Control of Stem Cell Dynamics by a Niche at Steady-State and During Aging

干细胞对于组织的动态平衡是必不可少的，而且通常局限于特定的利基环境， 控制它们的功能。通过这种方式，利基环境几乎控制了干细胞动力学的所有方面，并且 干细胞的这些特性对于组织的维持是必不可少的。最近的研究表明， 精确的蜂窝体系结构非常重要，以便利基能够与茎进行保真度的通信 它控制的细胞。一个主要问题是，该领域不理解在 组织，以及构成干细胞动力学的关键细胞生物学步骤，以及这些步骤是如何 受到利基信号的控制。在过去的五年里，我们的实验室在这些问题上取得了重大进展 多年的通用汽车资金。 首先，在确定了利基细胞规范的关键信号和转录调控因子后，我们揭示了 通过活体成像研究生态位形成的动力学。这使我们能够提出潜在的机制 对其功能至关重要的生态位形态发生。我们追寻其中的潜在机制 建议，利用我们对细胞骨架控制细胞-细胞组织的知识，并在 特别是肌动球蛋白的收缩和RhoA信号的参与。 其次，我们发现，这个利基对基本的细胞过程施加了精确的控制 例如脱落和中体遗传，以便在组织期间调节干细胞动力学 动态平衡和压力，如衰老。我们发现这两项中的任何一项的失调 基本的细胞生物学过程会损害组织功能。此外，对 提案中详细说明的中身继承应该会对我们的 了解正常细胞和癌细胞如何处理中心体数目缺陷。 为了解决我们的假设，我们结合了强大的遗传和分子方法，在 使用Drosohila，以及细胞力学中最先进的分析方法，包括高空间和 颞叶活体成像、FRAP和激光消融。 总而言之，我们的方法应该揭示出适当建立利基市场的令人不快的机制， 并揭示了允许干细胞维持组织的重要细胞功能。 好了！

Stem cells are necessary for tissue homeostasis, and are often localized to specialized niches that control their function. In this manner, niches control virtually all aspects of stem cell dynamics, and these properties of stem cells are essential to tissue maintenance. Recent work has shown that precise cellular architecture is important in order for a niche to communicate with fidelity to the stem cells it controls. A major issue is that the field does not understand how niches are initially formed in a tissue, nor the key cell biological steps that constitute stem cell dynamics., and how these are regulated by niche signals. Our lab made significant advances on these questions over the past five years of GM funding. First, after identifying key signals and transcriptional regulators of niche cell specification, we revealed the dynamics of niche formation by live-imaging. This enabled us to suggest mechanisms underlying niche morphogenesis that are so central to its function. We pursue the underlying mechanisms in this proposal, capitalizing on our knowledge of cytoskeletal control over cell-cell organization, and in particular the involvement of actomyosin contractility and RhoA signaling. Second, we discovered that the niche imposes precise control over fundamental cellular processes such as abscission and midbody inheritance in order to regulate stem cell dynamics during tissue homeostasis and upon stresses, such as aging. We found that dysregulations of either of these fundamental cell biological processes compromises tissue function. Furthermore, the control of midbody inheritance as detailed in the proposal should have an impact generally on our understanding of how normal and cancer cells deal with defects in centrosome number. To address our hyptheses, we combine the powerful genetic and molecalur approaches available in using Drosohila, with state-of-the-art assays in cellualr mechanics, which include high spatial and temporal live-imaging, FRAP and laser ablation. Collectively, our approaches should reveal the undelying mechnics that establish a niche properly, and reveal important cellular features that allow stem cells to maintain tissues. !