Smad4 Loss in the Mouse Intestinal Epithelium Alleviates the Pathological Fibrotic Response to Injury in the Colon
biorxiv(2024)
摘要
Mucosal healing is associated with better clinical outcomes in patients with inflammatory bowel diseases (IBDs). Unresolved injury and inflammation, on the other hand, increases pathological fibrosis and the predisposition to cancer. Loss of Smad4, a tumor suppressor, is known to increase colitis-associated cancer in mouse models of chronic IBD. Since common biological processes are involved in both injury repair and tumor growth, we sought to investigate the effect of Smad4 loss on the response to epithelial injury. To this end, Smad4 was knocked out specifically in the intestinal epithelium and transcriptomic and morphological changes compared between wild type mice and Smad4 knock out mice after DSS-induced injury. We find that Smad4 loss alleviates pathological fibrosis and enhances mucosal repair. The transcriptomic changes specific to epithelium indicate molecular changes that affect epithelial extracellular matrix (ECM) and promote enhanced mucosal repair. These findings suggest that the biological processes that promote wound healing alleviate the pathological fibrotic response to DSS. Therefore, these mucosal repair processes could be exploited to develop therapies that promote normal wound healing and prevent fibrosis.
NEW AND NOTEWORTHY We show that transcriptomic changes due to Smad4 loss in the colonic epithelium alleviates the pathological fibrotic response to DSS in an IBD mouse model of acute inflammation. Most notably, we find that collagen deposition in the epithelial ECM, as opposed to that in the lamina propria, correlates with epithelial changes that enhance wound healing. This is the first report on a mouse model providing alleviated fibrotic response in a DSS-IBD mouse model in vivo .
### Competing Interest Statement
The authors have declared no competing interest.
* α-SMA
: α-Smooth Muscle Actin
AOM
: Azoxymethane
BCA
: Bicinchoninic acid
BrdU
: Bromodeoxyuridine
CD
: Crohn’s Disease
CPA
: Collagen Proportionate Area
CRP
: C-reactive Protein
DEG
: Differentially Expressed Genes
DSS
: Dextran Sulfate Sodium
ECM
: Extracellular Matrix
EDTA
: Ethylenediaminetetraacetic acid
EdU
: 5-ethynyl-2’-deoxyuridine
EGTA
: ethylene glycol-bis (β-aminoethyl ether)-N, N,N′,N′-tetraacetic acid
FDR
: False Discovery Rate
GO
: Gene Ontology
Gp6
: Glycoprotein 6
GSEA
: Gene Set Enrichment Analysis
H&E
: Hematoxylin and Eosin
IBD
: Inflammatory Bowel Disease
IEC
: Intestinal Epithelial Cell
IFNα
: Interferon Alpha
IFNγ
: Interferon Gamma
iNOS
: inducible Nitric Oxide Synthase
IPA
: Ingenuity Pathways Analysis
KO
: Knockout
ORA
: Over-Representation Analysis
PBS
: Phosphate-Buffered Saline
Pdgfra
: Platelet-derived growth factor receptor alpha
Pdgfa
: Platelet-derived growth factor alpha
PSR
: Picrosirius Red
TAM
: Tamoxifen
UC
: Ulcerative Colitis
WT
: Wildtype
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