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Boosting Stem Cell Survival to Enhance Cardiac Therapy

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Review of “Preconditioning Human Cardiac Stem Cells with an HO-1 Inducer Exerts Beneficial Effects After Cell Transplantation in the Infarcted Murine Heart” from Stem Cells by Stuart P. Atkinson

The transplantation of stem cells, or stem cell-derived cells, aims to promote cellular regeneration and repair in the hopes of returning the patient back to health. However, if these cells cannot survive well in the often-inhospitable area of damage, their reparative potential may be lost.

This is the situation facing researchers aiming to construct stem cell therapies to treat the consequences of cardiac infarction and the associated ischemia/reperfusion injury [1]. Studies have found that the transplantation of cardiac stem cells (CSCs) can improve cardiac function after myocardial infarction (MI) in an animal model [2], but the minimal survival of cells in the long-term [3, 4] may mute this effect.

So what tools do we have to boost CSC survival? A previous study from researchers at the University of Louisville, Kentucky and Albany Medical College, New York, USA demonstrated that a CSC pre-treatment step with cobalt protoporphyrin (CoPP) can promote cell survival and resistance to oxidative stress in vitro [5] via the induction of HO-1, which itself mediates cellular protection under conditions of injury, inflammation, and oxidative stress. Their new study, published in Stem Cells, extends this study to now show that this strategy can lead to enhanced survival in vivo accompanied by improved cardiac function and structure [6].

Following isolation from human patients undergoing bypass surgery, in vitro expansion, and a 12-hour preconditioning step with CoPP, the authors transplanted GFP-tagged CSCs into the mouse infarcted heart. Encouragingly, a significantly higher proportion of preconditioned CSCs survived at 1 and 5 weeks post-transplantation compared to unconditioned cells, suggesting that CoPP enhances survival and/or proliferation.

Echocardiographic assessment at 5 weeks demonstrated that preconditioned CSC transplantation mediated a greater improvement in LV remodeling (See Figure) and in regional wall motion in the infarcted region while hemodynamic analysis found a significant improvement in load-independent measures of LV performance. Interestingly, both unconditioned and preconditioned CSCs reduced scar tissue and increased viable tissue present, although LV remodeling was more pronounced with the preconditioned CSCs.

At this point, cellular analysis correlated these improvements to an increase in the formation of newly formed cells expressing cardiac markers. Assessment of the newly formed human cells in the heart found an increase in the proliferation of preconditioned CSCs and also in the differentiation of CSCs towards mature cardiac cells, such as cardiomyocytes, even if this only represented a very small proportion of total cells. This, therefore, suggests that that preconditioned CSCs may mediate endogenous cardiac regeneration via a paracrine/support mechanism.

While the distinct mechanisms which contribute to the observed improvement in heart function remain to be discovered, CoPP treatment does appear to be a safe and effective means to improve CSC-based therapy. It is likely that paracrine mechanisms are key, with multiple factors acting in a synergistic manner, although the authors do note that there is room for improvement, given that some heart parameters measured did not improve upon CSC preconditioning.

References

  1. Hong KU and Bolli R Cardiac stem cell therapy for cardiac repair. Curr Treat Options Cardiovasc Med 2014;16:324.
  2. Bearzi C, Rota M, Hosoda T, et al. Human cardiac stem cells. Proc Natl Acad Sci U S A 2007;104:14068-14073.
  3. Hong KU, Li QH, Guo Y, et al. A highly sensitive and accurate method to quantify absolute numbers of c-kit+ cardiac stem cells following transplantation in mice. Basic Res Cardiol 2013;108:346.
  4. Hong KU, Guo Y, Li QH, et al. c-kit+ Cardiac stem cells alleviate post-myocardial infarction left ventricular dysfunction despite poor engraftment and negligible retention in the recipient heart. PLoS One 2014;9:e96725.
  5. Cai C, Teng L, Vu D, et al. The heme oxygenase 1 inducer (CoPP) protects human cardiac stem cells against apoptosis through activation of the extracellular signal-regulated kinase (ERK)/NRF2 signaling pathway and cytokine release. J Biol Chem 2012;287:33720-33732.
  6. Cai C, Guo Y, Teng L, et al. Preconditioning Human Cardiac Stem Cells with an HO-1 Inducer Exerts Beneficial Effects After Cell Transplantation in the Infarcted Murine Heart. STEM CELLS 2015;33:3596-3607.