Regulation of pancreas organoid plasticity: new strategies for diabetes

胰腺类器官可塑性的调节：糖尿病的新策略

• 批准号: MR/S000011/1
• 负责人: Rocio Sancho
• 金额: $ 60.5万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS000011%2F1
• 关键词: Regulation; pancreas; organoid; plasticity; new

Since the discovery of insulin almost a century ago, there has been an alarming increase in new diabetes cases, but the only treatment for diabetes is still based on delivering insulin via injections or pumps. While insulin administration can successfully control diabetic symptoms, the risk of complications is very high, and the continual blood sugar management required can be a real burden in patients' lives. Regenerative medicine offers new hopes of a curative treatment for diabetes by replacing lost beta cells, which respond to blood glucose levels and produce insulin. However, the source of replacement cells, the efficiency with which they can be produced and how well they work in the body are all still under investigation. Recent evidence suggests that the ductal cells of the pancreas, which are not damaged in diabetes, can change into other cell types when given the right trigger. Ductal cells can be grown long term outside the body as "organoids" in 3D culture. We and others have shown that when grown in special conditions or genetically modified to produce three key proteins responsible for making beta cells in the embryo (Ngn3/Pdx1/MafA), ductal cells change to beta-like cells. In our lab, we have exciting evidence that the reason the efficiency of conversion and functionality of the generated cells does not match "real" mature beta cells is firstly, because not all cells are equally responsive to the signals to become beta-cells, and secondly, because of the strong degradation mechanisms that operate on Ngn3, Pdx1 and MafA, inactivating them before they have a chance to work. We believe that by identifying the cells that can convert into beta-cells, and discovering how to stabilise Ngn3, Pdx1 and MafA we will be able to improve the chances of curing diabetes. In this proposal, we want to address these questions: What are the proteasomal mechanisms regulating proendocrine factors stability? How does the lysosome regulate the proendocrine factors? Can the variation of such mechanisms at a single cell level explain the heterogeneity of the ductal organoids? Altogether this research proposal will substantially increase our knowledge of beta cell generation from ductal cells. We hope that our findings pave the way for the development of new, more efficient strategies to replenish lost beta cells in diabetes patients, in order to achieve the ultimate therapy goal for diabetes: a "diabetes free" life.

自从近一个世纪前发现胰岛素以来，新发糖尿病病例出现了惊人的增长，但糖尿病的唯一治疗方法仍然是通过注射或泵输送胰岛素。虽然胰岛素治疗可以成功地控制糖尿病症状，但并发症的风险非常高，所需的持续血糖管理可能会成为患者生活的真正负担。再生医学为糖尿病的治疗带来了新的希望，它可以取代丢失的β细胞，这些细胞对血糖水平做出反应，并产生胰岛素。然而，替代细胞的来源、生产效率以及它们在体内的工作情况仍在调查中。最近的证据表明，在糖尿病中没有受损的胰腺导管细胞，在给予正确的触发后，可以转变为其他类型的细胞。在3D培养中，导管细胞可以在体外以“类器官”的形式长期生长。我们和其他人已经证明，当在特殊条件下生长或转基因产生三种关键蛋白质(Ngn3/Pdx1/Mafa)时，胚胎中的导管细胞会转变为类似β的细胞。在我们的实验室中，我们有令人兴奋的证据表明，产生的细胞的转换和功能的效率与“真正”成熟的β细胞不匹配的原因首先是因为并不是所有的细胞对信号都有相同的反应成为β细胞，其次是因为对Ngn3、Pdx1和MafA起作用的强大的降解机制，在它们有机会工作之前将它们灭活。我们相信，通过鉴定可以转化为β细胞的细胞，并发现如何稳定Ngn3、Pdx1和Mafa，我们将能够提高治愈糖尿病的机会。在这项提案中，我们想要解决这些问题：调节前内分泌因子稳定性的蛋白酶体机制是什么？溶酶体是如何调节前内分泌因子的？这种机制在单个细胞水平上的变化能解释导管类器官的异质性吗？总而言之，这项研究提案将大大增加我们对导管细胞生成β细胞的了解。我们希望我们的发现为开发新的、更有效的策略来补充糖尿病患者丢失的β细胞铺平道路，以实现糖尿病的最终治疗目标：“无糖尿病”的生活。

项目成果

Lung Based Engineered Micro-Pancreas Sustains Human Beta Cell Survival and Functionality.

基于肺的工程微胰腺维持人类β细胞的存活和功能。

• DOI: 10.1055/a-1041-3305
• 发表时间: 2019
• 期刊: Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme
• 作者: Goldman O

Stem/progenitor cells in normal physiology and disease of the pancreas.

• DOI: 10.1016/j.mce.2021.111459
• 发表时间: 2021-12-01
• 期刊: Molecular and cellular endocrinology
• 影响因子: 4.1
• 作者: Alvarez Fallas ME;Pedraza-Arevalo S;Cujba AM;Manea T;Lambert C;Morrugares R;Sancho R
• 通讯作者: Sancho R

USP7 controls NGN3 stability and pancreatic endocrine lineage development.

• DOI: 10.1038/s41467-023-38146-9
• 发表时间: 2023-04-28
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Manea, Teodora;Nelson, Jessica Kristine;Garrone, Cristina Maria;Hansson, Karin;Evans, Ian;Behrens, Axel;Sancho, Rocio
• 通讯作者: Sancho, Rocio

Differentiation of beta-like cells from human induced pluripotent stem cell-derived pancreatic progenitor organoids.

• DOI: 10.1016/j.xpro.2022.101656
• 发表时间: 2022-09-16
• 期刊: STAR PROTOCOLS
• 作者: Pedraza-Arevalo, Sergio;Cujba, Ana-Maria;Alvarez-Fallas, Mario Enrique;Sancho, Rocio
• 通讯作者: Sancho, Rocio

Single cell analysis of human foetal liver captures the transcriptional profile of hepatobiliary hybrid progenitors

• DOI: 10.1038/s41467-019-11266-x
• 发表时间: 2019-07-26
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Segal, Joe M.;Kent, Deniz;Rashid, S. Tamir
• 通讯作者: Rashid, S. Tamir