Dietary control of stem cells in physiology and cancer

生理学和癌症中干细胞的饮食控制

• 批准号: 9213850
• 负责人: Omer Yilmaz
• 金额: $ 40.95万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-23 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9213850
• 关键词: Acids; Adult; Aging; Agonist; Biological Assay; Biology; Cell physiology; Cells; Cellular biology; Colon Carcinoma; Cues; Daughter; Development; Diet; Disease; Engineering; Enzymes; Epidemiology; Fatty Acids; Foundations; Genetic; Genetic Transcription; Heterogeneity; High Fat Diet; Incidence; Intestinal Intraepithelial Neoplasia; Intestinal Neoplasms; Intestines; LGR5 gene; Lesion; Link; Maintenance; Malignant Neoplasms; Mammals; Maps; Mediating; Messenger RNA; Metabolic; Mus; Natural regeneration; Obesity; Organoids; PPAR alpha; PPAR delta; Pathway interactions; Pharmacology; Physiology; Population; Premalignant; Process; Production; Regulator Genes; Rodent; Role; Signal Transduction; Stem cells; Testing; Therapeutic; Transplantation; Tumor Initiators; Tumor Suppressor Genes; Tumor Suppressor Proteins; Tumorigenicity; cell type; delta opioid receptor; dietary control; experimental study; fatty acid oxidation; in vivo; intestinal epithelium; intestinal homeostasis; mouse model; oxidation; progenitor; programs; response; self-renewal; stem cell biology; stemness; tissue regeneration; tumor; tumor initiation; tumorigenesis; tumorigenic

PROJECT SUMMARY Organismal diet has a profound impact on tissue regeneration, aging, and disease in mammals. However, the mechanisms through which diet perturbs stem and progenitor cell biology and leads to diseases such as cancer are poorly understood. With the rise of obesity in the US population—more than 1 in 3 adults are obese –understanding the relationship between diet, stem cell biology, and cancer incidence takes on great importance. Focused on the mammalian intestine, we find that a pro-obesity high fat diet (HFD) augments the number and niche-independent function of Lgr5+ stem cells. Mechanistically, our studies indicate that a HFD induces a robust peroxisome proliferator-activated receptor delta (PPAR-d) signature in intestinal stem cells (ISCs) and progenitors (non-stem cells), and pharmacologic activation of PPAR-d recapitulates the effects that a HFD has on these cells. Furthermore, like a HFD, ex vivo treatment of intestinal organoid cultures with fatty acid constituents of the HFD enhances the self-renewal potential of these organoids in a PPAR-d dependent manner. Interestingly, both HFD- and agonist-activated PPAR-d signaling endow progenitors with the organoid-initiating capacity normally restricted to stem cells. In fact, agonist-enforced PPAR-d signaling permits these progenitors to form in vivo tumors upon loss of the tumor suppressor Apc. These observations provide a possible pathway for diet through modulating PPAR-d activation to alter not only the function of intestinal stem and progenitor cells but also their capacity to initiate tumors. Many questions remain regarding the impact of a HFD on the intestine, such as the in vivo, cell type-specific roles of PPAR-d in this process, and the identity of progenitor subsets that emerge in this diet to drive tumor development. Also, although PPAR-d is a master transcriptional regulator of genes involved in fatty acid oxidation (FAO), it is unclear whether intestinal stem and progenitor cells or tumors that arise in a HFD rely on this PPAR-d-activated FAO metabolic program for their maintenance. Specifically, we will test the hypotheses that PPAR-d mediates the in vivo effects of a HFD in ISCs and progenitors in intestinal homeostasis and tumor initiation (Aim 1); that a subset of non-stem cell progenitors acquire stemness and tumorigenic potential in a HFD and with enforced PPAR-d signaling (Aim 2); that a HFD or enforced PPAR-d signaling render ISCs, progenitors, or established tumors metabolically reliant on fatty acid oxidation for their maintenance (Aim 3).

项目概要 有机饮食对哺乳动物的组织再生、衰老和疾病有着深远的影响。然而， 饮食扰乱干细胞和祖细胞生物学并导致疾病的机制，例如 人们对癌症知之甚少。随着美国人口肥胖率的上升——超过三分之一的成年人患有肥胖症 –了解饮食、干细胞生物学和癌症发病率之间的关系意义重大 重要性。 以哺乳动物肠道为重点，我们发现促肥胖的高脂肪饮食 (HFD) 会增加 以及Lgr5+干细胞的不依赖于生态位的功能。从机制上讲，我们的研究表明，HFD 会导致 肠道干细胞 (ISC) 中强大的过氧化物酶体增殖物激活受体 δ (PPAR-d) 特征和 祖细胞（非干细胞）和 PPAR-d 的药理学激活概括了 HFD 的作用 在这些细胞上。此外，与 HFD 一样，用脂肪酸对肠道类器官培养物进行离体处理 HFD 的成分增强了 PPAR-d 依赖性类器官的自我更新潜力 方式。有趣的是，HFD 激活的 PPAR-d 信号传导和激动剂激活的 PPAR-d 信号传导都赋予祖细胞 类器官启动能力通常仅限于干细胞。事实上，激动剂强制执行的 PPAR-d 信号传导允许 这些祖细胞在肿瘤抑制因子 Apc 缺失后形成体内肿瘤。这些观察提供了 饮食的可能途径是通过调节 PPAR-d 激活来改变肠干的功能 和祖细胞，还有它们引发肿瘤的能力。关于影响的许多问题仍然存在 HFD 对肠道的影响，例如 PPAR-d 在此过程中的体内、细胞类型特异性作用，以及 这种饮食中出现的祖细胞亚群可驱动肿瘤的发展。另外，虽然PPAR-d是高手 参与脂肪酸氧化（FAO）基因的转录调节因子，目前尚不清楚肠干是否 HFD 中产生的祖细胞或肿瘤依赖于 PPAR-d 激活的 FAO 代谢程序 他们的维护。 具体来说，我们将测试以下假设：PPAR-d 介导 HFD 在 ISC 中的体内作用，并且 肠道稳态和肿瘤发生中的祖细胞（目标 1）；非干细胞祖细胞的一个子集 通过 HFD 和强制 PPAR-d 信号传导获得干性和致瘤潜力（目标 2）；一个 HFD 或强制的 PPAR-d 信号传导使得 ISC、祖细胞或已形成的肿瘤在代谢上依赖于脂肪 酸氧化以维持其状态（目标 3）。