Mammary basal/stem cell plasticity and regulation

项目总结 将无数分化的细胞重新编程为多能干细胞状态的能力突显了 体细胞具有显著的可塑性。要更好地了解组织的固有可塑性，还需要做出努力。 干细胞以及潜在的调控机制，这样我们就可以了解如何控制细胞 组织工程和再生医学的命运。很久以来，人们就知道上皮细胞具有固有的 可塑性，最好的表现是它们能够成为间充质细胞以及恢复为 上皮状态，在适当的刺激下。这种可塑性对于产生不同类型的间充质细胞很重要。 在胚胎发育过程中，它被认为是恶性肿瘤细胞形成远处转移所必需的。 最近的研究启发了一种假设，即调节这种可塑性的机制被用于 承诺组织上皮细胞来控制干细胞的命运。乳腺上皮细胞是一个杰出的模型 系统来检验这一假设，这是由于已建立的前瞻性隔离和功能隔离的成熟方法 他们的居住干细胞的特征。乳腺上皮的基底层含有多能干细胞。 在移植和怀孕等条件下可以转化为此类干细胞的细胞和细胞。我们 将把尖端的单细胞分析与先进的技术有机地结合在一起，例如组织特异性 基因敲除和诱导过表达、体内和体外干细胞检测以及分子研究 要解决以下根本重要的问题：1)多少个细胞类型子集或细胞状态 存在于乳腺基底细胞群中，这些状态是否对应于光谱中的不同位置 上皮/内胚层细胞的可塑性？2)多能干细胞或有能力成为这种干细胞的细胞 部分由其高度可塑性定义，即同时采用间充质样细胞和终末细胞的可能性 上皮细胞的命运？调节这种可塑性的关键分子回路是什么？是否/如何调节 电路决定了基底细胞是否处于干细胞状态？

PROJECT SUMMARY The ability to reprogram myriad differentiated cells back into a pluripotent stem cell state highlights the remarkable plasticity of somatic cells. Effort is needed to better understand the inherent plasticity of tissue stem cells as well as the underlying regulatory mechanisms, so that we can learn about how to control cell fates in tissue engineering and regenerative medicine. Epithelial cells are long known to possess inherent plasticity, best manifested by their ability to become mesenchymal cells as well as to revert back to an epithelial state, under appropriate stimuli. This plasticity is important for generating mesenchymal cell types during embryogenesis, and is thought to be required for malignant cancer cells to form distant metastases. Recent studies have inspired the hypothesis that the mechanisms that regulate this plasticity are used in committed tissue epithelial cells to control stem cell fates. The mammary epithelia serve an outstanding model system to test this hypothesis, owing to the well-established methods to prospectively isolate and functionally characterize their residential stem cells. The basal layer of the mammary epithelia harbors multipotent stem cells and cells that can turn into such stem cells under conditions such as transplantation and pregnancy. We will organically combine cutting-edge single-cell analysis with state-or-art technology such as tissue-specific gene knockout and inducible overexpression, in vivo and ex vivo stem cell assays, as well as molecular studies to address the following fundamentally important questions: 1) How many cell type subsets or cellular states exist in the mammary basal cell population and do these states correspond to distinct positions in the spectrum of epithelial/EMT plasticity? 2) Are multipotent stem cells or cells with the capacity to become such stem cells defined in part by their high plasticity, namely the potential to adopt both mesenchymal-like and terminal epithelial fates? 3) What is the key molecular circuitry that regulates such plasticity, and whether/how this circuitry dictates the stay of a basal cell in a stem cell state?