Abstract
BackgroundReplacement of dysfunctional β-cells in the islets of Langerhans by transdifferentiation of pancreatic acinar cells has been proposed as a regenerative therapy for diabetes. Adult acinar cells spontaneously revert to a multipotent state upon tissue dissociation in vitro and can be stimulated to redifferentiate into β-cells. Despite accumulating evidence that contact-mediated signals are involved, the mechanisms regulating acinar-to-islet cell transdifferentiation remain poorly understood.ResultsIn this study, we propose that the crosstalk between two contact-mediated signaling mechanisms, lateral inhibition and lateral stabilization, controls cell fate stability and transdifferentiation of pancreatic cells. Analysis of a mathematical model combining gene regulation with contact-mediated signaling reveals the multistability of acinar and islet cell fates. Inhibition of one or both modes of signaling results in transdifferentiation from the acinar to the islet cell fate, either by dedifferentiation to a multipotent state or by direct lineage switching.ConclusionsThis study provides a theoretical framework to understand the role of contact-mediated signaling in pancreatic cell fate control that may help to improve acinar-to-islet cell transdifferentiation strategies for β-cell neogenesis.
Highlights
Replacement of dysfunctional β-cells in the islets of Langerhans by transdifferentiation of pancreatic acinar cells has been proposed as a regenerative therapy for diabetes
By means of model analysis, one can reveal the existence of attractors that represent cellular phenotypes and understand the dynamics between states [27,28,29]. Using such a systems biological approach, we have previously shown that the results of genetic reprogramming experiments in the pancreas can be predicted from the hierarchical topology of the underlying gene regulatory network [30]
We construct a minimal model of the gene regulatory network and contact-mediated signaling pathways underlying endocrine/exocrine cell fate decisions and maintenance in the pancreas and analyse this model using a combination of bifurcation analysis and tissue-scale lattice simulation
Summary
Replacement of dysfunctional β-cells in the islets of Langerhans by transdifferentiation of pancreatic acinar cells has been proposed as a regenerative therapy for diabetes. Adult acinar cells spontaneously revert to a multipotent state upon tissue dissociation in vitro and can be stimulated to redifferentiate into β-cells. Despite accumulating evidence that contact-mediated signals are involved, the mechanisms regulating acinar-to-islet cell transdifferentiation remain poorly understood. Novel approaches in regenerative medicine aim at harnessing this cell type plasticity in order to replace diseased or damaged tissue by targeted conversion of cells from other tissues [3]. Transdifferentiation, known as lineage conversion, from one cell type to another often involves a dedifferentation step to reinstate multipotency, but it is possible to force cells to switch lineages directly [4]. Some cell types can be converted without genetic manipulation, by
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
