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)