MOLECULAR REGULATORY MECHANISM OF MESENCHYMAL STEM CELLS IN ADULT MOUSE INCISOR

PROJECT SUMMARY/ABSTRACT
Regulation of stem cell functions is crucial for tissue formation, growth, and homeostasis. In many tissues and
organs, stem cells give rise to transit amplifying cells (TACs), an undifferentiated progenitor population. TACs
function as transient but indispensable integrators of stem cell niche components. However, we have limited
understanding of how mesenchymal stem cells (MSCs) interact with TACs and provide feedback to MSCs in
regulating tissue homeostasis. The adult mouse incisor provides an excellent model for stem cell study because
it grows continuously. MSCs are a Gli1+ cell population surrounding the neurovascular bundle (NVB) near the
proximal region in the adult mouse incisor, making it an ideal model in which to investigate the regulatory
mechanisms of MSCs. The NVB may secrete signaling molecules, providing a niche for MSCs in the adult incisor.
However, the functional significance of signaling molecules from the nerve within the NVB and the molecular
mechanism by which they regulate MSCs are largely unknown. Significantly, our preliminary data shows that the
trigeminal nerve secretes Fgf1, which acts directly on MSCs via FGFR1 to regulate tissue homeostasis, as loss
of Fgfr1 in Gli1+ MSCs leads to retarded incisor growth, similar to the phenotype seen with compromised
innervation. Fgf signaling regulates important downstream epigenetic regulators such as Arid1a and Arid1b to
control the fate of TACs. Furthermore, loss of Arid1a specifically inhibits Wnt5a signaling, which may provide
feedback to MSCs. Importantly, we have recently discovered that Runx2+/Gli1+ cells in the adult incisor are
MSC niche cells, strategically positioned to coordinate MSC-to-TAC transition. Our study suggests that Runx2
is regulated by the epigenetic regulator Arid1b and controls p53 activity to mediate MSC-to-TAC transition and
feedback to MSCs. Collectively, based on our preliminary data and taking advantage of well-established animal
models, we propose to test the hypotheses that Fgf signaling from the trigeminal nerve regulates MSCs in the
adult mouse incisor, Arid1a and Arid1b act downstream of Fgf signaling to control MSC-to-TAC transition, and
Arid1b-Runx2 interaction regulates p53 activity to control TAC differentiation and feedback to MSCs to maintain
tissue homeostasis. We propose the following specific aims to test our hypotheses. Specific Aim 1: To
investigate whether Fgf signaling from the trigeminal nerve plays a crucial role in regulating MSCs in the adult
mouse incisor. We will explore the molecular mechanism of Fgf signaling and its downstream targets in regulating
the fate of MSCs to maintain mesenchymal tissue homeostasis. Specific Aim 2: To determine the role of Fgf-
regulated Arid1a and Arid1b activity in controlling the MSC-to-TAC transition and maintenance of incisor tissue
homeostasis. We will explore the mechanisms by which TAC fate is altered and their impact on MSCs in Arid1a
and Arid1b mutant mice. Specific Aim 3: To investigate the molecular mechanism by which Arid1b regulates
Runx2 expression and Runx2-regulated p53 signaling to control TAC differentiation. We will also investigate the
functional significance of p53 in regulating TACs and the fate of MSCs in adult mouse incisors.

Grant Number: 5R01DE025221-08
NIH Institute/Center: NIH
Principal Investigator: Yang Chai