Functional impairment of human resident cardiac stem cells by the cardiotoxic Antineoplastic agent trastuzumab

Andreas S. Barth, Yiqiang Zhang, Taosheng Li, Rachel R. Smith, Isotta Chimenti, Ioannis Terrovitis, Darryl R. Davis, Eddy Kizana, Alice S. Ho, O'Rourke Brian, C. Antonio Wolff, Gary Gerstenblith, Eduardo Marbán

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


Trastuzumab (TZM), a monoclonal antibody against the ERBB2 protein, increases survival in ERBB2-positive breast cancer patients. Its clinical use, however, is limited by cardiotoxicity. We sought to evaluate whether TZM cardiotoxicity involves inhibition of human adult cardiac-derived stem cells, in addition to previously reported direct adverse effects on cardiomyocytes. To test this idea, we exposed human cardiosphere-derived cells (hCDCs), a natural mixture of cardiac stem cells and supporting cells that has been shown to exert potent regenerative effects, to TZM and tested the effects in vitro and in vivo. We found that ERBB2 mRNA and protein are expressed in hCDCs at levels comparable to those in human myocardium. Although clinically relevant concentrations of TZM had no effect on proliferation, apoptosis, or size of the c-kit-positive hCDC subpopulation, in vitro assays demonstrated diminished potential for cardiogenic differentiation and impaired ability to form microvascular networks in TZM-treated cells. The functional benefit of hCDCs injected into the border zone of acutely infarcted mouse hearts was abrogated by TZM: infarcted animals treated with TZM + hCDCs had a lower ejection fraction, thinner infarct scar, and reduced capillary density in the infarct border zone compared with animals that received hCDCs alone (n = 12 per group). Collectively, these results indicate thatTZMinhibits the cardiomyogenic and angiogenic capacities of hCDCs in vitro and abrogates the morphological and functional benefits of hCDC transplantation in vivo. Thus, TZM impairs the function of human resident cardiac stem cells, potentially contributing to TZM cardiotoxicity.

Original languageEnglish (US)
Pages (from-to)289-297
Number of pages9
JournalStem Cells Translational Medicine
Issue number4
StatePublished - 2012


  • Adult stem cells
  • Angiogenesis
  • Cardiac
  • Chemotherapy

ASJC Scopus subject areas

  • Medicine(all)


Dive into the research topics of 'Functional impairment of human resident cardiac stem cells by the cardiotoxic Antineoplastic agent trastuzumab'. Together they form a unique fingerprint.

Cite this