Cellular mechanisms underlying cardiac engraftment of stem cells

ABSTRACT

Introduction: Over the past decade, it has become clear that long-term engraftment of any ex vivo expanded cell product transplanted into injured myocardium is modest and all therapeutic regeneration is mediated by stimulation of endogenous repair rather than differentiation of transplanted cells into working myocardium. Given that increasing the retention of transplanted cells boosts myocardial function, focus on the fundamental mechanisms limiting retention and survival of transplanted cells may enable strategies to help to restore normal cardiac function.

Areas covered: This review outlines the challenges confronting cardiac engraftment of ex vivo expanded cells and explores means of enhancing cell-mediated repair of injured myocardium.

Expert opinion: Stem cell therapy has already come a long way in terms of regenerating damaged hearts though the poor retention of transplanted cells limits the full potential of truly cardiotrophic cell products. Multifaceted strategies directed towards fundamental mechanisms limiting the long-term survival of transplanted cells will be needed to enhance transplanted cell retention and cell-mediated repair of damaged myocardium for cardiac cell therapy to reach its full potential.

KEYWORDS:

• Cardiac regeneration
• cell therapy
• engraftment
• heart failure
• myocardial infarction

Article highlights

• Preclinical data has shown that stem cell therapy restores myocardial function after injury but clinical trials have demonstrated only modest improvements.

• Long -term engraftment of all transplanted cells is limited by mechanical washout of cells and apoptosis within the low oxygen/nutrient/inflammatory infarct environment.

• Any study transplanting suspended cells into injured hearts is fortunate if long-term retention exceeds 2% of the initial injectate- as such, all therapeutic regeneration achieved to date has been mediated by stimulation of endogenous repair rather than differentiation of transplanted cells into working myocardium.

• Increasing long term engraftment of transplanted cells provides salutary effects toward cell-mediated repair of injured myocardium.

• The next generation of cardiac cell therapy will need to adopt a multifaceted approach directed towards boosting long-term cell engraftment of transplanted cells for the field to move beyond reliance on indirect cell-mediated repair and towards de novo cardiogenesis.

This box summarizes key points contained in the article.

Declaration of interest

DR Davis has CIHR Clinical Scientist Personal Support (MC2-121291) while P Kanda is supported by the CIHR Frederick Banting and Charles Best Canada Graduate Scholarship Doctoral Award (140330). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

The authors are supported by the Canadian Institutes of Health Research (CIHR) (Award No. 229694) and the Heart and Stroke Foundation of Canada (NA-7346)