Bri2 BRICHOS domain inhibits IAPP amyloid formation and improves beta cell function in stem cell-derived islets under metabolic stress

TL;DR

This study shows that the Bri2 BRICHOS domain prevents harmful IAPP amyloid formation and helps beta cells function better under stress in stem cell-derived islets.

Contribution

The study demonstrates that Bri2 BRICHOS overexpression reduces IAPP amyloid and protects beta cell function in stem cell-derived islets under metabolic stress.

Findings

IAPP colocalizes with insulin in SC-islet beta cells and forms amyloid under metabolic stress.

Bri2 BRICHOS overexpression prevents IAPP amyloid formation and partially protects beta cell function.

Amyloid reduction is not due to beta cell impairment but to protection against IAPP toxicity.

Abstract

Accumulation of islet amyloid polypeptide (IAPP) and amyloid formation is associated with beta cell dysfunction and cell death in human islets and may also contribute to graft failure post stem cell-derived islet (SC-islet) transplantation. The BRICHOS domain, a secretory peptide proteolysed from the Bri2 protein, possesses chaperone activity and has been shown to inhibit fibril formation of amyloid β-peptide in the brain and IAPP in human islets. In this study, we aimed to evaluate amyloid formation in SC-islets in vitro, as well as assess the role of Bri2 BRICHOS on amyloid formation and beta cell function.

Human SC-islets were used as an in vitro model to explore the accelerated amyloid formation and to investigate the role of Bri2 BRICHOS via adenovirus-transduced overexpression. SC-islets were cultured under normal glucose conditions or metabolic stress-like conditions. Subsequently, amyloid formation was determined by staining with the amyloid-specific ligand pentameric formyl thiophene acetic acid and transmission electron microscopy. Beta cell function was assessed by static glucose-stimulated insulin secretion and insulin content. The presence of relevant proteins was evaluated by immunostaining and confocal microscopy. The mRNA expression profile of genes of interest was evaluated by qRT-PCR.

We showed that IAPP is colocalised with insulin in SC-islet beta cells and, like human islets, SC-islets can develop amyloid under metabolic stress in vitro. Amyloid formation was increased and beta cell function was impaired in SC-islets under metabolic stress and overexpression of the Bri2 BRICHOS domain in SC-islets effectively prevented amyloid formation and partially protected beta cell function. The accentuated endogenous gene expression of ITM2B, ADAM10 and IAPP in SC-islets under the same glucose-induced metabolic stress condition was not affected by the overexpression of the Bri2 BRICHOS domain.

Our findings suggest that the molecular chaperone Bri2 colocalises with IAPP and insulin in SC-islet beta cells. The folding assistance has been ascribed to the BRICHOS domain in Bri2 and viral overexpression of the BRICHOS domain can prevent the formation of cytotoxic IAPP amyloid and improve beta cell function in SC-islets exposed to metabolic stress. A comprehensive analysis of SC-islet functionality excludes beta cell impairment as a cause for amyloid reduction but supports the protection against IAPP amyloid.

The online version of this article (10.1007/s00125-025-06582-5) contains peer-reviewed but unedited supplementary material.

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