PMID- 34464683
OWN - NLM
STAT- MEDLINE
DCOM- 20220321
LR  - 20240226
IS  - 1872-8057 (Electronic)
IS  - 0303-7207 (Linking)
VI  - 537
DP  - 2021 Nov 1
TI  - Mesenchymal stem cell-conditioned medium alleviates high fat-induced 
      hyperglucagonemia via miR-181a-5p and its target PTEN/AKT signaling.
PG  - 111445
LID - S0303-7207(21)00289-6 [pii]
LID - 10.1016/j.mce.2021.111445 [doi]
AB  - BACKGROUND: alpha-cell dysregulation gives rise to fasting and postprandial 
      hyperglycemia in type 2 diabetes mellitus(T2DM). Administration of Mesenchymal 
      stem cells (MSCs) or their conditioned medium can improve islet function and 
      enhance insulin secretion. However, studies showing the direct effect of MSCs on 
      islet alpha-cell dysfunction are limited. METHODS: In this study, we used high-fat 
      diet (HFD)-induced mice and alpha-cell line exposure to palmitate (PA) to determine 
      the effects of bone marrow-derived MSC-conditioned medium (bmMSC-CM) on glucagon 
      secretion. Plasma and supernatant glucagon were detected by enzyme-linked 
      immunosorbent assay(ELISA). To investigate the potential signaling pathways, 
      phosphatase and tensin homolog deleted on chromosome 10 (PTEN), AKT and 
      phosphorylated AKT(p-AKT) were assessed by Western blotting. RESULTS: In vivo, 
      bmMSC-CM infusion improved the glucose and insulin tolerance and protected 
      against HFD-induced hyperglycemia and hyperglucagonemia. Meanwhile, bmMSC-CM 
      infusion ameliorated HFD-induced islet hypertrophy and decreased alpha- and beta-cell 
      area. Consistently, in vitro, glucagon secretion from alpha-cells or primary islets 
      was inhibited by bmMSC-CM, accompanied by reduction of intracellular PTEN 
      expression and restoration of AKT signaling. Previous studies and the TargetScan 
      database indicate that miR-181a and its target PTEN play vital roles in 
      ameliorating alpha-cell dysfunction. We observed that miR-181a-5p was highly 
      expressed in BM-MSCs but prominently lower in alphaTC1-6 cells. Overexpression or 
      downregulation of miR-181a-5p respectively alleviated or aggravated glucagon 
      secretion in alphaTC1-6 cells via the PTEN/AKT signaling pathway. CONCLUSIONS: Our 
      observations suggest that MSC-derived miR-181a-5p mitigates glucagon secretion of 
      alpha-cells by regulating PTEN/AKT signaling, which provides novel evidence 
      demonstrating the potential for MSCs in treating T2DM.
CI  - Copyright (c) 2021. Published by Elsevier B.V.
FAU - Song, Jia
AU  - Song J
AD  - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, 
      Shandong, China.
FAU - He, Qin
AU  - He Q
AD  - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, 
      Shandong, China.
FAU - Guo, Xinghong
AU  - Guo X
AD  - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, 
      Shandong, China.
FAU - Wang, Lingshu
AU  - Wang L
AD  - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, 
      Shandong, China.
FAU - Wang, Jinbang
AU  - Wang J
AD  - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, 
      Shandong, China.
FAU - Cui, Chen
AU  - Cui C
AD  - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, 
      Shandong, China.
FAU - Hu, Huiqing
AU  - Hu H
AD  - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, 
      Shandong, China.
FAU - Yang, Mengmeng
AU  - Yang M
AD  - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, 
      Shandong, China.
FAU - Cui, Yixin
AU  - Cui Y
AD  - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, 
      Shandong, China.
FAU - Zang, Nan
AU  - Zang N
AD  - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, 
      Shandong, China.
FAU - Yan, Fei
AU  - Yan F
AD  - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, 
      Shandong, China.
