Key result
Brief doxorubicin exposure drives persistent mitochondrial dysfunction and transcriptional reprogramming without cell death in human iPSCs.
Why the study?
The mechanisms by which doxorubicin-mediated damage to stem cells or cardiomyocytes contributes to cardiotoxicity and cardiac regeneration remain unclear.
Mild exposure of stem cells to doxorubicin induces persistent mitochondrial and transcriptional changes that may impair regenerative capacity, suggesting a mechanism for late-onset cardiotoxicity in pediatric patients.
May link transient doxorubicin to late cardiotoxicity via stem-cell memory; hypothesis-generating and requires in vivo validation.
How Doxorubicin (Dox) mediated damage to stem cells or cardiomyocytes contributes to cardiotoxicity and cardiac regeneration is unclear. Using a human iPSC-based model together with corresponding iPSC-derived cardiomyocytes (iCMs) revealed that iPSCs are much more sensitive against single short pulse-treatments with Dox than iCMs. Major mitochondrial impairments such as increased mitochondrial fragmentation, loss of mitochondrial membrane potential, reduced ATP levels, and altered mitochondrial DNA (mtDNA) organization, yet neither increased ROS formation, nuclear DNA damage response, nor apoptosis were detected in Dox-treated iPSCs. Whole genome transcriptome profiling revealed major differences in the transcriptional response to Dox including downregulation of genes regulating cellular homeostasis and energy metabolism. Dox exposure at the iPSC stage, termed priming here, shifts the global transcriptional landscape of iCMs towards reduced cardiac muscle regeneration, energy metabolism, muscle contraction, and increased fibrosis. Functionally, priming caused iCMs to ‘memorize’ this early Dox treatment resulting in reduced ATP levels, altered mtDNA organization, and in impaired contractility and oscillating Ca 2+ handling. We propose that Dox-induced mitochondrial dysfunction and transcriptional priming in stem cells alters durably cardiac and bioenergetic properties of its progeny which may impair the regenerative capacity after differentiation. This may be of particular relevance for children and teenagers undergoing chemotherapy.
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Westerhoff et al. (2026) studied Doxorubicin-induced cardiotoxicity. Doxorubicin vs. Untreated control was evaluated on Mitochondrial function, cellular homeostasis, and viability. Short pulse-treatment of human iPSCs with moderate doses of doxorubicin caused persistent mitochondrial dysfunction and genome-wide transcriptional reprogramming without inducing apoptosis or nuclear DNA damage.
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