The matricellular protein Fibulin-5 regulates β-cell proliferation in an autocrine/paracrine manner

  • iScience. 2025 Jan 21;28(2):111856. doi: 10.1016/j.isci.2025.111856.
Tomoko Okuyama  1 ,  Takahiro Tsuno  1  2 ,  Ryota Inoue  1  2 ,  Setsuko Fukushima  2 ,  Mayu Kyohara  1 ,  Anzu Matsumura  2 ,  Daisuke Miyashita  1 ,  Kuniyuki Nishiyama  1  2 ,  Yusuke Takano  1 ,  Yu Togashi  1 ,  Makiko Meguro-Horike  3 ,  Shin-Ichi Horike  3 ,  Tatsuya Kin  4 ,  A M James Shapiro  4 ,  Hiromi Yanagisawa  5 ,  Yasuo Terauchi  1 ,  Jun Shirakawa  1  2
Affiliations
  • 1. Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
  • 2. Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, Japan.
  • 3. Research Center for Experimental Modeling of Human Disease, Kanazawa University, Kanazawa, Japan.
  • 4. Clinical Islet Laboratory and Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada.
  • 5. Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Japan.
PMID: 39995864 DOI: 10.1016/j.isci.2025.111856
Abstract

The matricellular protein Fibulin-5 (Fbln5) is a secreted protein that is essential for elastic fiber formation, and pancreatic islets are usually surrounded by the extracellular matrix (ECM), which includes elastic fibers. However, much uncertainty remains regarding the function of the ECM and its components in β-cells. Here, we describe the role of Fbln5 in β-cell replication. Fbln5 expression was increased upon glucose stimulation in β-cells of mouse and human islets. β-Cell-specific Fbln5-knockout (βFbln5KO) mice exhibit significantly reduced β-cell proliferation in vivo but not in vitro. Secreted extracellular Fbln5 enhances β-cell replication. Fbln5-deficient β-cells exhibit the downregulated expression of the gene encoding Polo-like kinase 1 (PLK1), which is accompanied by ERK-mediated FoxM1 nuclear export. These data suggest that Fbln5 is secreted from β-cells in response to glucose and plays important roles in the appropriate maintenance of β-cell functions in an autocrine or paracrine manner.

Keywords
Cell biology; Functional aspects of cell biology.
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