Pro-angiogenic induction of myeloid cells for therapeutic angiogenesis can induce mitogen-activated protein kinase p38-dependent foam cell formation

Abstract

Background aims. Clinical trials for therapeutic angiogenesis use blood- or bone marrow-derived hematopoietic cells, endothelial progenitor cells (EPC) and mesenchymal stromal cells (MSC) for vascular regeneration. Recently concerns have emerged that all three cell types could also contribute to atherosclerosis by foam cell formation. Therefore, we asked whether human myelomonocytic cells, EPC or MSC can accumulate lipid droplets (LD) and develop into foam cells. Methods. LD accumulation was quantified by flow cytometry, confocal microscopy and cholesterol measurement in each of the cell types. The impact of an initial pro-angiogenic induction on subsequent foam cell formation was studied to mimic relevant settings already used in clinical trials. The phosphorylation state of intracellular signaling molecules in response to the pro-angiogenic stimulation was determined to delineate the operative mechanisms and establish a basis for interventional strategies. Results. Foam cells were formed by monocytes but not by EPC or MSC after pro-angiogenic induction. Mitogen-activated protein kinase (MAPK) p38 phosphorylation was enhanced and kinase inhibition almost abrogated intracellular LD accumulation in monocytes. Conclusions. These data suggest that hematopoietic cell preparations containing monocytes bear the risk of foam cell formation after pro-angiogenic induction. Instead, EPC and MSC may drive vascular regeneration without atherogenesis aggravation. A thorough understanding of cell biology is necessary to develop new strategies combining pro-angiogenic and anti-atherogenic effects during cell therapy.

Key Words::

• atherogenesis
• foam cell formation
• mitogen-activated protein kinase inhibition
• stem cell therapy
• therapeutic angiogenesis

Acknowledgments

The authors thank Tatjana Kueznik and Daniela Thaler for their excellent technical assistance, Nathalie Liechtenstein-Etchart and Anna Ortner for helpful discussions, Tina Schreiner for assistance with figure layout, and Monica Farrell for linguistic editing.

This work was supported by the Austrian Research Foundation (FWF) [N211-NAN], the Austrian Research Promotion Agency (FFG) [N200] to DS, the SFB [F 3004], [P19186] to DK and The Adult Stem Cell Research Foundation (TASC^RF) to AR. NAH and AR are fellows of the PhD program ‘Molecular Medicine’ of the Medical University of Graz.

Conflict of interest: none declared.