PMID- 37335082
OWN - NLM
STAT- MEDLINE
DCOM- 20230707
LR  - 20230809
IS  - 1945-4589 (Electronic)
IS  - 1945-4589 (Linking)
VI  - 15
IP  - 12
DP  - 2023 Jun 16
TI  - hucMSCs treatment prevents pulmonary fibrosis by reducing 
      circANKRD42-YAP1-mediated mechanical stiffness.
PG  - 5514-5534
LID - 10.18632/aging.204805 [doi]
AB  - Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial pneumonia of 
      unknown cause. The most typical characteristic of IPF is gradual weakening of 
      pulmonary elasticity and increase in hardness/rigidity with aging. This study 
      aims to identify a novel treatment approach for IPF and explore mechanism of 
      mechanical stiffness underlying human umbilical cord mesenchymal stem cells 
      (hucMSCs) therapy. Target ability of hucMSCs was examined by labeling with cell 
      membrane dye Dil. Anti-pulmonary fibrosis effect of hucMSCs therapy by reducing 
      mechanical stiffness was evaluated by lung function analysis and MicroCT imaging 
      system and atomic force microscope in vivo and in vitro. Results showed that 
      stiff environment of fibrogenesis caused cells to establish a mechanical 
      connection between cytoplasm and nucleus, initiating expression of related 
      mechanical genes such as Myo1c and F-actin. HucMSCs treatment blocked force 
      transmission and reduced mechanical force. For further exploration of mechanism, 
      ATGGAG was mutated to CTTGCG (the binding site of miR-136-5p) in the full-length 
      sequence of circANKRD42. Wildtype and mutant plasmids of circANKRD42 were 
      packaged into adenovirus vectors and sprayed into lungs of mice. Mechanistic 
      dissection revealed that hucMSCs treatment repressed circANKRD42 reverse splicing 
      biogenesis by inhibiting hnRNP L, which in turn promoted miR-136-5p binds to 
      3'-Untranslated Region (3'-UTR) of YAP1 mRNA directly, thus inhibiting 
      translation of YAP1 and reducing YAP1 protein entering nucleus. The condition 
      repressed expression of related mechanical genes to block force transmission and 
      reduce mechanical forces. The mechanosensing mechanism mediated directly by 
      circANKRD42-YAP1 axis in hucMSCs treatment, which has potential general 
      applicability in IPF treatment.
FAU - Zhang, Haitong
AU  - Zhang H
AD  - Department of Respiratory and Critical Care Medicine, Binzhou Medical University 
      Hospital, Binzhou Medical University, Binzhou 256603, China.
FAU - Zhu, Qi
AU  - Zhu Q
AD  - Department of Cellular and Genetic Medicine, School of Pharmaceutical Sciences, 
      Binzhou Medical University, Yantai 264003, China.
FAU - Ji, Yunxia
AU  - Ji Y
AD  - Department of Respiratory and Critical Care Medicine, Binzhou Medical University 
      Hospital, Binzhou Medical University, Binzhou 256603, China.
FAU - Wang, Meirong
AU  - Wang M
AD  - Department of Cellular and Genetic Medicine, School of Pharmaceutical Sciences, 
      Binzhou Medical University, Yantai 264003, China.
FAU - Zhang, Qian
AU  - Zhang Q
AD  - Department of Pathology, Binzhou Medical University Hospital, Binzhou Medical 
      University, Binzhou 256603, China.
FAU - Liu, Weili
AU  - Liu W
AD  - Department of Respiratory and Critical Care Medicine, Binzhou Medical University 
      Hospital, Binzhou Medical University, Binzhou 256603, China.
FAU - Li, Ruiqiong
AU  - Li R
AD  - Department of Clinical Nursing, Binzhou Medical University Hospital, Binzhou 
      Medical University, Binzhou 256603, China.
FAU - Zhang, Jinjin
AU  - Zhang J
AD  - Department of Cellular and Genetic Medicine, School of Pharmaceutical Sciences, 
      Binzhou Medical University, Yantai 264003, China.
FAU - Xu, Pan
AU  - Xu P
AD  - Department of Respiratory and Critical Care Medicine, Binzhou Medical University 
      Hospital, Binzhou Medical University, Binzhou 256603, China.
FAU - Song, Xiaodong
AU  - Song X
AD  - Department of Cellular and Genetic Medicine, School of Pharmaceutical Sciences, 
      Binzhou Medical University, Yantai 264003, China.
FAU - Lv, Changjun
AU  - Lv C
AD  - Department of Respiratory and Critical Care Medicine, Binzhou Medical University 
      Hospital, Binzhou Medical University, Binzhou 256603, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230616
PL  - United States
TA  - Aging (Albany NY)
JT  - Aging
JID - 101508617
RN  - 0 (MicroRNAs)
RN  - 0 (MIRN136 microRNA, human)
RN  - 0 (Myo1c protein, mouse)
RN  - EC 3.6.1.- (Myosin Type I)
SB  - IM
MH  - Humans
MH  - Mice
MH  - Animals
MH  - *Idiopathic Pulmonary Fibrosis/metabolism
MH  - Fibrosis
MH  - Lung/pathology
MH  - *MicroRNAs/metabolism
MH  - *Mesenchymal Stem Cells/metabolism
MH  - Myosin Type I/metabolism
PMC - PMC10333056
OTO - NOTNLM
OT  - YAP1
OT  - circRNA
OT  - hucMSCs
OT  - mechanical stiffness
OT  - pulmonary fibrosis
COIS- CONFLICTS OF INTEREST: The authors declare no conflicts of interest related to 
      this study.
EDAT- 2023/06/19 13:08
MHDA- 2023/07/07 06:42
PMCR- 2023/06/30
CRDT- 2023/06/19 08:53
PHST- 2022/12/29 00:00 [received]
PHST- 2023/05/23 00:00 [accepted]
PHST- 2023/07/07 06:42 [medline]
PHST- 2023/06/19 13:08 [pubmed]
PHST- 2023/06/19 08:53 [entrez]
PHST- 2023/06/30 00:00 [pmc-release]
AID - 204805 [pii]
AID - 10.18632/aging.204805 [doi]
PST - ppublish
SO  - Aging (Albany NY). 2023 Jun 16;15(12):5514-5534. doi: 10.18632/aging.204805. Epub 
      2023 Jun 16.