Microenvironmentally Engineered Dental Pulp Stem Cells in Inferior Alveolar Nerve Regeneration
Inferior alveolar nerve (IAN) regeneration is
essential for proper nerve sensation as well as maintaining tooth integrity and
function. A promising attempt to regenerate peripheral nerve involves the
cell-based therapy that can differentiate to neurons and/or secrete trophic
factors to promote nerve regeneration. These processes are known to be
mediated by regeneration trophic factors secreted by transplanted cells. Regenerative
medicine has focused on the dental pulp stem cell (DPSC) as a ready source of
multipotential adult stem cells. DPSCs
are potentially well-suited to nerve regeneration given their less invasive
accessibility, neural crest origin, and better regenerative qualities. The proposed project adopts an innovative and
alternative approach to IAN regenerative sciences by leveraging the neurotrophic
features of microenvironmentally engineered DPSCs. Our preliminary data
demonstrate that adjusting the microenvironments during DPSC differentiation by
hypoxia, cell-to-cell contact and modification
of the receptor/intracellular signaling significantly enhanced
neurotrophic capacity of the differentiated cells. The goal of this project is
to define an optimal microenvironment for the neurogenic DPSC differentiation
to support IAN regeneration and validate the capacity of these cells.
Schematic representations of an Axon Investigation System (AXIS) (a).
Two peripheral chambers (chamber 1 and chamber 2) and one central
chamber (Chamber 3) constitute neurite outgrowth devices. (b) An AXIS
cross-section: Human neurons were seeded into C3; human pulp
fibroblasts were seeded into. R1, R1’, R2 and R2’. B- Schematic
representations of neurite outgrowth experiments and their
representative ß III tubulin staining picture and neurite trajectory
plots.
Role of Complement Receptors and p38a/CEBP/BDNF in Reparative Dentinogenesis
Dental
caries represents a common public health problem. The complement system, a key
player of innate immunity and inflammation, is expressed and activated in the
carious teeth. Very little information is available about the involvement of
the complement in the tooth’s response to the common infection, caries.
Moreover, inflammatory complement C5a’s role in caries-mediated dentin
regeneration has received little recognition. The aim of this study is to
determine the role of the complement C5a receptor-C5L2 in regulating dental
pulp stem cells (DPSC) dentinogenic differentiation and in tooth dentin
regeneration under an inflammatory context. We provide further evidence that
p38 map kinase (p38a) plays a key role in DPSC-mediated dentinogenesis. Here,
we explore ways of enhancing this odontoblastic function of DPSCs via a novel
C5L2 pathway involving p38a/CEBP/BDNF signaling. We will define the role of
C5L2 in the odontoblastic differentiation of DPSC and characterize the
mechanism of action of C5L2 during dentinogenesis. In vivo dentin
formation will be evaluated using the mouse pulp-capping/caries model combined
with the C5aR, C5L2, CEBP and DSPP/p38 knockout mice. These studies will
provide the basis for future potential therapeutic interventions of dentin-pulp
complex regeneration and vital tooth preservation.
Left: Hypothetical model.
Silencing of C5L2 in DPSCs increases DMP1 expression to promote dentin
repair. The mechanism involves removing C5L2 repression of p38-mediated
signaling through C/EBP to increase DMP1 gene expression. Right: In Vivo dentin regenration in the C5a-deficient mice after dentin injury/pulp capping..(A-C)
Representative Micro-CT images of upper molars obtained from C5a-deficient mice
(B, C) and respective controls (C) after 4 weeks of dentin injury.
Current Funding:
NIH/NIDCR R01 2022-2026 Total $1,886,040 (PI) NIH/NIDCR R56 2020-2022 Total $380,000 (PI) NIH/NIDCR R03 2020-2023 Total $319,800 (PI) COD OB fund no expiration Total $250,000 (PI) .
Equipment: (Exclusively to Chung Lab)
We are happy to share our equipment with researchers.
Seunghyuk Chung University of Illinois at Chicago