Membrane sphingolipid composition orchestrating adult stem cell maintenance and fate

膜鞘脂成分协调成体干细胞的维持和命运

• 批准号: 455963994
• 负责人: Dr. Franziska Peters
• 金额: --
• 依托单位: Abteilung Zell- und Entwicklungsbiologie
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 财政年份: 2020
• 资助国家: 德国
• 起止时间: 2019-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/455963994?language=en
• 关键词: Membrane; sphingolipid; composition; orchestrating; adult

The aim of this project is to understand how lipids, in particular ceramides, control stem cell behaviour and contribute to stem cell aging, and thus to the regenerative capacity of a tissue. Lipids play an essential role in energy homeostasis, membrane mechanics and signalling. Ceramides, synthesized by ceramide synthases (CerS), are the essential building blocks of all cellular membranes and can serve as signalling molecules. The capacity of stem cells to self-renew or differentiate can be attributed to distinct metabolic states, and emerging evidence suggests that lipid metabolism plays a fundamental role in stem cell homeostasis (1,2), but the mechanisms are unclear. Our objective is to identify the molecular and cellular mechanisms by which ceramides control the fate and dynamic behaviour of adult stem cells using the stem cells of the skin epidermis as a paradigm. Our preliminary data indicate that the membrane lipid composition is altered in CerS-deficient and aged stem cells, and we postulate that this change, via altering (mechano)chemical signalling, compromises stem cell renewal and alters lineage fidelity. We furthermore hypothesize that interfering with membrane lipid compositions is a potent mechanism to restore impairments of stem cell function of CerS-deficient and aged stem cells. We will address these hypotheses by: 1. Determining how CerS expression and age control the sphingolipidomes of the epidermis and its stem- and progenitor cells 2. Identifying functional defects of CerS-deficient and aged stem- and progenitor cells and restoring their function ex vivo 3. Deciphering signalling and/ or mechanochemical events leading to reduced stem cell numbers upon CerS-deficiency and ageing This project is central to understand how ceramide-associated metabolic and mechanochemical signals are integrated to control stem cell function and fate within tissues. Understanding these principles are key to understanding how aging alters adult stem cell renewal and fate to drive aging-associated diseases, such as (skin) cancer, fibrosis and impaired wound healing. Exploring the novel role of lipids will further facilitate the development of approaches to enhance stem cell expansion and differentiation in vitro for the use of regenerative medicine. It may, in the long run, also allow tuning stem cell behaviour in vivo, by modulating lipid metabolic pathways pharmacologically or through diet, serving as therapeutic tools for aging-associated diseases.

该项目的目的是了解脂质，特别是神经酰胺，如何控制干细胞的行为，并有助于干细胞老化，从而提高组织的再生能力。脂质在能量稳态、膜力学和信号传导中起重要作用。由神经酰胺酶（CerS）合成的神经酰胺是所有细胞膜的基本构件，并且可以充当信号分子。干细胞自我更新或分化的能力可归因于不同的代谢状态，新出现的证据表明，脂质代谢在干细胞稳态中起着重要作用（1，2），但机制尚不清楚。我们的目标是确定神经酰胺控制的命运和动态行为的成体干细胞的皮肤表皮干细胞作为范例的分子和细胞机制。我们的初步数据表明，CerS缺陷和老年干细胞的膜脂质组成发生改变，我们假设这种变化，通过改变（机械）化学信号，损害干细胞更新和改变谱系保真度。我们进一步假设，干扰膜脂质组成是一种有效的机制，以恢复CerS缺陷和老化干细胞的干细胞功能的损伤。我们将解决这些假设：1。确定CerS表达和年龄如何控制表皮及其干细胞和祖细胞的鞘脂体2.鉴定CerS缺陷和老化的干细胞和祖细胞的功能缺陷并体外恢复其功能3.在CerS缺乏和老化时，破译导致干细胞数量减少的信号传导和/或机械化学事件该项目对于了解神经酰胺相关的代谢和机械化学信号如何整合以控制组织内的干细胞功能和命运至关重要。了解这些原则是了解衰老如何改变成体干细胞更新和命运以驱动衰老相关疾病的关键，如（皮肤）癌症，纤维化和伤口愈合受损。探索脂质的新作用将进一步促进体外增强干细胞扩增和分化以用于再生医学的方法的发展。从长远来看，它还可以通过调节脂质代谢途径或通过饮食调节干细胞在体内的行为，作为衰老相关疾病的治疗工具。