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Published on: August 26, 2017
G-CSF induced arteriogenesis in humans: molecular insights into a randomized controlled trial
Pascal Meier1, Steffen Gloekler, Berna Oezdemir
1The Heart Hospital, University College London Hospitals, London, UK.
Aims:
Recent data have demonstrated the feasibility of therapeutic induction of coronary collateral growth (arteriogenesis); however, mechanisms of action of such therapeutic collateral stimulation in humans are unknown. The aim of this study was to evaluate potential mechanisms, especially the involvement of arteriogenesis-relevant genes.
Methods And Results:
A total of 52 patients were randomized into two groups: subcutaneous G-CSF (10 μg/kg; n=26) or placebo (n=26). Before and after this 2-week treatment, collateral-flow index (CFI) was determined by simultaneous measurement of mean aortic, distal coronary occlusive and central venous pressure. CD34+ endothelial progenitor cells (EPC) and monocytes were quantified before, during and after treatment; gene-expression analysis of monocytes was performed with real-time polymerase chain reaction (RT-PCR). G-CSF lead to a significant increase of EPC and monocytes (4.8 and 2.6 fold, p < 0.05); for both cell types, the extent of increase correlated with CFI increase (r=0.23 and 0.14, p < 0.05). G-CSF also induced a change in gene expression of pro-and anti-arteriogenic genes in monocytes. Among nine assessed genes, three were found to be differentially regulated (IL8, JAK2, and PNPLa4; p < 0.05).
Conclusions:
The mechanism of induction of collateral growth by G-CSF is related to an increase of EPC and of peripheral monocytes. It also leads to a change toward a pro-arteriogenic gene expression in peripheral monocytes.
Insights
Granulocyte-colony stimulating factor (G-CSF) therapy increases endothelial progenitor cells (EPCs) and monocytes, promoting coronary collateral growth (arteriogenesis) through altered gene expression in monocytes.
Area of Science:
- Cardiovascular Research
- Regenerative Medicine
- Molecular Biology
Background:
- Therapeutic induction of coronary collateral growth (arteriogenesis) is feasible.
- Mechanisms of therapeutic collateral stimulation in humans remain largely unknown.
Purpose of the Study:
- To investigate the mechanisms of therapeutic collateral stimulation.
- To evaluate the involvement of arteriogenesis-relevant genes in response to G-CSF therapy.
Main Methods:
- Randomized controlled trial with 52 patients (G-CSF vs. placebo).
- Collateral-flow index (CFI) measurement before and after treatment.
- Quantification of CD34+ endothelial progenitor cells (EPCs) and monocytes.
- Gene expression analysis of monocytes using RT-PCR.
Main Results:
- G-CSF significantly increased EPCs and monocytes (4.8-fold and 2.6-fold, respectively).
- Increases in EPCs and monocytes correlated with CFI increase.
- G-CSF altered gene expression of pro- and anti-arteriogenic genes in monocytes, notably IL8, JAK2, and PNPLa4.
Conclusions:
- G-CSF induces collateral growth by increasing EPCs and peripheral monocytes.
- G-CSF shifts peripheral monocyte gene expression towards a pro-arteriogenic profile.
