Membrane sphingolipid composition orchestrating adult stem cell maintenance and fate

该项目的目的是了解脂质，特别是神经酰胺，如何控制干细胞行为，促进干细胞老化，从而促进组织的再生能力。脂质在能量稳态、膜力学和信号传导中起着重要作用。神经酰胺是由神经酰胺合成酶（CerS）合成的，是所有细胞膜的基本组成部分，可以作为信号分子。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），但其机制尚不清楚。我们的目标是确定神经酰胺控制成体干细胞命运和动态行为的分子和细胞机制，以皮肤表皮干细胞为范例。我们的初步数据表明，在ers缺陷和衰老的干细胞中，膜脂成分发生了改变，我们假设这种变化通过改变（机械）化学信号传导，损害了干细胞的更新并改变了谱系的保真度。我们进一步假设，干扰膜脂成分是一种有效的机制，可以恢复cer缺陷和衰老干细胞的干细胞功能损伤。我们将通过以下方式来解决这些假设：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瘤识别cers缺陷和衰老的干细胞和祖细胞的功能缺陷并在体外恢复其功能该项目是了解神经酰胺相关的代谢和机械化学信号如何集成来控制组织内干细胞的功能和命运的核心。了解这些原理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干细胞体外扩增和分化的发展，以用于再生医学。从长远来看，它也可能允许通过药理学或饮食调节脂质代谢途径来调节体内干细胞的行为，作为衰老相关疾病的治疗工具。

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.