Preconditioning with melatonin improves therapeutic outcomes of bone marrow-derived mesenchymal stem cells in targeting liver fibrosis induced by CCl4

Abstract

Preconditioning of mesenchymal stem cells (MSCs) with melatonin (MT) has shown promising results in animal models of myocardial infarction, renal ischemia and cerebral ischemia. Here, we use this strategy in the liver fibrosis induced by CCl4. There were five groups: normal, CCl4, CCl4 + vehicle, CCl4 + BMMSCs and CCl4 + MT-bone marrow (BM)-derived MSCs (MT-BMMSCs). CCl4 was injected twice weekly for 8 weeks and treatment either with cells or vehicle was performed at the beginning of week 5 with a single dose. BMMSCs were preconditioned with MT for 24 h before injection. MT-BMMSCs had a high ability of homing into the injured liver (P ≤ 0.05 vs. BMMSCs). The CCl4 + MT-BMMSCs group showed higher percentage of glycogen storage but lower percentage of collagen and lipid accumulation (P ≤ 0.05 vs. CCl4 + BMMSCs). The CCl4 + MT-BMMSCs group showed lower expressions of transforming growth factor-β1 (TGF-β1) and Bax and lower content of sera alanine aminotransferase (ALT) but higher expressions of matrix metalloproteinases (MMPs) and Bcl2 compared with the BMMSCs group (P ≤ 0.05). The results showed the better therapeutic outcomes of MT preconditioning by probably improving cell homing and also better maintenance of the balance between matrix degrading and accumulating factors.

Melatonin and circadian rhythms in liver diseases: Functional roles and potential therapies

“…Stem cell transplantation decreased serum ALT and AST levels as well as liver fibrosis, and melatonin pretreatment of stem cells enhanced these therapeutic effects . Melatonin treatment elevated expression levels of MT 1 and MT 2 melatonin receptors in stem cells, which may be associated with those effects …”

“…Stem cell therapy performs transplantation of stem cells to facilitate liver regeneration and improve conditions in various liver diseases including cirrhosis . A previous study treated bone marrow‐derived mesenchymal stem cells with or without 5 μM melatonin for 24 hours and infused them into CCl 4 ‐administered rats via tail vein . Stem cell transplantation decreased serum ALT and AST levels as well as liver fibrosis, and melatonin pretreatment of stem cells enhanced these therapeutic effects .…”

Human hepatocellular carcinoma: Protection by melatonin

“…Melatonin is a secretory product of the pineal gland and gastrointestinal tract during night and daytime, respectively (Margheri et al, ). Melatonin is responsible for a variety of physiological functions (Mortezaee, Khanlarkhani, Sabbaghziarani et al, ; Mortezaee, Sabbaghziarani et al, ), including antioxidant (Mortezaee & Khanlarkhani, ; Mortezaee et al, ; Mortezaee, Khanlarkhani, Beyer, & Zendedel, ), anti‐apoptotic (Mortezaee, Majidpoor, Daneshi, Abouzaripour, & Abdi, ), and pro‐apoptotic (Lin et al, ) activities. Melatonin is the only known chronobotic hormone for regulation of neoplastic cell growth (Blask, Sauer, & Dauchy, ).…”

Pre‐treatments enhance the therapeutic effects of mesenchymal stem cells in liver diseases

“…Melatonin‐pre‐treated MSCs showed increased homing capacity to the injured liver site and significantly improved the percentage of glycogen storage while decreasing collagen and lipid accumulation in fibrotic liver tissue; this outcome stemmed from decreased expression of TGF‐β1 and Bax and increased expression of matrix metalloproteinases (MMPs) and Bcl‐2 . Furthermore, melatonin pre‐conditioning significantly increased the engraftment of MSCs and attenuated liver fibrosis in rat models .…”