Can the Stem Cell Secretome Support Longer Storage of Donor Hearts and Boost Transplantation Numbers?

Review of “Adipose Stem Cell Secretome Markedly Improves Rodent Heart and hiPSC-derived Cardiomyocyte Recovery from Cardioplegic Transport Solution Exposure” from STEM CELLS by Stuart P. Atkinson

While heart transplantation remains a crucial therapy for end‐stage organ failure, deterioration during transportation can limit the availability of donated hearts [1]. Studies from researchers led by Keith L. March and Pinar Zorlutuna (University of Notre Dame, Notre Dame, IN, USA) [2] and others [3] have shown that the secretome of adipose-derived mesenchymal stem cells (ASCs) contains factors that may rescue tissues from post‐ischemic damage in vivo by targeting multiple physiological pathways involved in tissue rescue/repair [4]. Therefore, exposure to the ASC secretome may represent an exciting means to ameliorate heart damage and increase the number of acceptable hearts for transplantation.

Reporting in a recent STEM CELLS study [5], Ellis et al. aimed to explore the influence of the ASC secretome on the transplantation of human‐induced pluripotent stem cell (iPSC)‐derived cardiomyocytes [6], used as a useful and available proxy for the human heart, into the mouse heart after exposure to current clinical protocols for cardiac transportation. Encouragingly, their findings suggest that the ASC secretome may allow the lengthening of heart storage time before significant deterioration, thereby increasing the number of available hearts for transplantation.

The authors compared the influence of the ASC secretome on the recovery of mouse hearts and iPSC‐derived cardiomyocytes following six-hours of preservation in cold University of Wisconsin cardioplegic solution, regarded as the gold standard for organ preservation. Cold ischemic periods extending beyond four hours progressively compromise recovery of heart function and worsen prognosis following transplantation, and the six-hour preservation employed in this study prompted a loss of contractile activity and an increase in cell apoptosis; however, the addition of the ASC secretome effectively inhibited any preservation-associated adverse effects. Overall, augmenting UW cardioplegic solution with the ASC secretome significantly improved both the degree of mouse heart functional recovery and, importantly, the duration of acceptable storage of iPSC‐derived cardiomyocytes.

Interestingly, the authors also established that the expression and secretion of specific antioxidant enzymes (extracellular superoxide dismutase and catalase) and the associated cellular clearance of reactive oxygen species by ASCs mediated a significant proportion of the cardiomyocyte‐protective effect. This finding could pave the way for stem cell engineering-approaches to further potentiate the therapeutic potential of the ASC secretome.

Overall, the authors anticipate that the augmentation of standard preservation solutions with concentrated solutions of the ASC secretome following organ donation could significantly expand the usable donor pool, thereby addressing a critical medical need for advanced heart failure patients.

For more on the power of the stem cell secretome, stay tuned to the Stem Cells Portal!

Reference

1. Young JB, Hauptman PJ, Naftel DC, et al., Determinants of early graft failure following cardiac transplantation, a 10-year, multi-institutional, multivariable analysis. The Journal of Heart and Lung Transplantation 2001;20:212.
2. Rehman J, Traktuev D, Li J, et al., Secretion of Angiogenic and Antiapoptotic Factors by Human Adipose Stromal Cells. Circulation 2004;109:1292-1298.
3. Wang M, Crisostomo PR, Herring C, et al., Human progenitor cells from bone marrow or adipose tissue produce VEGF, HGF, and IGF-I in response to TNF by a p38 MAPK-dependent mechanism. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 2006;291:R880-R884.
4. Cai L, Johnstone BH, Cook TG, et al., IFATS Collection: Human Adipose Tissue-Derived Stem Cells Induce Angiogenesis and Nerve Sprouting Following Myocardial Infarction, in Conjunction with Potent Preservation of Cardiac Function. STEM CELLS 2009;27:230-237.
5. Ellis BW, Traktuev DO, Merfeld-Clauss S, et al., Adipose stem cell secretome markedly improves rodent heart and human induced pluripotent stem cell-derived cardiomyocyte recovery from cardioplegic transport solution exposure. STEM CELLS 2021;39:170-182.
6. Ellis BW, Acun A, Can UI, et al., Human iPSC-derived myocardium-on-chip with capillary-like flow for personalized medicine. Biomicrofluidics 2017;11:024105.