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Background: Treatment with bone marrow mesenchymal stem cells (BM-MSCs) has been demonstrated to be an excellent cellular-based therapeutic strategy for treating myocardial infarction (MI). However, most of the patients suffering with MI are elderly. Hypoxic conditions can cause apoptosis of BM-MSCs, and this type of apoptosis is more prevalent in aged BM-MSCs. Decreased autophagy is one of the mechanisms underlying aging. The aim of this study is to uncover whether the increased hypoxic injury of aged BM-MSCs is due to autophagy and whether reducing autophagy diminishes the tolerance of hypoxia in aged BM-MSCs., Methods: Young and aged BM-MSCs were isolated from male young and aged GFP/Fluc transgenic C57BL/6 mice respectively and then exposed to hypoxia and serum deprivation (H/SD) injury. The apoptosis level induced by H/SD was measured by terminal deoxynucleotidy transferase-mediated dUTP nick end-labeling (TUNEL) assay. Additionally, autophagy was analyzed via transfection with plasmids encoding green fluorescent protein-microtubule-associated protein lightchain3 (GFP-LC3), and autophagic vacuoles were visualized with transmission electron microscopy. Meanwhile, protein expression was measured by western blot analysis. Autophagic activity was manipulated by the administration of IGF-1 (insulin-like growth factor siRNA) and 3-methyladenine (3MA). Furthermore, young, aged, and the IGF-1 siRNA-transfected aged BM-MSCs were transplanted to myocardial infarcted adult C57BL/6 mice respectively. In vivo longitudinal in vivo bioluminescence imaging (BLI) of transplanted BM-MSCs was performed to monitor the survival of transplanted BM-MSCs in each groups., Results: Aged BM-MSCs exhibited a higher rate of apoptosis compared with young BM-MSCs under hypoxic conditions. Additionally, the level of autophagy was lower in aged BM-MSCs compared with young BM-MSCs under normoxic and hypoxic conditions. Meanwhile, hypoxia decreased the activity of the protein kinase B (Akt) and mammalian target of rapamycin (mTOR) signaling pathway in young and aged BM-MSCs, but aged BM-MSCs exhibited a relatively stronger Akt/mTOR activity compared with young BM-MSCs. In addition, IGF-1 knockdown significantly decreased the level of apoptosis in aged BM-MSCs under normoxic and hypoxic conditions. IGF-1 knockdown also decreased the activity of the Akt/mTOR signaling pathway and increased the level of autophagy in aged BM-MSCs under hypoxic condition. Furthermore, IGF-1 knockdown protected aged BM-MSCs from hypoxic injury by increasing the level of autophagy, thereby promoting the survival of aged BM-MSCs after myocardial infarction transplantation., Conclusion: This study demonstrates that reducing autophagy decreases the hypoxia tolerance of aged BM-MSCs. Maintaining optimal levels of autophagy may serve as a new strategy in treating MI by BM-MSC transplantation in aged patients.

Background: Stem cell therapy has emerged as a promising therapeutic strategy for myocardial infarction (MI). However, the poor viability of transplanted stem cells hampers their therapeutic efficacy. Hypoxic preconditioning (HPC) can effectively promote the survival of stem cells. The aim of this study was to investigate whether HPC improved the functional survival of bone marrow mesenchymal stem cells (BM-MSCs) and increased their cardiac protective effect., Methods: BM-MSCs, isolated from Tg(Fluc-egfp) mice which constitutively express both firefly luciferase (Fluc) and enhanced green fluorescent protein (eGFP), were preconditioned with HPC (1% O 2 ) for 12 h, 24 h, 36 h, and 48 h, respectively, followed by 24 h of hypoxia and serum deprivation (H/SD) injury., Results: HPC dose-dependently increased the autophagy in BM-MSCs. However, the protective effects of HPC for 24 h are most pronounced. Moreover, hypoxic preconditioned BM-MSCs ( HPC MSCs) and nonhypoxic preconditioned BM-MSCs ( NPC MSCs) were transplanted into infarcted hearts. Longitudinal in vivo bioluminescence imaging (BLI) and immunofluorescent staining revealed that HPC enhanced the survival of engrafted BM-MSCs. Furthermore, HPC MSCs significantly reduced fibrosis, decreased apoptotic cardiomyocytes, and preserved heart function. However, the beneficial effect of HPC was abolished by autophagy inhibition with 3-methyladenine (3-MA) and Atg7siRNA., Conclusion: This study demonstrates that HPC may improve the functional survival and the therapeutic efficiencies of engrafted BM-MSCs, at least in part through autophagy regulation. Hypoxic preconditioning may serve as a promising strategy for optimizing cell-based cardiac regenerative therapy.

The article "Retraction Note: Knockdown of insulin-like growth factor 1 exerts a protective effect on hypoxic injury of aged BM-MSCs: role of autophagy" by Ming Yang, Tong Wen, and Haixu Chen has been retracted by the Editor-in-Chief and the publisher due to concerns about incorrect images presented in the figures. The retraction was requested by the authors themselves after discrepancies were found in the images, leading to a loss of confidence in the data presented. Some authors disagreed with the retraction, while others did not respond to correspondence regarding the issue. The publisher, Springer Nature, remains neutral in this matter. [Extracted from the article]

Endotoxemia in sepsis remains a problem due to a lack of effective strategies. Our previous studies have demonstrated that melatonin (Mel) protects against ischemic heart injury and arteriosclerosis. However, its role in endotoxemia-exposed cardiomyocytes remains poorly understood. This study explored, for the first time, the protective effect of Mel on the pyroptosis of human stem cell-derived cardiomyocytes (hiPSC-CMs) exposed to lipopolysaccharide (LPS). Our results showed that treatment with 1 μM or 10 μM Mel for 12 h significantly improved 1 μg/ml LPS-induced hiPSC-CM injuries, as reflected by drastically decreased LDH release and increased cell viability, which was accompanied by the overt induction of autophagy. Specifically, Mel profoundly alleviated LPS-induced cell pyroptosis, as evidenced by decreased propidium iodide (PI) and active caspase-1 double-positive cell rates; suppressed the expression of NLRP3, cleaved caspase-1 (activated form of caspase-1), and GSDMD-NT (functional N-terminal fragment of GSDMD) expression; and inhibited the production of the cleaved IL-1β and cleaved IL-18 cytokines. Additionally, double-membrane autophagosomes were observed in LPS-injured hiPSC-CMs treated with 1 μM or 10 μM Mel. The hiPSC-CMs treated with LPS exhibited considerably fewer acidic vesicles (as revealed by LAMP1 staining) and autophagosomes (as revealed by LC3-II staining); however, Mel reversed this outcome in a dose-dependent manner. Furthermore, coincubation with rapamycin (an autophagy activator) or 3-MA (an autophagy inhibitor) accentuated and attenuated the antipyroptotic actions of Mel, respectively. Collectively, our findings demonstrate that Mel shields hiPSC-CMs against pyroptosis during endotoxemia by activating autophagy. [ABSTRACT FROM AUTHOR]