Document text
Principal Investigator: XIAOFANG WANG
Organization: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
Fiscal Year: 2024
Award: $346,938
Funding agency: National Institute of Dental and Craniofacial Research
Project summary/Abstract
MSCs play critical roles in tissue turnover and injury healing processes, making them highly valuable in the
field of regenerative medicine. The murine teeth present an excellent model for investigating MSC
homeostasis due to the rapid turnover and regenerative abilities in incisors and the limited injury healing
capacity in molars that resembles human teeth. Understanding how MSCs homeostasis is regulated in
murine teeth will provide valuable insights for applying MSCs to regenerative dentistry. MSC homeostasis
involves the maintenance of stem cell niche, directed migration, re-entry into the cell cycle for proliferation,
and guided differentiation, etc. By employing a newly developed knockout mouse model, we found that a
predicted gene, Din (
4930453N24Rik
), plays pivotal roles in governing MSC homeostasis in murine teeth by
regulating Rho GTPases, RhoA and RAC1. The incisor growth in Din-KO mice arrested after eruption, and
the injury healing process was significantly impaired in both incisors and molars. A series of lineage-specific
knockouts revealed that Din is crucial for dental MSCs but dispensable for differentiated odontoblasts and
dental epithelium-derived cells. Din-KO MSCs showed diminished stemness, reduced motility and sign of
aging, along with compromised osteogenesis ability and enhanced adipogenesis potential. Transcriptomic,
proteomic and computational analyses identified DIN as a novel regulator of the binary molecular switches,
Rho GTPases. The interactions between DIN and GTPases likely occur through potential binding sites
within a highly conserved NTF2 domain in DIN and several critical function domains in GTPases, which
appear to further trigger downstream signaling, such as canonical WNT pathway. Based on these findings,
we hypothesize that Din regulates MSC homeostasis in murine teeth during tissue turnover and injury
healing by interacting with Rho GTPases and their downstream signaling pathways, including the canonical
WNT signaling pathway. To test this hypothesis, we propose two Specific Aims: 1) To determine Din role
and the cell fate of Din+ vs. Din- MSCs in different MSC subsets during tissue turnover and injury healing
processes, and 2) To determine how Din regulates Rho GTPases RhoA and Rac1 and their downstream
effectors. Successful completion of the proposed study will advance our understanding of the regulatory
mechanism governing MSC homeostasis in murine teeth during tissue turnover and injury healing
processes. The discovery of a novel GTPases regulator and the elucidation of its associated mechanism
will have broad impact beyond the dental research field.
Terms: <Aging><Ameloblasts><Autoregulation><Binding Sites><Body Tissues><Bone Formation><Cell Body><Cell Communication and Signaling><Cell Cycle><Cell Division Cycle><Cell Growth in Number><Cell Lineage><Cell Multiplication><Cell Proliferation><Cell Signaling><Cells><Cellular Proliferation><Cephalic><Combining Site><Computer Analysis><Cranial><Defect><Dental><Dental Research><Dentistry><Down-Regulation><Epithelial Cells><Epithelium><GTP Phosphohydrolases><GTPases><Generalized Growth><Genes><Growth><Guanosine Triphosphate Phosphohydrolases><Guanosinetriphosphatases><Homeostasis><Human><Impairment><Incisor><Injury><Intracellular Communication and Signaling><KO mice><Knock-out><Knock-out Mice><Knockout><Knockout Mice><Knowledge><Maintenance><Mesenchymal Progenitor Cell><Mesenchymal Stem Cells><Mesenchymal progenitor><Mesenchymal stromal/stem cells><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Motility><Murine><Mus><NTF2><Neural Crest><Null Mouse><Odontoblasts><Osteogenesis><P67-phox><P67phox><Pathway interactions><Pattern><Physiological Homeostasis><Play><Process><Progenitor Cells><Proliferating><Proteomics><Reactive Site><Regenerative Medicine><Regenerative capacity><Regulation><Research><Role><Series><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Stem Cell like><Testing><Tissue Growth><Tissues><Tooth><Tooth structure><WNT Signaling Pathway><WNT signaling><adipogenesis><biological signal transduction><bone tissue formation><computational analyses><computational analysis><computer analyses><epithelial progenitor><epithelial progenitor cell><epithelial stem cell><guanosinetriphosphatase><healing><injuries><injury to tissue><insight><lipid biosynthesis><lipogenesis><mesenchymal stromal progenitor cells><mesenchymal-derived stem cells><migration><mouse model><murine model><neutrophil NADPH-oxidase activation factor p67><neutrophil cytosol factor 67K><novel><nuclear transport factor 2><ontogeny><overexpress><overexpression><pathway><progenitor cell homeostasis><progenitor cell niche><progenitor niche><regenerate new tissue><regenerate tissue><regenerating damaged tissue><regenerating tissue><regeneration ability><regeneration capacity><regenerative><response><rho G-Proteins><rho GTP-Binding Proteins><rho GTPases><rho Protein P21><rho Small GTP-Binding Proteins><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><stem and progenitor cell niche><stem cell characteristics><stem cell homeostasis><stem cell niche><stem cells><stemness><teeth><tissue injury><tissue regeneration><tissue regrowth><tissue renewal><tissue specific regeneration><transcriptomics>