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Stem Cell Secretome Guides Therapeutic Outcomes in the Infarcted Heart

Review of “Secretome signature of cardiopoietic cells echoed in rescued infarcted heart proteome” from STEM CELLS Translational Medicine by Stuart P. Atkinson

The limited integration of administered mesenchymal stem cell-derived cardiopoietic stem cells [1] suggests that their therapeutic output, when applied to ischemic heart failure, mainly derives from paracrine acting factors [2, 3]. These findings combined with the mixed results observed in stem cell-based clinical trials [4, 5] prompted researchers led by Andre Terzic (Mayo Clinic, Rochester, Minnesota, USA) to survey the composition and functionality of cardiopoietic stem cell secretomes with high and low therapeutic potential in the hope of discovering features that improve patient outcomes.

In their recent STEM CELLS Translational Medicine study [6], Arrell et al. now report that the cardiopoietic stem cell secretome confers a therapeutic molecular imprint on recipient hearts and that predictive systems profiling can inform on therapeutic responses.

The authors systematically analyzed biobanked human cardiopoietic stem cells to explore potential links between the cardiopoietic secretome and therapeutic outcomes; this provided a profile of 155 proteins secreted by “therapeutically-optimal” cardiopoietic stem cells. Subsequent ingenuity pathway analysis expanded these findings into a network of 520 nodes that suggested the overall importance of enhanced indicators of vasculogenesis and cardiac and smooth muscle differentiation and development to improved outcomes.

By next applying this pathway analysis to the results of next-generation RNA sequencing, the study provided evidence for miR-146 as a master controller of the therapeutically-optimal secretome output of cardiopoietic stem cells, which may function through the activation of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), signal transducer and activator of transcription (STAT)1/6, and CAMP Responsive Element Binding Protein 1 (CREB1) transcription pathways.

Finally, and perhaps most interestingly, the authors analyzed infarcted mouse hearts treated with therapeutically-optimal cardiopoietic stem cell therapy one month after injury by label-free peptide quantification following nano-flow liquid chromatography-electrospray tandem mass spectrometry [7]. These results established that the recovery of function was accompanied by the recovery of a healthy-like proteome that mirrored the cardiopoietic cell secretome pattern.

Overall, this proof-of-concept study suggests that pre-treatment profiling of the cardiopoietic cell secretome may predict therapeutic efficacy in the infarcted heart.

For more on cardiopoietic cells, secretomes, systems analysis, and new, efficient cardioregenerative therapies, stay tuned to the Stem Cells Portal!


References

  1. Bartunek J, Behfar A, Dolatabadi D, et al., Cardiopoietic Stem Cell Therapy in Heart Failure: The C-CURE (Cardiopoietic stem Cell therapy in heart failURE) Multicenter Randomized Trial With Lineage-Specified Biologics. Journal of the American College of Cardiology 2013;61:2329-2338.
  2. Behfar A, Yamada S, Crespo-Diaz R, et al., Guided Cardiopoiesis Enhances Therapeutic Benefit of Bone Marrow Human Mesenchymal Stem Cells in Chronic Myocardial Infarction. Journal of the American College of Cardiology 2010;56:721-734.
  3. Emmert MY, Wolint P, Jakab A, et al., Safety and efficacy of cardiopoietic stem cells in the treatment of post-infarction left-ventricular dysfunction – From cardioprotection to functional repair in a translational pig infarction model. Biomaterials 2017;122:48-62.
  4. Terzic A and Behfar A, Stem cell therapy for heart failure: Ensuring regenerative proficiency. Trends in Cardiovascular Medicine 2016;26:395-404.
  5. Behfar A and Terzic A, Regeneration for All: An Odyssey in Biotherapy: Authors from the Mayo Clinic discuss the evolution of the regenerative paradigm and look to the future. European Heart Journal 2019;40:1033-1035.
  6. Arrell DK, Crespo-Diaz RJ, Yamada S, et al., Secretome signature of cardiopoietic cells echoed in rescued infarcted heart proteome. STEM CELLS Translational Medicine 2021;10:1320-1328.
  7. Arrell DK, Rosenow CS, Yamada S, et al., Cardiopoietic stem cell therapy restores infarction-altered cardiac proteome. npj Regenerative Medicine 2020;5:5.