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. The 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 ?-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.
Stem cells have the crucial roles of forming tissues during development and governing tissue homeostasis and injury repair in adults. Currently, little is understood about how mesenchymal stem cells are supported in their niche or how they transition into transit amplifying cells before differentiating into various cell types. Our study in the continuously growing mouse incisor will investigate these processes and serve as the foundation for future studies in stem cell biology and stem cell-mediated tissue regeneration.
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