Haemin pre‐treatment augments the cardiac protection of mesenchymal stem cells by inhibiting mitochondrial fission and improving survival

Abstract

The cardiac protection of mesenchymal stem cell (MSC) transplantation for myocardial infarction (MI) is largely hampered by low cell survival. Haem oxygenase 1 (HO‐1) plays a critical role in regulation of cell survival under many stress conditions. This study aimed to investigate whether pre‐treatment with haemin, a potent HO‐1 inducer, would promote the survival of MSCs under serum deprivation and hypoxia (SD/H) and enhance the cardioprotective effects of MSCs in MI. Bone marrow (BM)‐MSCs were pretreated with or without haemin and then exposed to SD/H. The mitochondrial morphology of MSCs was determined by MitoTracker staining. BM‐MSCs and haemin‐pretreated BM‐MSCs were transplanted into the peri‐infarct region in MI mice. SD/H induced mitochondrial fragmentation, as shown by increased mitochondrial fission and apoptosis of BM‐MSCs. Pre‐treatment with haemin greatly inhibited SD/H‐induced mitochondrial fragmentation and apoptosis of BM‐MSCs. These effects were partially abrogated by knocking down HO‐1. At 4 weeks after transplantation, compared with BM‐MSCs, haemin‐pretreated BM‐MSCs had greatly improved the heart function of mice with MI. These cardioprotective effects were associated with increased cell survival, decreased cardiomyocytes apoptosis and enhanced angiogenesis. Collectively, our study identifies haemin as a regulator of MSC survival and suggests a novel strategy for improving MSC‐based therapy for MI.

Mitochondrial Dynamics: Fission and Fusion in Fate Determination of Mesenchymal Stem Cells

“…Oxidative stress with ROS evaluation induced directly by H 2 O 2 treatment leads to mitochondrial fragmentation in hMSCs; moreover, the combination of N-acetylcysteine, a biologic antioxidant, and ascorbic acid 2-phosphate, an oxidation-resistant derivative of ascorbic acid, successfully inhibits mitochondrial fission, decreases ROS production, and stabilizes mitochondrial membrane potential (Li et al, 2015). In another similar study of oxidative stress conditions stimulated by serum deprivation and hypoxia treatment, BMSCs had increased mitochondrial fragmentation along with upregulation of p-Drp1 Ser616 expression and downregulation of Mfn2 expression (Deng et al, 2020). In addition, an in vitro study underscored that CoCl 2 , a hypoxia mimetic, promoted mitochondrial fission in PDLSCs mediated by Drp1 elevation (He et al, 2018).…”

Conditioned medium from induced pluripotent stem cell-derived mesenchymal stem cells accelerates cutaneous wound healing through enhanced angiogenesis

“…The morphology of mitochondria was examined by MitoTracker staining (Cell Signaling, 9074) as previously described [22]. The percentage of mitochondrial fragmentation was calculated by comparing the number of cells with fragmented mitochondria to the total number of cells.…”

Apelin Rejuvenates Aged Human Mesenchymal Stem Cells by Regulating Autophagy and Improves Cardiac Protection After Infarction

“…The primers were listed in Table 1 . Human Alu-sx repeat sequences in heart tissue from the different groups was evaluated by genomic PCR as previously described ( Deng et al, 2020 ). The human Alu-sx primers were: F:5′-GGCGCGGTGGCTCACG-3′, R:5′-TTTTTTGAGACGGAGTCTCGCTC-3′.…”

“…Hypoxia promotes MSC proliferation by activating the apelin/APJ/autophagy signaling pathway, and these effects are partially abrogated by downregulation of APJ ( Li et al, 2015 ). The therapeutic efficacy of MSCs for MI is largely attributed to their paracrine effects ( Deng et al, 2020 ; Sid-Otmane et al, 2020 ). Notably, Apelin also regulates angiogenesis ( Uribesalgo et al, 2019 ); it improves MSC vascularization under hypoxic conditions by upregulating the level of vascular endothelial growth factor ( Hou et al, 2017 ).…”