FAU - Liu, Fuqiang
AU  - Liu F
AD  - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, 
      Shandong, China.
FAU - Sun, Yujing
AU  - Sun Y
AD  - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, 
      Shandong, China.
FAU - Liang, Kai
AU  - Liang K
AD  - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, 
      Shandong, China.
FAU - Qin, Jun
AU  - Qin J
AD  - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, 
      Shandong, China.
FAU - Zhao, Ruxing
AU  - Zhao R
AD  - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, 
      Shandong, China.
FAU - Wang, Chuan
AU  - Wang C
AD  - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, 
      Shandong, China.
FAU - Sun, Zheng
AU  - Sun Z
AD  - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, 
      Shandong, China.
FAU - Hou, Xinguo
AU  - Hou X
AD  - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, 
      Shandong, China; Institute of Endocrine and Metabolic Diseases of Shandong 
      University, Jinan, 250012, Shandong, China; Key Laboratory of Endocrine and 
      Metabolic Diseases, Shandong Province Medicine & Health, Jinan, 250012, Shandong, 
      China; Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan, 
      250012, Shandong, China.
FAU - Li, Wenjuan
AU  - Li W
AD  - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, 
      Shandong, China; Institute of Endocrine and Metabolic Diseases of Shandong 
      University, Jinan, 250012, Shandong, China; Key Laboratory of Endocrine and 
      Metabolic Diseases, Shandong Province Medicine & Health, Jinan, 250012, Shandong, 
      China; Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan, 
      250012, Shandong, China. Electronic address: liwenjuan@qiluhospital.com.
FAU - Chen, Li
AU  - Chen L
AD  - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, 
      Shandong, China; Institute of Endocrine and Metabolic Diseases of Shandong 
      University, Jinan, 250012, Shandong, China; Key Laboratory of Endocrine and 
      Metabolic Diseases, Shandong Province Medicine & Health, Jinan, 250012, Shandong, 
      China; Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan, 
      250012, Shandong, China. Electronic address: chenli3@email.sdu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210828
PL  - Ireland
TA  - Mol Cell Endocrinol
JT  - Molecular and cellular endocrinology
JID - 7500844
RN  - 0 (Culture Media, Conditioned)
RN  - 0 (MicroRNAs)
RN  - 0 (mirn181 microRNA, mouse)
RN  - 9007-92-5 (Glucagon)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 3.1.3.67 (PTEN Phosphohydrolase)
SB  - IM
MH  - Animals
MH  - Base Sequence
MH  - Cell Line
MH  - Culture Media, Conditioned/*pharmacology
MH  - Diet, High-Fat
MH  - Glucagon/*blood
MH  - Hyperglycemia/etiology/genetics
MH  - Male
MH  - Mesenchymal Stem Cells/*chemistry
MH  - Mice, Inbred C57BL
MH  - MicroRNAs/genetics/*metabolism
MH  - PTEN Phosphohydrolase/*metabolism
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - Rats
MH  - Reproducibility of Results
MH  - *Signal Transduction
MH  - Mice
OTO - NOTNLM
OT  - PTEN/AKT
OT  - bmMSC-CM
OT  - glucagon secretion
OT  - miR-181a-5p
OT  - alpha-cells
EDAT- 2021/09/01 06:00
MHDA- 2022/03/22 06:00
CRDT- 2021/08/31 20:12
PHST- 2021/04/15 00:00 [received]
PHST- 2021/08/08 00:00 [revised]
PHST- 2021/08/25 00:00 [accepted]
PHST- 2021/09/01 06:00 [pubmed]
PHST- 2022/03/22 06:00 [medline]
PHST- 2021/08/31 20:12 [entrez]
AID - S0303-7207(21)00289-6 [pii]
AID - 10.1016/j.mce.2021.111445 [doi]
PST - ppublish
SO  - Mol Cell Endocrinol. 2021 Nov 1;537:111445. doi: 10.1016/j.mce.2021.111445. Epub 
      2021 Aug 28.