PMID- 35414044
OWN - NLM
STAT- MEDLINE
DCOM- 20220414
LR  - 20220531
IS  - 1757-6512 (Electronic)
IS  - 1757-6512 (Linking)
VI  - 13
IP  - 1
DP  - 2022 Apr 12
TI  - 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.
PG  - 164
LID - 10.1186/s13287-022-02832-0 [doi]
LID - 164
AB  - 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. 
      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);  upper left and right quadrants ( Direct Inhibitory modification); -->  upper and lower left quadrants (Multistep inhibitory 
      modification);  upward arrow (Up regulate);  downward arrow (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).
CI  - (c) 2022. The Author(s).
FAU - Aierken, Aili
AU  - Aierken A
AUID- ORCID: 0000-0002-5980-6442
AD  - College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering and 
      Technology, Northwest A&F University, YanglingShaanxi, 712100, China.
FAU - Li, Balun
AU  - Li B
AD  - College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering and 
      Technology, Northwest A&F University, YanglingShaanxi, 712100, China.
FAU - Liu, Peng
AU  - Liu P
AD  - Department of Endocrinology and Metabolism, Shanghai Key Laboratory of Diabetes 
      Mellitus, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 
      Shanghai, 200233, China.
FAU - Cheng, Xuedi
AU  - Cheng X
AD  - College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering and 
      Technology, Northwest A&F University, YanglingShaanxi, 712100, China.
FAU - Kou, Zheng
AU  - Kou Z
AD  - College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering and 
      Technology, Northwest A&F University, YanglingShaanxi, 712100, China.
FAU - Tan, Ning
AU  - Tan N
AD  - College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering and 
      Technology, Northwest A&F University, YanglingShaanxi, 712100, China.
FAU - Zhang, Mengfei
AU  - Zhang M
AD  - College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering and 
      Technology, Northwest A&F University, YanglingShaanxi, 712100, China.
FAU - Yu, Shuai
AU  - Yu S
AD  - College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering and 
      Technology, Northwest A&F University, YanglingShaanxi, 712100, China.
FAU - Shen, Qiaoyan
AU  - Shen Q
AD  - College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering and 
      Technology, Northwest A&F University, YanglingShaanxi, 712100, China.
FAU - Du, Xiaomin
AU  - Du X
AD  - College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering and 
      Technology, Northwest A&F University, YanglingShaanxi, 712100, China.
FAU - Enkhbaatar, Bold Bayar
AU  - Enkhbaatar BB
AD  - College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering and 
      Technology, Northwest A&F University, YanglingShaanxi, 712100, China.
FAU - Zhang, Juqing
AU  - Zhang J
AD  - College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering and 
      Technology, Northwest A&F University, YanglingShaanxi, 712100, China.
FAU - Zhang, Rui
AU  - Zhang R
AD  - College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering and 
      Technology, Northwest A&F University, YanglingShaanxi, 712100, China.
FAU - Wu, Xiaolong
AU  - Wu X
AD  - College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering and 
      Technology, Northwest A&F University, YanglingShaanxi, 712100, China.
FAU - Wang, Ruibin
AU  - Wang R
AD  - College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering and 
      Technology, Northwest A&F University, YanglingShaanxi, 712100, China.
FAU - He, Xin
AU  - He X
AD  - College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering and 
      Technology, Northwest A&F University, YanglingShaanxi, 712100, China.
FAU - Li, Na
AU  - Li N
AD  - College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering and 
      Technology, Northwest A&F University, YanglingShaanxi, 712100, China.
FAU - Peng, Sha
AU  - Peng S
AD  - College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering and 
      Technology, Northwest A&F University, YanglingShaanxi, 712100, China.
FAU - Jia, Wenwen
AU  - Jia W
AD  - Institute for Regenerative Medicine, National Stem Cell Translational Resource 
      Center, Shanghai East Hospital, School of Life Sciences and Technology, Tongji 
      University, Shanghai, 200092, China. wuj3@tongji.edu.cn.
FAU - Wang, Congrong
AU  - Wang C
AD  - Department of Endocrinology and Metabolism, Shanghai Fourth People's Hospital, 
      School of Medicine, Tongji University, Shanghai, 200434, China. 
      crwang@tongji.edu.cn.
FAU - Hua, Jinlian
AU  - Hua J
AD  - College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering and 
      Technology, Northwest A&F University, YanglingShaanxi, 712100, China. 
      jinlianhua@nwsuaf.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220412
PL  - England
TA  - Stem Cell Res Ther
JT  - Stem cell research & therapy
JID - 101527581
RN  - 0 (Phosphatidylinositols)
RN  - 0 (bcl-2-Associated X Protein)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - JL5DK93RCL (Melatonin)
SB  - IM
MH  - Animals
MH  - *Diabetes Mellitus, Type 2/therapy
MH  - Humans
MH  - *Insulin Resistance
MH  - *Melatonin/pharmacology/therapeutic use
MH  - *Mesenchymal Stem Cell Transplantation/methods
MH  - Mice
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphatidylinositols/therapeutic use
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Signal Transduction
MH  - Umbilical Cord
MH  - bcl-2-Associated X Protein
PMC - PMC9006413
OTO - NOTNLM
OT  - Human umbilical cord mesenchymal stem cell (hUC-MSC)
OT  - Melatonin
OT  - PI3K/AKT signaling pathway
OT  - Type II diabetes mellitus
COIS- The authors declare no competing financial interest.
EDAT- 2022/04/14 06:00
MHDA- 2022/04/15 06:00
PMCR- 2022/04/12
CRDT- 2022/04/13 05:18
PHST- 2021/08/17 00:00 [received]
PHST- 2022/03/01 00:00 [accepted]
PHST- 2022/04/13 05:18 [entrez]
PHST- 2022/04/14 06:00 [pubmed]
PHST- 2022/04/15 06:00 [medline]
PHST- 2022/04/12 00:00 [pmc-release]
AID - 10.1186/s13287-022-02832-0 [pii]
AID - 2832 [pii]
AID - 10.1186/s13287-022-02832-0 [doi]
PST - epublish
SO  - Stem Cell Res Ther. 2022 Apr 12;13(1):164. doi: 10.1186/s13287-022-02832-0.