Establishing AMP-activated protein kinase as a regulator of adipose stem cell plasticity and function in health and disease

建立 AMP 激活蛋白激酶作为脂肪干细胞可塑性和健康和疾病功能的调节剂

• 批准号: BB/W009633/1
• 负责人: Alice Pollard
• 金额: $ 51.48万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW009633%2F1
• 关键词: Establishing; AMP; activated; protein; kinase

To grow, replicate and function, cells must sense and respond to their environment. Energy, in the form of adenosine triphosphate (ATP) is required for all cellular processes; to build proteins, replicate DNA, repair membranes and fight infections. To maintain optimal ATP concentrations, multi-protein systems continuously monitor nucleotide levels within the cell, driving growth and proliferation when ATP is plentiful, and by halting energy expenditure and initiating catabolism when ATP is scarce. One such network is governed by AMP-activated protein kinase (AMPK), an enzyme found in almost all organisms, responsible for directly sensing cellular energy levels. Activation of AMPK under energy stress drives the breakdown of energy stores and the removal of damaged or malfunctioning mitochondria (mitophagy), where the majority of ATP is generated. AMPK activation also increases the production of new, healthy mitochondria (biogenesis), leading to efficient ATP production, and encourages the uptake of glucose by the cell, to restore and maintain ATP. AMPK therefore presents an attractive drug target for the treatment of many diseases in which alterations in energy homeostasis feature prominently. Stem cells reside in most tissues, and are responsible for tissue maintenance and repair after damage. Metabolic diseases, such as obesity, diabetes and cardiovascular disease, often occur when energy balance is dysregulated, and are difficult to reverse with lifestyle change alone. Under conditions of metabolic stress, such as inflammation, hypoxia and cell exhaustion, these stem cells do not respond appropriately and the damage becomes irreversible. This process is also true of aging, when stem cells that reach their limits of self-renewal are no longer capable of tissue repair.White adipose tissue, a specialised organ primarily responsible for hormone production and the safe storage of lipids, is often implicated in metabolic disease. Excessive expansion of white adipose tissue leads to adipocyte death, systemic inflammation and insulin resistance, hallmarks of metabolic syndrome. Adipose-derived stem cells (ADSCs) share many features of pluripotent stem cells, capable of forming a diverse range of cell types, including cartilage, bone, skeletal and cardiac muscle. The combination of accessibility and plasticity make ADSCs attractive for targeted stem cell therapies in regenerative and restorative medicine. Our previous work identified a novel population of adipocytes, which we termed SMART cells, generated by genetically activating AMPK in a mouse model of obesity. These cells have a high mitochondrial content, increased mitophagy and express proteins usually found in muscle that allow them to generate heat, protecting the mice from diet-induced obesity and associated organ damage. As SMART cells express these muscle-specific proteins when stimulated in culture, they may be useful for the treatment of metabolic and age-related disease. However, little is known about the origin of these cells, or why they develop instead of normal white adipocytes when AMPK is active. Our aim is to understand the role of AMPK in the development of normal human adipose tissue, and the consequence of metabolic alterations at key points in stem cell differentiation on cell fate and function. Using human immortalised adipocyte derived stem cells (h-iADSCs), and fresh human ADSCs, we aim to establish the role of AMPK in adipose stem cell maintenance, in the specification of cell lineage, and in the resulting function of the mature adipocyte. The work will also explore the effect of metabolic instability on adipocyte lineage and function by isolating ADSCs from patients with metabolic disease. To determine the therapeutic value of AMPK activation, we will transplant patient-derived ADSCs, treated with AMPK activator C455, into mice, where we will assess their ability to form whole adipose tissue, and their effect on whole-body energy homeostasis.

为了生长、复制和发挥功能，细胞必须感知环境并做出反应。能量以三磷酸腺苷（ATP）的形式存在，是所有细胞过程所必需的;构建蛋白质，复制DNA，修复膜和对抗感染。为了维持最佳的ATP浓度，多蛋白系统持续监测细胞内的核苷酸水平，当ATP丰富时驱动生长和增殖，当ATP缺乏时停止能量消耗并启动catalysis。一个这样的网络是由AMP激活的蛋白激酶（AMPK）控制的，AMPK是一种几乎在所有生物体中发现的酶，负责直接感知细胞能量水平。在能量应激下AMPK的激活驱动能量储存的破坏和受损或故障线粒体的去除（线粒体自噬），其中产生大部分ATP。AMPK激活还增加新的健康线粒体的产生（生物发生），导致有效的ATP产生，并鼓励细胞摄取葡萄糖，以恢复和维持ATP。因此，AMPK为治疗许多疾病提供了一个有吸引力的药物靶点，其中能量稳态的改变具有显著特征。干细胞存在于大多数组织中，并负责组织损伤后的维护和修复。代谢性疾病，如肥胖、糖尿病和心血管疾病，通常发生在能量平衡失调时，并且仅通过改变生活方式难以逆转。在代谢应激的条件下，如炎症，缺氧和细胞衰竭，这些干细胞不会做出适当的反应，损伤变得不可逆转。当干细胞达到其自我更新的极限时，衰老也是如此。白色脂肪组织是一种专门的器官，主要负责激素的产生和脂质的安全储存，通常与代谢疾病有关。白色脂肪组织的过度扩张导致脂肪细胞死亡、全身性炎症和胰岛素抵抗，这是代谢综合征的标志。脂肪源性干细胞（ADSC）具有多能干细胞的许多特征，能够形成多种细胞类型，包括软骨、骨、骨骼和心肌。可及性和可塑性的结合使得ADSC对于再生和恢复医学中的靶向干细胞疗法具有吸引力。我们以前的工作确定了一种新的脂肪细胞群体，我们称之为SMART细胞，通过在肥胖小鼠模型中遗传激活AMPK产生。这些细胞具有高线粒体含量，增加线粒体自噬，并表达通常在肌肉中发现的蛋白质，使它们能够产生热量，保护小鼠免受饮食诱导的肥胖和相关器官损伤。由于SMART细胞在培养中受到刺激时表达这些肌肉特异性蛋白质，因此它们可能有助于治疗代谢和年龄相关疾病。然而，关于这些细胞的起源，或者为什么当AMPK被激活时它们而不是正常的白色脂肪细胞发育，我们知之甚少。我们的目的是了解AMPK在正常人脂肪组织发育中的作用，以及干细胞分化关键点的代谢改变对细胞命运和功能的影响。使用人永生化脂肪细胞衍生的干细胞（h-iADSC）和新鲜的人ADSC，我们的目的是建立AMPK在脂肪干细胞维持、细胞谱系的特化和成熟脂肪细胞的最终功能中的作用。这项工作还将通过从代谢疾病患者中分离ADSC来探索代谢不稳定对脂肪细胞谱系和功能的影响。为了确定AMPK激活的治疗价值，我们将用AMPK激活剂C455处理的患者来源的ADSC移植到小鼠中，在那里我们将评估它们形成整个脂肪组织的能力，以及它们对全身能量稳态的影响。

项目成果

AMPK activation protects against prostate cancer by inducing a catabolic cellular state.

AMPK激活通过诱导分解代谢的细胞状态来预防前列腺癌。

• DOI: 10.1016/j.celrep.2023.112396
• 发表时间: 2023-04-25
• 期刊: Cell reports
• 影响因子: 8.8