15 Mar Using Small Carriers Increases Number of Cardiac Stem Cells Remaining in Heart
MedicalResearch.com Interview with:
Joost P.G. Sluijter, PhD, FESC
Department of Cardiology
Experimental Cardiology Laboratory
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Sluijter: Cell transplantation therapy for ischemic heart disease has entered the arena of clinical trials more than a decade ago. Multiple cell types have been used since these first endeavors, and there is accumulating evidence that different cell types positively influence the damaged heart through paracrine and/or regenerative mechanisms. One of the most promising cell types to be used are the cardiac-located stem cells. Cardiac stem cells (CSCs) have been found to reside in the adult heart and can differentiate towards all cell types that are needed in the normal functional heart. These cells have shown great potential as a regenerative therapeutic upon myocardial infarction (MI) in animal models and are currently being tested in some clinical studies. However, although promising, no systematic overview and subsequent meta-analysis of preclinical data exists to date for this cell type and if they are consistently effective. Our systematic approach, yielded 80 studies and included over 1900 animals, confirms the consistent effect of CSCs and provides us with a first comprehensive overview of pre-clinical MI studies in an unbiased and systematic manner. Nowadays we are aware of a failure in therapeutic effect size for the translation axis, where we try to bridge fundamental findings from the lab to the bedside. This means that effects we observe in our initial studies on cardiac performance are slowly getting less successful when we are getting closer to a real clinical scenario.
Through our meta-analysis, we observed a consistent therapeutic effect of Cardiac stem cells therapy on cardiac function after MI, where 12% of functional improvements is observed in rodents, and only an 8% improvement was still present in large animal models. From previous observations, we know that this leaves a 3-4% of effect in a patient population. In addition to the difference in effect size between small and large animal models, also a difference in study quality and attrition bias was observed. Interestingly, although additional support to the idea that Cardiac stem cells are efficacious in preclinical studies were observed, we did not find any influence of immunosuppression, cell source, comorbidity of CSC donors, culture methods, or model of ischemia on the outcomes.
MedicalResearch.com: What should clinicians and patients take away from your report?
Dr. Sluijter: What we learned from one of our recent in-depth large animal studies is that cell injection into the myocardium is far from being as effective as we hoped for. We already knew that injecting cells in the myocardium leaves only a 10% of cells behind in the region that we injected but we did not completely understand why. To complete our understanding and try to improve this, we used an experimental set-up in our facilities that reflects the clinical scenario’s in patients. We visualize the real-time dynamics of intra-myocardial stem-cell injections and observed a massive, immediate wash-out via the venous drainage, accounting for the low retention. This means that immediately upon injection, cells are taking the exit route of the heart and start circulating in our blood stream.
Fortunately, we developed a technology that can overcome this dramatic effect by using small carriers of natural materials that help the cells to maintain their presence in the myocardium. If we place our stem cells on these small carriers they remain in the myocardium in both the small and large animal models, thereby reaching a 20-30 fold increase in cell numbers. The cells do not experience any negative side-effects and this seems a simple but effective approach to move the cardiac stem cell field forward.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Dr. Sluijter: I think that these studies show that we have an ambitious and great team of people that try to connect the bed and lab to get closer to a solution of issues for this new therapeutic field. I think this essential to overcome these translation failures in the experimental setting and come to real efficacy in the patients.
MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.
– Zwetsloot PP, Végh AM, Jansen Of Lorkeers SJ, van Hout GP, Currie GL, Sena ES, Gremmels H, Buikema JW, Goumans MJ, Macleod MR, Doevendans PA, Chamuleau SA, Sluijter JP. Cardiac Stem Cell Treatment in Myocardial Infarction: A Systematic Review and Meta-Analysis of Preclinical Studies. Circ Res. 2016 Feb 17. pii: CIRCRESAHA.115.307676
– van den Akker F, Feyen DA, van den Hoogen P, van Laake LW, van Eeuwijk EC, Hoefer I, Pasterkamp G, Chamuleau SA, Grundeman PF, Doevendans PA, Sluijter JP. Intramyocardial stem cell injection: go(ne) with the flow. Eur Heart J. 2016 Feb 24. pii: ehw056. [Epub ahead of print]
– Feyen DA, Gaetani R, Deddens J, van Keulen D, van Opbergen C, Poldervaart M, Alblas J, Chamuleau S, van Laake LW, Doevendans PA, Sluijter JP. Gelatin Microspheres as Vehicle for Cardiac Progenitor Cells Delivery to the Myocardium. Adv Healthc Mater. 2016 Feb 23. doi: 10.1002/adhm.201500861. [Epub ahead of print]
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Joost P.G. Sluijter (2016). Using Small Carriers Increases Number of Cardiac Stem Cells Remaining in Heart MedicalResearch.com