Membrane sphingolipid composition orchestrating adult stem cell maintenance and fate

这个项目的目的是了解脂类，特别是神经酰胺，如何控制干细胞的行为，促进干细胞老化，从而促进组织的再生能力。脂质在能量平衡、膜机制和信号转导中起着重要的作用。神经酰胺是由神经酰胺合成酶(CERs)合成的，是所有细胞膜的重要组成部分，可以作为信号分子。干细胞自我更新或分化的能力可以归因于不同的代谢状态，新出现的证据表明，脂代谢在干细胞稳态中起着基础性作用(1，2)，但其机制尚不清楚。我们的目标是以皮肤表皮干细胞为范例，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。我们的初步数据表明，CERs缺乏和老化的干细胞的膜脂成分发生了变化，我们假设这种变化通过改变(机械的)化学信号，损害干细胞的更新和改变谱系的保真度。我们进一步假设，干扰膜脂成分是恢复CERs缺陷和衰老干细胞干细胞功能受损的有效机制。我们将通过以下方式解决这些假设：1.确定CERs的表达和AGE如何控制表皮及其干细胞和祖细胞的鞘脂体2.识别CERs缺乏和老化的干/祖细胞的功能缺陷并在体外恢复它们的功能3.破译CERs缺乏和衰老时导致干细胞数量减少的信号和/或机械力化学事件这个项目对于了解神经酰胺相关的代谢和机械力化学信号如何整合来控制干细胞的功能和组织内的命运至关重要。理解这些原理是理解衰老如何改变成人干细胞更新和命运的关键，以推动与衰老相关的疾病，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促进干细胞体外扩增和分化用于再生医学的方法的发展。从长远来看，它还可以通过药物或饮食调节脂肪代谢途径，调整干细胞在体内的行为，作为治疗衰老相关疾病的工具。

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.