de Back Walter, Zimm Roland, Brusch Lutz
Center for Information Services and High Performance Computing, Technische Universität Dresden, Dresden, 01062, Germany.
BMC Syst Biol. 2013 Aug 13;7:77. doi: 10.1186/1752-0509-7-77.
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.
In 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.
This 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.
胰腺腺泡细胞转分化为朗格汉斯胰岛中功能失调的β细胞，已被提议作为糖尿病的一种再生疗法。成年腺泡细胞在体外组织解离时会自发恢复为多能状态，并可被刺激重新分化为β细胞。尽管越来越多的证据表明接触介导的信号参与其中，但调节腺泡向胰岛细胞转分化的机制仍知之甚少。
在本研究中，我们提出两种接触介导的信号传导机制——侧向抑制和侧向稳定之间的相互作用，控制着胰腺细胞的命运稳定性和转分化。对一个将基因调控与接触介导信号相结合的数学模型的分析揭示了腺泡和胰岛细胞命运的多稳定性。抑制一种或两种信号传导模式会导致从腺泡细胞命运向胰岛细胞命运的转分化，要么通过去分化为多能状态，要么通过直接的谱系转换。
本研究提供了一个理论框架，以理解接触介导信号在胰腺细胞命运控制中的作用，这可能有助于改进用于β细胞新生的腺泡向胰岛细胞转分化策略。
