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Published on: April 1, 2021
Rspo3 regulates the abnormal differentiation of small intestinal epithelial cells in diabetic state
Ti-Dong Shan1, Han Yue2, Xue-Guo Sun2
1Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao University, 16 Jiang Su Road, Qingdao, Shandong, 262000, P.R. China. shantidong26@163.com.
Background:
The complications caused by diabetes mellitus (DM) are the focus of clinical treatment. However, little is known about diabetic enteropathy (DE) and its potential underlying mechanism.
Methods:
Intestinal epithelial cells (IECs) and intestinal epithelial stem cells (IESCs) were harvested from BKS.Cg-Dock7m+/+Leprdb/JNju (DM) mice, and the expression of R-Spondin 3 (Rspo3) was detected by RT-qPCR, Western blotting, immunohistochemistry, and immunofluorescence. The role of Rspo3 in the abnormal differentiation of IECs during DM was confirmed by knockdown experiments. Through miRNA expression profiling, bioinformatics analysis, and RT-qPCR, we further analyzed the differentiation-related miRNAs in the IECs from mice with DM.
Results:
Abnormal differentiation of IECs was observed in the mice with DM. The expression of Rspo3 was upregulated in the IECs from the mice with DM. This phenomenon was associated with Rspo3 overexpression. Additionally, Rspo3 is a major determinant of Lgr5+ stem cell identity in the diabetic state. Microarray analysis, bioinformatics analysis, and luciferase reporter assays revealed that microRNA (miR)-380-5p directly targeted Rspo3. Moreover, miR-380-5p upregulation was observed to attenuate the abnormal differentiation of IECs by regulating Rspo3 expression.
Conclusions:
Together, our results provide definitive evidence of the essential role of Rspo3 in the differentiation of IECs in DM.
Insights
Diabetic enteropathy involves abnormal intestinal cell differentiation. This study reveals R-Spondin 3 (Rspo3) is upregulated in diabetes, driving this issue, but microRNA-380-5p can regulate Rspo3 to normalize cell differentiation.
Area of Science:
- Gastroenterology
- Endocrinology
- Cell Biology
Background:
- Diabetes mellitus (DM) complications are clinically significant, yet diabetic enteropathy (DE) mechanisms remain unclear.
- Understanding DE pathogenesis is crucial for managing diabetes-related gastrointestinal issues.
Purpose of the Study:
- To investigate the role of R-Spondin 3 (Rspo3) in intestinal epithelial cell (IEC) differentiation in diabetic mice.
- To identify regulatory mechanisms, including microRNAs, involved in Rspo3-mediated DE.
Main Methods:
- Harvested IECs and IESCs from diabetic (DM) and control mice.
- Quantified Rspo3 expression using RT-qPCR, Western blotting, immunohistochemistry, and immunofluorescence.
- Performed knockdown experiments to assess Rspo3 function and miRNA profiling to identify regulatory miRNAs.
Main Results:
- Diabetic mice exhibited abnormal IEC differentiation and upregulated Rspo3 expression.
- Rspo3 was identified as a key regulator of Lgr5+ stem cell identity in diabetes.
- MicroRNA-380-5p was found to directly target and downregulate Rspo3, mitigating abnormal IEC differentiation.
Conclusions:
- R-Spondin 3 (Rspo3) plays a critical role in intestinal epithelial cell differentiation during diabetes mellitus.
- MicroRNA-380-5p acts as a negative regulator of Rspo3, offering a potential therapeutic target for diabetic enteropathy.
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