Autophagy Promotes the Survival of Adipose Mesenchymal Stem/Stromal Cells and Enhances Their Therapeutic Effects in Cisplatin-Induced Liver Injury via Modulating TGF-β1/Smad and PI3K/AKT Signaling Pathways

Abstract

Autophagy is a key metabolic process where cells can recycle its proteins and organelles to regenerate its own cellular building blocks. Chemotherapy is indispensable for cancer treatment but associated with various side-effects, including organ damage. Stem cell-based therapy is a promising approach for reducing chemotherapeutic side effects, however, one of its main culprits is the poor survival of transplanted stem cells in damaged tissues. Here, we aimed to test the effects of activating autophagy in adipose-derived mesenchymal stem/stromal cells (ADSCs) on the survival of ADSCs, and their therapeutic value in cisplatin-induced liver injury model. Autophagy was activated in ADSCs by rapamycin (50 nM/L) for two hours before transplantation and were compared to non-preconditioned ADSCs. Rapamycin preconditioning resulted in activated autophagy and improved survival of ADSCs achieved by increased autophagosomes, upregulated autophagy-specific LC3-II gene, decreased protein degradation/ubiquitination by downregulated p62 gene, downregulated mTOR gene, and finally, upregulated antiapoptotic BCL-2 gene. In addition, autophagic ADSCs transplantation in the cisplatin liver injury model, liver biochemical parameters (AST, ALT and albumin), lipid peroxidation (MDA), antioxidant profile (SOD and GPX) and histopathological picture were improved, approaching near-normal conditions. These promising autophagic ADSCs effects were achieved by modulation of components in TGF-β1/Smad and PI3K-AKT signaling pathways, besides reducing NF-κB gene expression (marker for inflammation), reducing TGF-β1 levels (marker for fibrosis) and increasing SDF-1 levels (liver regeneration marker) in liver. Therefore, current results highlight the importance of autophagy in augmenting the therapeutic potential of stem cell therapy in alleviating cisplatin-associated liver damage and opens the path for improved cell-based therapies, in general, and with chemotherapeutics, in particular.

Hepatoprotective Effects of Hyaluronic Acid-Preconditioned Bone Marrow Mesenchymal Stem Cells against Liver Toxicity via the Inhibition of Apoptosis and the Wnt/β-Catenin Signaling Pathway

“…In the current study, stem cell groups showed more meaningful upregulation in SDF1α expression than the control and DOX groups. This was also observed by El Nashar et al [56], Akcora et al [57], and Du et al [58]. Moreover, BMSCs preconditioned with HA showed the highest SDF1α level among all treated groups, suggesting the role of HA in enhancing cell migration.…”

Autophagy and necroptosis in cisplatin-induced acute kidney injury: Recent advances regarding their role and therapeutic potential

“…In Choi et al's (2019) study, pretreatment with necroptotic inhibitor, Necrostatin-1 markedly suppressed CP-induced auditory cell death, while the treatment of apoptosis inhibitor, ZVAD did not. Likewise, the protective effect of the autophagy pathway was also reported in CP-induced damage to the liver cells (Qu et al, 2019;Nashar et al, 2021), and cochlear cells (Fang and Xiao, 2014;Yang Q. et al, 2018;Liu et al, 2019;Pang et al, 2019). More Interestingly, trehalose which alleviated CP-induced AKI by activating autophagy (Zhu et al, 2020), recently, its pro-autophagic activity has made it also a potential treatment for CP-induced ototoxicity (Li et al, 2022b).…”

Liquiritigenin Confers Liver Protection by Enhancing NRF2 Signaling through Both Canonical and Non-canonical Signaling Pathways

“…Besides the NRF2 signal pathway, some groups also have reported LQ-induced promiscuous activation of multiple pathways in the liver. For example, LQ treatment improves liver fibrosis via regulating TGF-β1/Smad and Hippo/YAP pathways, and both TGF-β1/Smad and Hippo/YAP pathways are related with liver injury. , In addition, LQ is also considered as an AMPK activator and enhances the phosphorylation of AMPK in hepatocytes, which confers to the therapeutic action of LQ against oxidative hepatic injury and mitochondrial dysfunction . Moreover, cyclophosphamide-induced liver sinusoidal endothelial injury and inflammatory injury can be alleviated by LQ treatment via regulating the TLR4-NFκB signal pathway .…”