel heart disease treatments, Journal of Molecular Medicine, 2017, pp. 1-3, DOI: 10.1007/s00109-017-1569-6