Melatonin treatment improves human umbilical cord mesenchymal stem cell therapy in a mouse model of type II diabetes mellitus via the PI3K/AKT signaling pathway

Abstract

Background Mesenchymal stem cells (MSCs) are promising candidates for tissue regeneration and disease treatment. However, long-term in vitro passaging leads to stemness loss of MSCs, resulting in failure of MSC therapy. This study investigated whether the combination of melatonin and human umbilical cord mesenchymal stem cells (hUC-MSCs) was superior to hUC-MSCs alone in ameliorating high-fat diet and streptozocin (STZ)-induced type II diabetes mellitus (T2DM) in a mouse model. Methods Mice were divided into four groups: normal control (NC) group; T2DM group; hUC-MSCs treatment alone (UCMSC) group and pretreatment of hUC-MSCs with melatonin (UCMSC/Mel) group. Results RNA sequence analysis showed that certain pathways, including the signaling pathway involved in the regulation of cell proliferation signaling pathway, were regulated by melatonin. The blood glucose levels of the mice in the UCMSC and UCMSC/Mel treatment groups were significantly reduced compared with the T2DM group without treatment (P < 0.05). Furthermore, hUC-MSCs enhance the key factor in the activation of the PI3K/Akt pathway in T2DM mouse hepatocytes. Conclusion The pretreatment of hUC-MSCs with melatonin partly boosted cell efficiency and thereby alleviated impaired glycemic control and insulin resistance. This study provides a practical strategy to improve the application of hUC-MSCs in diabetes mellitus and cytotherapy. Graphical abstract Overview of the PI3K/AKT signaling pathway. (A) Underlying mechanism of UCMSC/Mel inhibition of hyperglycemia and insulin resistance T2DM mice via regulation of PI3K/AKT pathway. hUC-MSCs stimulates glucose uptake and improves insulin action thus should inhibition the clinical signs of T2DM, through activation of the p-PI3K/Akt signaling pathway and then regulates glucose transport through activating AS160. UCMSC/Mel increases p53-dependent expression of BCL2, and inhibit BAX and Capase3 protein activation. Leading to the decrease in apoptosis. (B) Melatonin modulated PI3K/AKT signaling pathway. Melatonin activated PI3K/AKT response pathway through binding to MT1and MT2 receptor. Leading to the increase in hUC-MSCs proliferation, migration and differentiation. → (Direct stimulatory modification); ┴ ( Direct Inhibitory modification); → ┤ (Multistep inhibitory modification); ↑ (Up regulate); ↓ (Down regulate); PI3K (Phosphoinositide 3-Kinase); AKT ( protein kinase B); PDK1 (Phosphoinositide-dependent protein kinase 1); IR, insulin receptor; GLUT4 ( glucose transporter type 4); ROS (reactive oxygen species); BCL-2 (B-cell lymphoma-2); PDK1 (phosphoinositide-dependent kinase 1) BAX (B-cell lymphoma-2-associated X protein); PCNA (Proliferating cell nuclear antigen); Cell cycle-associated proteins (KI67, cyclin A, cyclin E)

Network exploration of gene signatures underlying low birth weight induced metabolic alterations

“…This pathway is not only a key regulator of early embryonic development but also closely connected with the development of insulin resistance. [18][19][20] Insulin resistance is a disorder of glucose metabolism that plays a crucial role in T2DM. [21] The activation of the PI3K/AKT signaling pathway could improve insulin sensitivity and alleviate T2DM.…”

Melatonin in food allergy: Mechanism and potential therapy

“…Under the effect of melatonin, activated MT2 receptors are coupled with G i/o , leading to the activation of the PLCγ/ PKC pathway 141 (Figure 2B). Moreover, melatonin promotes the activation of the PI3K signaling pathway in different cell types [142][143][144][145][146] (Figure 2C). PI3K can enhance antigen-mediated Ca 2+ mobilization by recruiting PLCγ to the plasma membrane, where PLCγ is subsequently phosphorylated and activated by BTK.…”

Perinatal Stem Cell Therapy to Treat Type 1 Diabetes Mellitus: A Never-Say-Die Story of Differentiation and Immunomodulation

“…The results showed that differentiated cells improved blood glucose levels due to insulin secreted by transplanted cells surviving in islets, while undifferentiated cells improved the inflammation milieu, but had only a slight effect on glucose levels. Recently, the combination of melatonin with WJ-MSCs was investigated in diabetic mice and the pre-treatment with melatonin alleviated blood glucose levels [ 107 ]. In another study, some decellularized matrices were used as a scaffold to support the differentiation of WJ-MSCs into IPCs.…”