Dietary control of stem cells in physiology and cancer

项目摘要 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。但 饮食干扰干细胞和祖细胞生物学并导致疾病的机制， 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肥胖 了解饮食、干细胞生物学和癌症发病率之间的关系， 重要性 聚焦于哺乳动物的肠道，我们发现促肥胖高脂肪饮食（HFD）增加了 和Lgr 5+干细胞的小生境非依赖性功能。从机制上讲，我们的研究表明，HFD诱导 肠干细胞（ISCs）中强过氧化物酶体增殖物激活受体δ（PPAR-d）特征， 祖细胞（非干细胞），PPAR-d的药理学激活概括了HFD具有的作用， 这些细胞。此外，像HFD一样，用脂肪酸对肠类器官培养物进行离体处理是可行的。 HFD的成分增强了这些类器官的自我更新潜力， 方式有趣的是，HFD和激动剂激活的PPAR-d信号转导都赋予祖细胞以特异性的转录因子。 类器官启动能力通常仅限于干细胞。事实上，激动剂增强的PPAR-d信号传导允许 这些祖细胞在失去肿瘤抑制因子Apc后形成体内肿瘤。这些观察提供了一个 饮食可能通过调节PPAR-d的活化，不仅改变肠干的功能， 和祖细胞，以及它们引发肿瘤的能力。许多问题仍然存在的影响， HFD对肠的影响，如PPAR-d在该过程中的体内细胞类型特异性作用，以及 在这种饮食中出现的祖细胞亚群来驱动肿瘤的发展。此外，虽然PPAR-d是一个主 转录调控基因参与脂肪酸氧化（粮农组织），目前还不清楚是否肠干 HFD中出现的祖细胞或肿瘤依赖于这种PPAR-d激活的FAO代谢程序， 他们的维护。 具体而言，我们将检验PPAR-d介导HFD在ISCs中的体内作用的假设， 在肠道内稳态和肿瘤发生（Aim 1）的祖细胞;非干细胞祖细胞的子集 在HFD中获得干性和致瘤潜力，并具有增强的PPAR-d信号传导（目的2）; HFD 或增强的PPAR-d信号传导使ISCs、祖细胞或已建立的肿瘤在代谢上依赖于脂肪代谢。 酸氧化以维持它们（目标3）。

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).