MOLECULAR REGULATORY MECHANISM OF MESENCHYMAL STEM CELLS IN ADULT MOUSE INCISORS

 描述（由申请人提供）：干细胞是显着的。它们在发育过程中形成组织，维持组织稳态并在成人中进行损伤修复。小鼠切牙为干细胞研究提供了一个很好的模型，因为它在整个生命过程中不断生长。在成年小鼠中，位于切牙近端区域的干细胞可以在一个月内补充所有切牙细胞。我们最近发现，在成年小鼠切牙的间充质干细胞（MSC）是一个Gli 1+细胞群周围的神经血管束（NVB）附近的颈环区域，他们管理组织的稳态和修复。NVB分泌Shh，并在切牙中为MSC提供小生境。然而，从NVB内的感觉神经分泌的Shh的功能意义仍需要研究。在正常稳态期间，MSC从其小生境退出并成为转运扩增（TA）细胞，在终末分化之前经历一系列分裂。从MSC到TA细胞的过渡过程是不同器官的共同特征，但对控制这种过渡的可能复杂的信号网络知之甚少。基于我们的数据并利用成熟的动物模型，我们假设（i）感觉神经分泌Shh支持成年小鼠切牙中的MSC，以及（ii）Wnt信号传导和Wnt/Bmp相互作用控制MSC向TA细胞的转化和MSC的命运，以维持成年小鼠切牙中的间充质细胞稳态。为了验证我们的假设，我们将在以下特定目标下进行研究。在具体目标1中，我们将研究切牙Gli 1 + MSC是否有助于TA细胞群维持间充质组织稳态。我们将测试Gli 1 + MSC的分化特性，并确定感觉神经分泌的Shh是否支持成年小鼠门牙中的MSC。在具体目标2中，我们将确定Wnt信号传导在MSC向TA细胞转化的调节和门齿间充质细胞稳态的维持中的作用。我们将进一步探索β-连环蛋白突变小鼠中TA细胞命运改变的分子和细胞机制。在具体目标3中，我们将研究Bmp信号传导是否与牙齿间充质中的Wnt信号传导相互作用以控制MSC的命运。最终，这项研究将提供重要的知识，信号网络，调节从骨髓间充质干细胞到TA细胞在维持组织稳态的过渡。从这项研究中获得的理解将作为MSC生物学和干细胞介导的组织再生的未来研究的基础。

 DESCRIPTION (provided by applicant): Stem cells are remarkable. They form tissues during development, maintain tissue homeostasis and perform injury repair in adults. The mouse incisor provides an excellent model for stem cell study because it grows continuously throughout life. Stem cells residing in the proximal region of the incisor in adult mice can replenish all incisor cells within one month. We have recently shown that the mesenchymal stem cells (MSCs) in the adult mouse incisor are a Gli1+ cell population surrounding the neurovascular bundle (NVB) near the cervical loop region and that they govern tissue homeostasis and repair. The NVB secretes Shh and provides a niche for MSCs in the incisor. However, the functional significance of Shh secreted from the sensory nerve within the NVB still needs to be investigated. During normal homeostasis, MSCs exit from their niche and become transit- amplifying (TA) cells, undergoing a series of divisions before terminal differentiation. Te transition process from MSC to TA cell is a common feature in diverse organs but little is known about the presumably complex signaling network that governs this transition. Based on our data and taking advantage of well-established animal models, we hypothesize that (i) secretion of Shh by the sensory nerve supports MSCs in the adult mouse incisor and that (ii) Wnt signaling and Wnt/Bmp interactions control the MSC to TA cell transition and the fate of MSCs to maintain mesenchymal cell homeostasis in the adult mouse incisor. To test our hypotheses, we will perform studies under the following specific aims. In Specific Aim 1, we will investigate whether incisor Gli1+ MSCs contribute to the TA cell population to maintain mesenchymal tissue homeostasis. We will test the differentiation property of Gli1+ MSCs and ascertain whether secretion of Shh by the sensory nerve supports MSCs in the adult mouse incisor. In Specific Aim 2, we will determine the role of Wnt signaling in the regulation of the MSC to TA cell transition and maintenance of incisor mesenchymal cell homeostasis. We will further explore the molecular and cellular mechanisms of the altered fate of TA cells in β-catenin mutant mice. In Specific Aim 3, we will investigate whether Bmp signaling interacts with Wnt signaling in the dental mesenchyme to control the fate of MSCs. Ultimately, this study will provide important knowledge of the signaling network that regulates the transition from MSCs to TA cells in maintaining tissue homeostasis. The understanding gained from this study will serve as the foundation for future studies in MSC biology and stem cell-mediated tissue regeneration.