PMID- 34215590
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240502
IS  - 2375-2548 (Electronic)
IS  - 2375-2548 (Linking)
VI  - 7
IP  - 27
DP  - 2021 Jul
TI  - Exendin-4 gene modification and microscaffold encapsulation promote 
      self-persistence and antidiabetic activity of MSCs.
LID - 10.1126/sciadv.abi4379 [doi]
LID - eabi4379
AB  - Mesenchymal stem cell (MSC)-based therapy to combat diabetic-associated metabolic 
      disorders is hindered by impoverished cell survival and limited therapeutic 
      effects under high glucose stress. Here, we genetically engineered MSCs with 
      Exendin-4 (MSC-Ex-4), a glucagon-like peptide-1 (GLP-1) analog, and demonstrated 
      their boosted cellular functions and antidiabetic efficacy in the type 2 diabetes 
      mellitus (T2DM) mouse model. Mechanistically, MSC-Ex-4 achieved self-augmentation 
      and improved survival under high glucose stress via autocrine activation of the 
      GLP-1R-mediated AMPK signaling pathway. Meanwhile, MSC-Ex-4-secreted Exendin-4 
      suppressed senescence and apoptosis of pancreatic beta cells through endocrine 
      effects, while MSC-Ex-4-secreted bioactive factors (e.g., IGFBP2 and APOM) 
      paracrinely augmented insulin sensitivity and decreased lipid accumulation in 
      hepatocytes through PI3K-Akt activation. Furthermore, we encapsulated MSC-Ex-4 in 
      3D gelatin microscaffolds for single-dose administration to extend the 
      therapeutic effect for 3 months. Together, our findings provide mechanistic 
      insights into Exendin-4-mediated MSCs self-persistence and antidiabetic activity 
      that offer more effective MSC-based therapy for T2DM.
CI  - Copyright (c) 2021 The Authors, some rights reserved; exclusive licensee American 
      Association for the Advancement of Science. No claim to original U.S. Government 
      Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 
      (CC BY-NC).
FAU - Zhang, Yuanyuan
AU  - Zhang Y
AUID- ORCID: 0000-0002-4222-6302
AD  - Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center 
      for Life Sciences, Tsinghua University, Beijing 100084, China.
FAU - Gao, Shuang
AU  - Gao S
AUID- ORCID: 0000-0002-1154-4711
AD  - Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center 
      for Life Sciences, Tsinghua University, Beijing 100084, China.
FAU - Liang, Kaini
AU  - Liang K
AUID- ORCID: 0000-0002-4174-4853
AD  - Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center 
      for Life Sciences, Tsinghua University, Beijing 100084, China.
FAU - Wu, Zhaozhao
AU  - Wu Z
AD  - Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center 
      for Life Sciences, Tsinghua University, Beijing 100084, China.
FAU - Yan, Xiaojun
AU  - Yan X
AD  - Beijing CytoNiche Biotechnology Co. Ltd., Beijing 100195, China.
FAU - Liu, Wei
AU  - Liu W
AD  - Beijing CytoNiche Biotechnology Co. Ltd., Beijing 100195, China.
FAU - Li, Junyang
AU  - Li J
AUID- ORCID: 0000-0002-2953-3535
AD  - Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center 
      for Life Sciences, Tsinghua University, Beijing 100084, China.
FAU - Wu, Bingjie
AU  - Wu B
AD  - Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center 
      for Life Sciences, Tsinghua University, Beijing 100084, China.
FAU - Du, Yanan
AU  - Du Y
AUID- ORCID: 0000-0003-2627-9727
AD  - Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center 
      for Life Sciences, Tsinghua University, Beijing 100084, China. 
      duyanan@tsinghua.edu.cn.
LA  - eng
PT  - Journal Article
DEP - 20210702
PL  - United States
TA  - Sci Adv
JT  - Science advances
JID - 101653440
SB  - IM
PMC - PMC11060038
EDAT- 2021/07/04 06:00
MHDA- 2021/07/04 06:01
PMCR- 2021/07/02
CRDT- 2021/07/03 05:36
PHST- 2021/03/09 00:00 [received]
PHST- 2021/05/20 00:00 [accepted]
PHST- 2021/07/03 05:36 [entrez]
PHST- 2021/07/04 06:00 [pubmed]
PHST- 2021/07/04 06:01 [medline]
PHST- 2021/07/02 00:00 [pmc-release]
AID - 7/27/eabi4379 [pii]
AID - abi4379 [pii]
AID - 10.1126/sciadv.abi4379 [doi]
PST - epublish
SO  - Sci Adv. 2021 Jul 2;7(27):eabi4379. doi: 10.1126/sciadv.abi4379. Print 2021 Jul.