Melatonin Reverses the Loss of Stemness Induced by TNF-α in Human Bone Marrow Mesenchymal Stem Cells through Upregulation of YAP Expression

Abstract

Mesenchymal stem cells (MSCs) are promising candidates for tissue regeneration and disease treatment. However, long-term in vitro culture results in loss of MSC stemness. The inflammation that occurs at stem cell transplant sites (such as that resulting from TNF-α) is a contributing factor for stem cell treatment failure. Currently, there is little evidence regarding the protective role of melatonin with regard to the negative effects of TNF-α on the stemness of MSCs. In this study, we report a melatonin-based method to reduce the inflammatory effects on the stemness of bone marrow mesenchymal stem cells (BMMSCs). The results of colony formation assays, Alizarin red staining, western blotting, and reverse transcription-polymerase chain reactions suggest that melatonin can reverse the inflammatory damage caused by TNF-α treatment in the third, seventh, and tenth generations of primary BMMSCs (vs. control and the TNF-α-treated group). Meanwhile, a detailed analysis of the molecular mechanisms showed that the melatonin receptor and YAP signaling pathway are closely related to the role that melatonin plays in negative inflammatory effects against BMMSCs. In addition, in vivo experiments showed that melatonin could reverse the damage caused by TNF-α on bone regeneration by BMMSCs in nude mice. Overall, our results suggest that melatonin can reverse the loss of stemness caused by inflammatory factor TNF-α in BMMSCs. Our results also provide a practical strategy for the application of BMMSCs in tissue engineering and cell therapy.

Yes-Associated Protein 1: Role and Treatment Prospects in Orthopedic Degenerative Diseases

“…Therefore, YAP1 is essential for the proliferation and differentiation of both osteocytes and chondrocytes. In addition, YAP1/TAZ also affects the stemness development of marrow-derived mesenchymal stem cells (MSCs), which can affect the differentiation of osteoblasts (OBs), osteoclasts (OCs) and adipocytes (Wang et al, 2019). As precursor cells of chondrocytes, osteoblasts and adipocytes, MSCs are gradually becoming a potential cell source for the treatment of a variety of inflammatory, degenerative and autoimmune diseases (Su et al, 2017).…”

“…The specific mechanism involves the miR-1263-mediated inhibition of Mob1 expression, which activates YAP1 and inhibits apoptosis. In the ovariectomized osteoporosis nude mouse model, YAP1 can mediate the therapeutic effect of melatonin toward OP, while the YAP1 inhibitor VP can attenuate the therapeutic effect of melatonin against OP ( Wang et al, 2019 ). Another study showed that myocardin-related transcription factors (MRTFs) can regulate the balance between the adipogenic and osteogenic differentiation of MSCs, which promotes the osteogenic activity of YAP1/TAZ by maintaining the production of smooth muscle actin (SMA) in MSCs ( Bian et al, 2016 ).…”

“…However, none of these YAP1 agonists have been studied in OP, and their efficacy against OP remains unknown. In addition to YAP1 agonists, YAP1 can also mediate the therapeutic effects of the genes or proteins mentioned above in OP ( Bian et al, 2016 ; Li et al, 2019 ; Wang et al, 2019 ; Lin et al, 2020 ; Yang et al, 2020 ).…”

Melatonin and Mesenchymal Stem Cells as a Key for Functional Integrity for Liver Cancer Treatment

“…In this regard, MSCs pulsed with tumor-derived microvesicles showed an enhanced antitumor activity in HCC [ 166 ]. Some previous report revealed the use of melatonin enhanced the potential therapeutic role MSCs in treatment various diseases such as acute kidney injury, metabolic syndromes including diabetes through various mechanisms that include through the activation of antioxidative pathways, inhibition of the inflammatory response and reduction of apoptosis and fibrosis [ 19 , 167 , 168 , 169 , 170 ]. More interestingly, few recent reports revealed the beneficial effects of the combination between melatonin and MSCs on targeting inflammation in HCC [ 171 , 172 , 173 , 174 , 175 ].…”

Melatonin Promotes Bone Marrow Mesenchymal Stem Cell Osteogenic Differentiation and Prevents Osteoporosis Development Through Modulating circ_0003865 that Sponges miR-3653-3p

“…Mice in the OP + sh-hsa_circ_0003865 group were injected with 10 µl of sh-hsa_circ_0003865 (10 13 copies/mouse) in the distal femur and then subjected to ovariectomy. Bone microstructure analysis by micro-CT examination was conducted as previously described [16]. Quantitative RT-PCR was used to detect the relative expression of circ-0003865, ALP, RUNX2, OPN, GAS1, and miR-3865-3P in bone tissues.…”