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The pancreatic islets comprising only 1%-2% of the volume are highly vascularized and innervated mini-organs. They contain five endocrine cell types, including β cells that secrete insulin, which is synthesized as a single polypeptide chain, preproinsulin, processed to proinsulin, and finally to insulin and C-peptide. This process is complex and regulated, involving the Golgi complex, the endoplasmic reticulum, and the secretory granules of the β cell.
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TGFβ Pathway Inhibition Redifferentiates Human Pancreatic Islet β Cells Expanded In Vitro.

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Area of Science:

  • Endocrinology
  • Cell Biology
  • Regenerative Medicine

Background:

  • In vitro expansion of human pancreatic islet cells offers potential for diabetes cell therapy.
  • Proliferation of beta-cell-derived (BCD) cells leads to dedifferentiation and epithelial-mesenchymal transition (EMT).
  • BCD cells retain open chromatin at beta-cell genes, indicating potential for redifferentiation.

Purpose of the Study:

  • To investigate the role of the transforming growth factor beta (TGFβ) pathway in human islet cell expansion.
  • To determine if blocking the TGFβ pathway can inhibit dedifferentiation and promote redifferentiation of BCD cells.
  • To explore therapeutic strategies for generating functional insulin-producing cells from expanded human islets.

Main Methods:

  • Utilized short hairpin RNA (shRNA) to block TGFβ Receptor 1 (TGFBR1, also known as ALK5) activation.
  • Assessed BCD cell proliferation, phenotype, and gene expression following ALK5 inhibition.
  • Investigated the involvement of AKT-FOXO1 signaling in the observed effects.
  • Evaluated the synergistic effect of ALK5 inhibition with a soluble factor cocktail.

Main Results:

  • In vitro expansion of human islet cells showed upregulation of the TGFβ pathway.
  • ALK5 shRNA treatment inhibited BCD cell proliferation and dedifferentiation.
  • ALK5 inhibition promoted redifferentiation of expanded BCD cells, evidenced by restored beta-cell gene expression and reduced proliferation.
  • ALK5 inhibition's effects were partly mediated by AKT-FOXO1 signaling.
  • Combined ALK5 inhibition and soluble factors synergistically enhanced BCD cell redifferentiation.

Conclusions:

  • The TGFβ pathway is crucial in regulating human islet cell dedifferentiation during in vitro expansion.
  • Targeting ALK5 effectively inhibits dedifferentiation and promotes redifferentiation of BCD cells.
  • Combined therapeutic strategies involving ALK5 inhibition show promise for generating abundant functional insulin-producing cells for diabetes treatment.