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TBK1 regulates regeneration of pancreatic ?-cells.

ABSTRACT: Small-molecule inhibitors of non-canonical I?B kinases TANK-binding kinase 1 (TBK1) and I?B kinase ? (IKK?) have shown to stimulate ?-cell regeneration in multiple species. Here we demonstrate that TBK1 is predominantly expressed in ?-cells in mammalian islets. Proteomic and transcriptome analyses revealed that genetic silencing of TBK1 increased expression of proteins and genes essential for cell proliferation in INS-1 832/13 rat ?-cells. Conversely, TBK1 overexpression decreased sensitivity of ?-cells to the elevation of cyclic AMP (cAMP) levels and reduced proliferation of ?-cells in a manner dependent on the activity of cAMP-hydrolyzing phosphodiesterase 3 (PDE3). While the mitogenic effect of (E)3-(3-phenylbenzo[c]isoxazol-5-yl)acrylic acid (PIAA) is derived from inhibition of TBK1, PIAA augmented glucose-stimulated insulin secretion (GSIS) and expression of ?-cell differentiation and proliferation markers in human embryonic stem cell (hESC)-derived ?-cells and human islets. TBK1 expression was increased in ?-cells upon diabetogenic insults, including in human type 2 diabetic islets. PIAA enhanced expression of cell cycle control molecules and ?-cell differentiation markers upon diabetogenic challenges, and accelerated restoration of functional ?-cells in streptozotocin (STZ)-induced diabetic mice. Altogether, these data suggest the critical function of TBK1 as a ?-cell autonomous replication barrier and present PIAA as a valid therapeutic strategy augmenting functional ?-cells.

SUBMITTER: Jia YF

PROVIDER: S-EPMC7653919 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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TBK1 regulates regeneration of pancreatic β-cells.

Jia Yun-Fang YF Jeeva Subbiah S Xu Jin J Heppelmann Carrie Jo CJ Jang Jin Sung JS Slama Michael Q MQ Tapadar Subhasish S Oyelere Adegboyega K AK Kang Sang-Moo SM Matveyenko Aleksey V AV Peterson Quinn P QP Shin Chong Hyun CH

Scientific reports 20201109 1

Small-molecule inhibitors of non-canonical IκB kinases TANK-binding kinase 1 (TBK1) and IκB kinase ε (IKKε) have shown to stimulate β-cell regeneration in multiple species. Here we demonstrate that TBK1 is predominantly expressed in β-cells in mammalian islets. Proteomic and transcriptome analyses revealed that genetic silencing of TBK1 increased expression of proteins and genes essential for cell proliferation in INS-1 832/13 rat β-cells. Conversely, TBK1 overexpression decreased sensitivity of ...[more]

PMID: 33168920

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Project description:BackgroundMesenchymal stem cells (MSC) are non-haematopoietic, fibroblast-like multipotent stromal cells. In the injured pancreas, these cells are assumed to secrete growth factors and immunomodulatory molecules, which facilitate the regeneration of pre-existing β-cells. However, when MSC are delivered intravenously, their majority is entrapped in the lungs and does not reach the pancreas. Therefore, the aim of this investigation was to compare the regenerative support of hTERT-MSC (human telomerase reverse transcriptase mesenchymal stem cells) via intrapancreatic (IPR) and intravenous route (IVR).MethodshTERT-MSC were administered by IPR and IVR to 50% pancreatectomized NMRI nude mice. After eight days, blood glucose level, body weight, and residual pancreatic weight were measured. Proliferating pancreatic β-cells were labelled and identified with bromodeoxyuridine (BrdU) in vivo. The number of residual islets and the frequency of proliferating β-cells were compared in different groups with sequential pancreatic sections. The pancreatic insulin content was evaluated by enzyme-linked immunosorbent assay (ELISA) and the presence of hTERT-MSC with human Alu sequence. Murine gene expression of growth factors, β-cell specific molecules and proinflammatory cytokines were inspected by real-time polymerase chain reaction (RT-PCR) and Western blot.ResultsThis study evaluated the regenerative potential of the murine pancreas post-hTERT-MSC administration through the intrapancreatic (IPR) and intravenous route (IVR). Both routes of hTERT-MSC transplantation (IVR and IPR) increased the incorporation of BrdU by pancreatic β-cells compared to control. MSC induced epidermal growth factor (EGF) expression and inhibited proinflammatory cytokines (IFN-γ and TNF-α). FOXA2 and PDX-1 characteristics for pancreatic progenitor cells were activated via AKT/ PDX-1/ FoxO1 signalling pathway.ConclusionThe infusion of hTERT-MSC after partial pancreatectomy (Px) through the IVR and IPR facilitated the proliferation of autochthonous pancreatic β-cells and provided evidence for a regenerative influence of MSC on the endocrine pancreas. Moderate benefit of IPR over IVR was observed which could be a new treatment option for preventing diabetes mellitus after pancreas surgery.

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TBK1 regulates regeneration of pancreatic ?-cells.

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TBK1 regulates regeneration of pancreatic β-cells.

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