Distinct influence of the anthracycline derivative doxorubicin on the differentiation efficacy of mESC-derived endothelial progenitor cells

• Published in: Biochimica et biophysica acta. Molecular cell research 2020-07, Vol.1867 (7), p.118711, Article 118711
• Main Authors: Jahn, Sarah K., Hennicke, Tatiana, Kassack, Matthias U., Drews, Leonie, Reichert, Andreas S., Fritz, Gerhard
• Format: Article
• Language: English
• Subjects: Cardiotoxicity; Doxorubicin; Endothelial cell functions; Endothelial progenitor cells; Genotoxic stress; mESC
• ISSN: 0167-4889; 1879-2596
• DOI: 10.1016/j.bbamcr.2020.118711

Cardiotoxicity is a highly relevant, because often life-threatening, adverse effect of doxorubicin (Doxo)-based anticancer therapy. Here, we investigated the Doxo-response of cardiovascular stem/progenitor cells employing a mouse embryonic stem cell (mESC)-based in vitro differentiation model. Endothelial progenitor cells revealed a pronounced Doxo sensitivity as compared to mESC, differentiated endothelial-like (EC) and cardiomyocyte-like cells (CM) and CM progenitors, which rests on the activation of senescence. Doxo treatment of EC progenitors altered protein expression of individual endothelial markers, actin cytoskeleton morphology, mRNA expression of genes related to mitochondrial functions, autophagy, apoptosis, and DNA repair as well as mitochondrial DNA content, respiration and ATP production in the surviving differentiated EC progeny. By contrast, LDL uptake, ATP-stimulated Ca2+ release, and cytokine-stimulated ICAM-1 expression remained unaffected by the anthracycline treatment. Thus, exposure of EC progenitors to Doxo elicits isolated and persistent dysfunctions in the surviving EC progeny. In conclusion, we suggest that Doxo-induced injury of EC progenitors adds to anthracycline-induced cardiotoxicity, making this cell-type a preferential target for pharmacoprotective and regenerative strategies. •EC progenitors are more sensitive to Doxo than mESC and differentiated cells.•Doxo pulse-treatment of EC progenitors alters morphology of differentiated progeny.•Doxo causes sustained alterations in the expression of susceptibility factors in EC.•Doxo exposure of EC progenitors affects mitochondrial functions of differentiated EC.•Doxo-induced injury of EC progenitors adds to anthracycline-induced cardiotoxicity.