Novel mechanism of intestinal stem cell aging

摘要 许多细胞周转率高的哺乳动物器官(如皮肤、肠道和血液)都是由短暂的 需要体细胞干细胞持续补充的细胞。衰老导致这些组织不能 以维持动态平衡。过去十年积累的证据发现，可衡量的和连续的 从成年期到老年，不同器官中干细胞活性随年龄的下降，包括 造血、肠道和肌肉。这种与年龄相关的干细胞功能下降导致了 人类和小鼠的再生能力，这可能会限制寿命。确定衰老的机制 干细胞表型和功能与年轻干细胞相似可能是迈向 设计合理的方法来改善临床上的干细胞老化。根据我们的初步结果，我们 假设β-连环蛋白信号的下降和相关的微生物区系变化在 在小鼠和人类中，ISC的功能随着年龄的增长而变化。为了实现这一假设，我们将执行三项操作 目标。在目标1中，我们将通过以下方式确定单个ISCs中β-连环蛋白信号变化的程度 单细胞测序方法及Wnt表达变化对β-连环蛋白信号和蛋白表达的影响 随着年龄的增长，ISCs的功能下降。在目标2中，我们将研究不同的生态位细胞对 体内胰岛素样干细胞中β-连环蛋白信号的增龄相关变化。在目标3中，我们将确定 微生物区系在Wnt配体表达中的作用及其在调节β-连环蛋白信号和功能中的作用 ISCs在衰老时的数量。这项拟议的研究将揭示一种新的关联β-连环蛋白变化的机制 信号和微生物区系与肠道干细胞的生理性衰老过程和组织变化 动态平衡。该提案的发现可能会导致未来的治疗干预，防止或逆转 组织老化。

Abstract Many mammalian organs with high cellular turnover (e.g. skin, intestine and blood) are composed of short-lived cells that require continuous replenishment by somatic stem cells. Aging results in the inability of these tissues to maintain homeostasis. Evidence accumulated over the past decade has found measurable and successive age-dependent decline in stem cell activity from adulthood to old age, in various organs, including hematopoietic, intestinal and muscle. This age-associated decline in stem cell function leads to a decline in the regenerative capacity in humans and mice, which may limit lifespan. Identifying mechanisms under which aged stem cells become phenotypically and functionally similar to young stem cells may be a first step towards designing rationale approaches to ameliorate stem cell aging in the clinics. Based on our preliminary results we hypothesize that the declining beta-catenin signaling and associated microbiota changes play a causal role in ISC functional changes upon aging in both mice and humans. To pursue this hypothesis, we will perform three aims. In aim 1, we will determine the extend of changes in beta-catenin signaling in single ISCs upon aging via single-cell sequencing approaches and the impact of Wnt expression changes on beta-catenin signaling and a decline in the function of ISCs upon aging. In aim 2, we will investigate the contribution of various niche cells to aging-associated changes in beta-catenin signaling in ISCs in vivo. In aim 3, we will determine the role of microbiota in Wnt ligand expression in the niche cells and in regulating beta-catenin signaling and the function of ISCs upon aging. The proposed studies will unveil a new mechanism of changes in associating beta-catenin signaling and microbiota with the physiologic aging process of intestinal stem cells and alterations in tissue homeostasis. The findings of the proposal may lead to future therapeutic interventions preventing or reversing tissue aging.