MiR-10b-5p Rescues Diabetes and Gastrointestinal Dysmotility
| Autor: | Sandra M. Poudrier, Seungil Ro, Hannah Zogg, Addison Morales, Kenton M. Sanders, Jong Kun Park, Andres Gottfried-Blackmore, Rajan Singh, Byungchang Jin, Lai Wei, Brian G. Jorgensen, Allison Bartlett, Se Eun Ha, Moon Young Lee, Yu Heon Chung, Sung Cho, Chanjae Park, Charles F. Ronkon, Linda Nguyen |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Adult Blood Glucose Male Gastroparesis Normal diet Pharmacology Article 03 medical and health sciences symbols.namesake Mice Young Adult 0302 clinical medicine Diabetes mellitus Insulin-Secreting Cells Conditional gene knockout medicine Diabetes Mellitus Animals Humans Gastrointestinal Transit Gastrointestinal dysmotility Aged Mice Knockout Type 1 diabetes Hepatology business.industry Gastroenterology Middle Aged medicine.disease Interstitial Cells of Cajal Interstitial cell of Cajal Mice Inbred C57BL Repressor Proteins Disease Models Animal MicroRNAs Proto-Oncogene Proteins c-kit 030104 developmental biology HEK293 Cells Gastric Emptying Knockout mouse symbols NIH 3T3 Cells 030211 gastroenterology & hepatology Female business Apoptosis Regulatory Proteins |
| Zdroj: | Gastroenterology |
| Popis: | Background & Aims Interstitial cells of Cajal (ICCs) and pancreatic β cells require receptor tyrosine kinase (KIT) to develop and function properly. Degeneration of ICCs is linked to diabetic gastroparesis. The mechanisms linking diabetes and gastroparesis are unclear, but may involve microRNA (miRNA)-mediated post-transcriptional gene silencing in KIT+ cells. Methods We performed miRNA-sequencing analysis from isolated ICCs in diabetic mice and plasma from patients with idiopathic and diabetic gastroparesis. miR-10b-5p target genes were identified and validated in mouse and human cell lines. For loss-of-function studies, we used KIT+ cell-restricted mir-10b knockout mice and KIT+ cell depletion mice. For gain-of-function studies, a synthetic miR-10b-5p mimic was injected in multiple diabetic mouse models. We compared the efficacy of miR-10b-5p mimic treatment vs antidiabetic and prokinetic medicines. Results miR-10b-5p is highly expressed in ICCs from healthy mice, but drastically depleted in ICCs from diabetic mice. A conditional knockout of mir-10b in KIT+ cells or depletion of KIT+ cells in mice leads to degeneration of β cells and ICCs, resulting in diabetes and gastroparesis. miR-10b-5p targets the transcription factor Kruppel-like factor 11 (KLF11), which negatively regulates KIT expression. The miR-10b-5p mimic or Klf11 small interfering RNAs injected into mir-10b knockout mice, diet-induced diabetic mice, and TALLYHO polygenic diabetic mice rescue the diabetes and gastroparesis phenotype for an extended period of time. Furthermore, the miR-10b-5p mimic is more effective in improving glucose homoeostasis and gastrointestinal motility compared with common antidiabetic and prokinetic medications. Conclusions miR-10b-5p is a key regulator in diabetes and gastrointestinal dysmotility via the KLF11-KIT pathway. Restoration of miR-10b-5p may provide therapeutic benefits for these disorders. |
| Databáze: | OpenAIRE |
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