Permanent neonatal diabetes-causing insulin mutations have dominant negative effects on beta cell identity

Zhang, Yuwei; Sui, Lina; Du, Qian; Haataja, Leena; Yin, Yishu; Viola, Ryan; Xu, Shuangyi; Nielsson, Christian Ulrik; Leibel, Rudolph L.; Barbetti, Fabrizio; Arvan, Peter; Egli, Dieter

doi:10.1016/j.molmet.2024.101879

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2024

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Cited by 4 publications

References 80 publications

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Synthetic Studies of the Mutant Proinsulin Syndrome Demonstrate Correlation Between Folding Efficiency and Age of Diabetes Onset

Dhayalan,

Chen,

et al. 2024

Int J Pept Res Ther

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Synthetic Studies of the Mutant Proinsulin Syndrome Demonstrate Correlation Between Folding Efficiency and Age of Diabetes Onset

Dhayalan,

Chen,

et al. 2024

Int J Pept Res Ther

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Recent progress in modeling and treating diabetes using stem cell-derived islets

Maestas,

Bui,

Millman

2024

Stem Cells Translational Medicine

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Stem cell-derived islets (SC-islets) offer the potential to be an unlimited source of cells for disease modeling and the treatment of diabetes. SC-islets can be genetically modified, treated with chemical compounds, or differentiated from patient derived stem cells to model diabetes. These models provide insights into disease pathogenesis and vulnerabilities that may be targeted to provide treatment. SC-islets themselves are also being investigated as a cell therapy for diabetes. However, the transplantation process is imperfect; side effects from immunosuppressant use have reduced SC-islet therapeutic potential. Alternative methods to this include encapsulation, use of immunomodulating molecules, and genetic modification of SC-islets. This review covers recent advances using SC-islets to understand different diabetes pathologies and as a cell therapy.

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Depolymerizing F-actin accelerates the exit from pluripotency to enhance stem cell-derived islet differentiation

Hogrebe,

Schmidt,

Augsornworawat

et al. 2024

Preprint

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Improving generation of insulin-producing islets from human pluripotent stem cells (hPSCs) would enhance their clinical relevance for treating diabetes. Here, we demonstrate that cytoskeletal state at the onset of differentiation is critical for definitive endoderm formation. Depolymerizing F-actin with latrunculin A (latA) during the first 24 hours of differentiation facilitates rapid exit from pluripotency and alters Activin/Nodal, BMP, JNK-JUN, and WNT pathway signaling dynamics during definitive endoderm formation. These signaling changes influence downstream patterning of the gut tube, leading to improved pancreatic progenitor identity and decreased expression of markers for other endodermal lineages. Continued differentiation generates islets containing a higher percentage of β cells that exhibit improved maturation, insulin secretion, and ability to reverse hyperglycemia. Furthermore, this latA treatment reduces enterochromaffin cells in the final cell population and corrects differentiations from hPSC lines that otherwise fail to consistently produce pancreatic islets, highlighting the importance of cytoskeletal signaling during differentiation onset.

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Permanent neonatal diabetes-causing insulin mutations have dominant negative effects on beta cell identity

Cited by 4 publications

References 80 publications

Synthetic Studies of the Mutant Proinsulin Syndrome Demonstrate Correlation Between Folding Efficiency and Age of Diabetes Onset

Synthetic Studies of the Mutant Proinsulin Syndrome Demonstrate Correlation Between Folding Efficiency and Age of Diabetes Onset

Recent progress in modeling and treating diabetes using stem cell-derived islets

Depolymerizing F-actin accelerates the exit from pluripotency to enhance stem cell-derived islet differentiation

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