한빛사 논문
Rajan Singh1*, Se Eun Ha1*, Lai Wei1, Byungchang Jin1, Hannah Zogg1, Sandra M. Poudrier1 , Brian G. Jorgensen1, Chanjae Park1, Charles F Ronkon1, Allison Bartlett1, Sung Cho1, Addison Morales1, Yu Heon Chung2, Moon Young Lee1,3, Jong Kun Park2, Andrés Gottfried-Blackmore4, Linda Nguyen4, Kenton M. Sanders1, Seungil Ro1†
1Department of Physiology and Cell Biology, School of Medicine, University of Nevada, Reno, NV, 89557, USA 2Division of Biological Sciences, Wonkwang University, Iksan, Chonbuk, Korea 3Department of Physiology, Wonkwang Digestive Disease Research Institute and Institute of Wonkwang Medical Science, School of Medicine, Wonkwang University, Iksan, Chonbuk, Korea 4Division of Gastroenterology & Hepatology, Stanford University School of Medicine, Stanford, CA, 94305, USA
*These authors contributed equally to this work.
†Corresponding author: Seungil Ro, PhD
Abstract
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 miRNA mediated post-transcriptional gene silencing in KIT+ cells.
METHODS
We performed miRNA-seq 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 Krüppel-like factor 11 (KLF11), which negatively regulates KIT expression. The miR-10b-5p mimic or Klf11 siRNAs injected into mir-10b knockout mice, diet-induced diabetic mice, and TALLYHO polygenic diabetic mice rescues 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 GI motility as compared with common antidiabetic and prokinetic medications.
CONCLUSION
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.
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