PMID- 35954231
OWN - NLM
STAT- MEDLINE
DCOM- 20220815
LR  - 20240516
IS  - 2073-4409 (Electronic)
IS  - 2073-4409 (Linking)
VI  - 11
IP  - 15
DP  - 2022 Aug 3
TI  - Modeling MEN1 with Patient-Origin iPSCs Reveals GLP-1R Mediated Hypersecretion of 
      Insulin.
LID - 10.3390/cells11152387 [doi]
LID - 2387
AB  - Multiple endocrine neoplasia type 1 (MEN1) is an inherited disease caused by 
      mutations in the MEN1 gene encoding a nuclear protein menin. Among those 
      different endocrine tumors of MEN1, the pancreatic neuroendocrine tumors (PNETs) 
      are life-threatening and frequently implicated. Since there are uncertainties in 
      genotype and phenotype relationship and there are species differences between 
      humans and mice, it is worth it to replenish the mice model with human cell 
      resources. Here, we tested whether the patient-origin induced pluripotent stem 
      cell (iPSC) lines could phenocopy some defects of MEN1. In vitro beta-cell 
      differentiation revealed that the percentage of insulin-positive cells and 
      insulin secretion were increased by at least two-fold in MEN1-iPSC derived cells, 
      which was mainly resulted from significantly higher proliferative activities in 
      the pancreatic progenitor stage (Day 7-13). This scenario was paralleled with 
      increased expressions of prohormone convertase1/3 (PC1/3), glucagon-like 
      peptide-1 (GLP-1), GLP-1R, and factors in the phosphatidylinositol 3-kinase 
      (PI3K)/AKT signal pathway, and the GLP-1R was mainly expressed in beta-like cells. 
      Blockages of either GLP-1R or PI3K significantly reduced the percentages of 
      insulin-positive cells and hypersecretion of insulin in MEN1-derived cells. 
      Furthermore, in transplantation of different stages of MEN1-derived cells into 
      immune-deficient mice, only those beta-like cells produced tumors that mimicked the 
      features of the PNETs from the original patient. To the best of our knowledge, 
      this was the first case using patient-origin iPSCs modeling most phenotypes of 
      MEN1, and the results suggested that GLP-1R may be a potential therapeutic target 
      for MEN1-related hyperinsulinemia.
FAU - Cheng, Ziqi
AU  - Cheng Z
AD  - Center for Health Research, Guangzhou Institutes of Biomedicine and Health, 
      Chinese Academy of Sciences, Guangzhou 510530, China.
AD  - University of Chinese Academy of Sciences, Beijing 100049, China.
AD  - Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of 
      Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
AD  - CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine 
      and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
AD  - Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of 
      Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
FAU - Guo, Dongsheng
AU  - Guo D
AUID- ORCID: 0000-0002-9702-7327
AD  - Center for Health Research, Guangzhou Institutes of Biomedicine and Health, 
      Chinese Academy of Sciences, Guangzhou 510530, China.
FAU - Ruzi, Aynisahan
AU  - Ruzi A
AD  - Center for Health Research, Guangzhou Institutes of Biomedicine and Health, 
      Chinese Academy of Sciences, Guangzhou 510530, China.
FAU - Pan, Tingcai
AU  - Pan T
AD  - Center for Health Research, Guangzhou Institutes of Biomedicine and Health, 
      Chinese Academy of Sciences, Guangzhou 510530, China.
FAU - You, Kai
AU  - You K
AD  - Center for Health Research, Guangzhou Institutes of Biomedicine and Health, 
      Chinese Academy of Sciences, Guangzhou 510530, China.
FAU - Chen, Yan
AU  - Chen Y
AD  - Center for Health Research, Guangzhou Institutes of Biomedicine and Health, 
      Chinese Academy of Sciences, Guangzhou 510530, China.
AD  - Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of 
      Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
AD  - CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine 
      and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
AD  - Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of 
      Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
FAU - Huang, Xinping
AU  - Huang X
AUID- ORCID: 0000-0002-3110-2128
AD  - Center for Health Research, Guangzhou Institutes of Biomedicine and Health, 
      Chinese Academy of Sciences, Guangzhou 510530, China.
AD  - University of Chinese Academy of Sciences, Beijing 100049, China.
AD  - Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of 
      Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
AD  - CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine 
      and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
AD  - Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of 
      Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
FAU - Zhang, Jiaye
AU  - Zhang J
AD  - Center for Health Research, Guangzhou Institutes of Biomedicine and Health, 
      Chinese Academy of Sciences, Guangzhou 510530, China.
FAU - Yang, Fan
AU  - Yang F
AD  - Ministry of Education CNS Regeneration Collaborative Joint Laboratory, 
      Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, 
      Guangzhou 510632, China.
FAU - Niu, Lizhi
AU  - Niu L
AD  - Guangzhou Fuda Cancer Hospital, Guangzhou 510305, China.
FAU - Xu, Kecheng
AU  - Xu K
AD  - Guangzhou Fuda Cancer Hospital, Guangzhou 510305, China.
FAU - Li, Yin-Xiong
AU  - Li YX
AD  - Center for Health Research, Guangzhou Institutes of Biomedicine and Health, 
      Chinese Academy of Sciences, Guangzhou 510530, China.
AD  - University of Chinese Academy of Sciences, Beijing 100049, China.
AD  - Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of 
      Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
AD  - CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine 
      and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
AD  - Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of 
      Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
AD  - State Key Laboratory of Respiratory Disease, Guangzhou 510000, China.
AD  - China-New Zealand Joint Laboratory of Biomedicine and Health, Guangzhou 510530, 
      China.
LA  - eng
GR  - 27302C0031/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220803
PL  - Switzerland
TA  - Cells
JT  - Cells
JID - 101600052
RN  - 0 (Glucagon-Like Peptide-1 Receptor)
RN  - 0 (Insulin)
RN  - 0 (Insulin, Regular, Human)
RN  - 0 (Men1 protein, mouse)
RN  - 0 (Proto-Oncogene Proteins)
SB  - IM
MH  - Animals
MH  - Glucagon-Like Peptide-1 Receptor/metabolism
MH  - Humans
MH  - *Induced Pluripotent Stem Cells/metabolism
MH  - Insulin/metabolism
MH  - Insulin, Regular, Human
MH  - Mice
MH  - *Multiple Endocrine Neoplasia Type 1
MH  - *Neuroectodermal Tumors, Primitive
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Proto-Oncogene Proteins
PMC - PMC9368616
OTO - NOTNLM
OT  - GLP-1R
OT  - MEN1
OT  - disease modeling
OT  - hyperinsulinemia
OT  - beta-cell differentiation
COIS- The authors declare no conflict of interest.
EDAT- 2022/08/13 06:00
MHDA- 2022/08/16 06:00
PMCR- 2022/08/03
CRDT- 2022/08/12 01:04
PHST- 2022/05/05 00:00 [received]
PHST- 2022/07/27 00:00 [revised]
PHST- 2022/07/29 00:00 [accepted]
PHST- 2022/08/12 01:04 [entrez]
PHST- 2022/08/13 06:00 [pubmed]
PHST- 2022/08/16 06:00 [medline]
PHST- 2022/08/03 00:00 [pmc-release]
AID - cells11152387 [pii]
AID - cells-11-02387 [pii]
AID - 10.3390/cells11152387 [doi]
PST - epublish
SO  - Cells. 2022 Aug 3;11(15):2387. doi: 10.3390/cells11152387.