Adipose stem cell secretome markedly improves rodent heart and human induced pluripotent stem cell-derived cardiomyocyte recovery from cardioplegic transport solution exposure

Abstract

Heart transplantation is a life-saving therapy for end-stage organ failure. Organ deterioration during transportation limits storage to 4 hours, limiting hearts available. Approaches ameliorating organ damage could increase the number of hearts acceptable for transplantation. Prior studies show that adipose-derived stem/stromal cell secretome (ASC-S) rescues tissues from postischemic damage in vivo. This study tested whether ASC-S preserved the function of mouse hearts and human induced pluripotent stem cell-derived cardiomyocytes (iCM) exposed to organ transportation and transplantation conditions. Hearts were subjected to cold University of Wisconsin (UW) cardioplegic solution ± ASC-S for 6 hours followed by analysis using the Langendorff technique. In parallel, the effects of ASC-S on the recovery of iCM from UW solution were examined when provided either during or after cold cardioplegia. Exposure of hearts and iCM to UW deteriorated contractile activity and caused cell apoptosis, worsening in iCM as a function of exposure time; these were ameliorated by augmenting with ASC-S. Silencing of superoxide dismutase 3 and catalase expression prior to secretome generation compromised the ASC-S cardiomyocyte-protective effects. In this study, a novel in vitro iCM model was developed to complement a rodent heart model in assessing efficacy of approaches to improve cardiac preservation. ASC-S displays strong cardioprotective activity on iCM either with or following cold cardioplegia. This effect is associated with ASC-S-mediated cellular clearance of reactive oxygen species. The effect of ASC-S on the temporal recovery of iCM function supports the possibility of lengthening heart storage by augmenting cardioplegic transport solution with ASC-S, expanding the pool of hearts for transplantation.

Human Heart Anoxia and Reperfusion Tissue (HEART) Model for the Rapid Study of Exosome Bound miRNA Expression As Biomarkers for Myocardial Infarction

“…After day 9, media was changed every three days, and beating was observed generally by day 21 of differentiation as stated in previous papers. [ 29–31,48 ]…”

“…After day 9, media was changed every three days, and beating was observed generally by day 21 of differentiation as stated in previous papers. [29][30][31]48] 2.5. Induced Endothelial Cell (iEC) Differentiation iEC differentiation induction was performed using a previously established protocol.…”

Toward transplantation tolerance with adipose tissue-derived therapeutics

“…However, acquiring EVs with high yield and consistent biological activities remains challenging. New technologies, such as microfluidics, are being developed to overcome this impediment (64,65).…”

“…When streptozotocininduced diabetic mice were transplanted with islets that were previously preserved in the presence of these two AD-MSC secretome fractions, the recipients exhibited better glycemic control (73). Ellis et al reported that functional deterioration of murine heart allografts was mitigated when AD-MSC secretome was added to the cold preservation solution (65). Wang et al showed that miR-199-3p in the heart allograft was depleted during cold preservation, and the level can be recovered when the AD-MSC-derived EVs in the preservation solution transferred miR-199-3p to the graft (74).…”

“…In summary, current data have demonstrated that applying adipose-derived therapeutics to allografts can potentially promote graft function and survival after transplantation. Adding AD-MSC secretome to a cold preservation solution has been shown to improve graft function after transplantation (65,72,73). However, the benefits may be limited if the grafts undergo prolonged cold preservation before the application of AD-MSCs in NMP (77,80).…”