Melatonin protects ADSCs from ROS and enhances their therapeutic potency in a rat model of myocardial infarction

Abstract

Myocardial infarction (MI) is a major cause of death and disability worldwide. In the last decade, mesenchymal stem cells (MSCs) based cell therapy has emerged as a promising therapeutic strategy. Although great advance have been made using MSCs to treat MI, the low viability of transplanted MSCs severely limits the efficiency of MSCs therapy. Here, we show evidence that ex vivo pre-treatment with melatonin, an endogenous hormone with newly found anti-oxidative activity, could improve survival and function of adipose tissue derived MSCs (ADSCs) in vitro as well as in vivo. ADSCs with 5 μM melatonin pre-treatment for 24 hrs showed increased expression of the antioxidant enzyme catalase and Cu/Zn superoxide dismutase (SOD-1), as well as pro-angiogenic and mitogenic factors like insulin-like growth factor 1, basic fibroblast growth factor, hepatocyte growth factor (HGF), epidermal growth factor. Furthermore, melatonin pre-treatment protected MSCs from reactive oxygen species (ROS) induced apoptosis both directly by promoting anti-apoptosis kinases like p-Akt as well as blocking caspase cascade, and indirectly by restoring the ROS impaired cell adhesion. Using a rat model of MI, we found that melatonin pre-treatment enhanced the viability of engrafted ADSCs, and promoted their therapeutic potency. Hopefully, our results may shed light on the design of more effective therapeutic strategies treating MI by MSCs in clinic.

All‐trans retinoic acid preconditioning enhances proliferation, angiogenesis and migration of mesenchymal stem cell in vitro and enhances wound repair in vivo

“…Over the last decade, stem cell‐based therapy has emerged as an appealing approach for promoting therapy for various diseases and therapeutic potential of adult stem cells is the main focus of scientific research. Nonetheless, the current stem cell‐based therapies have not yet reached to many synthetic drug delivery system achievements . Hence, pre‐treatment strategies for promotion function of stem cell before transplantation can increase the efficacy of the treatment and personalized medicine …”

Regulation of the mitochondrial reactive oxygen species: Strategies to control mesenchymal stem cell fates ex vivo and in vivo

“…Preconditioning with Vitamin E eliminates H 2 O 2 ‐induced injury in MSCs in vitro, and transplantation of these pretreated MSCs increases the proteoglycan content of cartilage matrix for tissue repair of osteoarthritis in vivo . In addition, metformin can be applied to rescue H 2 O 2 ‐induced senescence, long‐term culture‐induced senescence and hypoxia/serum deprivation (Hy/SD)‐induced apoptosis in MSCs …”

“…Melatonin maintains MSC survival and their osteogenic differentiation capacity and chondrogenesis in an IL‐1 β ‐induced inflammatory environment by down‐regulating MMP expression and up‐regulating that of SOD . Preconditioning with melatonin significantly increased the expression of the antioxidant enzyme catalase and Cu/Zn SOD‐1 and the other factors including pro‐angiogenic and mitogenic factors in MSCs in vitro; moreover, melatonin pre‐treatment enhanced the activity of engrafted adipose derived MSCs and enhanced their therapeutic potency in a rat model of myocardial infarction (MI) . Combination of melatonin and apoptotic adipose‐derived MSCs was superior to apoptotic adipose‐derived MSCs alone in protecting the kidneys from sepsis‐induced injury, as this group well‐maintained the kidney function via decreasing the protein expressions of inflammatory, apoptotic, fibrotic markers, ROS and oxidative stress .…”

Melatonin facilitates adipose‐derived mesenchymal stem cells to repair the murine infarcted heartviathe SIRT1 signaling pathway

“…Melatonin has been demonstrated to exhibit cyto‐protective effects against ischemic injury in various organs, such as heart , brain , liver and kidney . In particular, melatonin was found to induced an overexpression of the antioxidant enzyme catalase and superoxide dismutase‐1 and increased the resistance of MSCs to hydrogen peroxide‐dependent apoptosis . Given that modulating ischemic microenvironment by suppressing excessive inflammation and oxidative stress had been demonstrated to improve efficacy of MSCs in ischemic injury , we investigated whether the anti‐inflammatory and antioxidant properties of melatonin could facilitate AD‐MSCs’ cardioprotective effects.…”