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Principal Investigator: Jimmy Kuang-Hsien Hu
Organization: UNIVERSITY OF CALIFORNIA LOS ANGELES
Fiscal Year: 2024
Award: $353,364
Funding agency: National Institute of Dental and Craniofacial Research
Project Summary
Effective utilization of somatic stem cells to repair injured tissues or to bioengineer organs is an important goal
in regenerative medicine. However, clinically-proven application of stem cells in therapies remains limited in
medicine today. The translational hurdles are in large part due to our lack of ability to precisely control stem cell
proliferation and differentiation, which is critical for safe and effective clinical use. To overcome this challenge,
we must first deepen our knowledge of normal stem cell regulation in organs. In addition to biochemical signals,
tissue mechanical forces exerted by cell pulling and pushing can in theory serve as a signaling mechanism to
regulate gene expression and various cellular processes in adult stem cells. However, the modulation and
influence of these force signals within a 3D tissue are dramatically understudied, leaving open questions around
how stem cells sense and interpret forces. We and others have demonstrated the mouse incisor as a powerful
model system to study adult epithelial stem cells and we have previously shown that the transcription co-factor
Yes-associated protein (YAP) and chromatin repression are important for regulating incisor epithelial stem cells.
Our initial studies indicate that both mechanical deformation of cells and the cell geometry associated with dense
packing can influence the expression of YAP and repressive chromatin marks in the incisor stem cell niche. The
mouse incisor thus provides a valuable in vivo platform to study how cellular organizations coordinate mechanical
signals to control stem cell functions via YAP and chromatin. In this application, we propose to test the hypothesis
that dense cell packing modulates the effect of tissue forces on nuclear deformations, which in turn regulate YAP
nuclear entry and H3K27me3-mediated transcriptional repression in the dental epithelial stem cells. To test this:
Aim 1 will characterize the force patterns, magnitude, and nuclear stiffness in wild type incisors, specifically in
the densely packed dental epithelial stem cells and the more loosely packed transit amplifying cells.
Aim 2 will study how changes in the cell geometry and packing affect tissue force patterns, nuclear deformations,
YAP localization, and chromatin states. We will perform mechanical rescue experiments to test the role of forces.
Aim 3 will address the functional role of lamin A in regulating nuclear stiffness and heterochromatin formation in
the dental epithelial stem cells, as well as its scaling response to cell packing.
Together, these studies will deliver a mechanistic understanding of how tissue forces control dental stem cells
and yield findings that will be of general interest to both dental researchers and to the stem cell and regenerative
medicine communities.
Terms: <21+ years old><3-D><3-Dimensional><3D><Ablation><Address><Adult><Adult Human><Affect><Alleles><Allelomorphs><Architecture><Atomic Force Microscopy><Biochemical><Biologic Models><Biological Models><Biomechanics><Biomedical Engineering><Body Tissues><Cell Body><Cell Communication and Signaling><Cell Density><Cell Differentiation><Cell Differentiation process><Cell Function><Cell Growth and Maintenance><Cell Maintenance><Cell Nucleus><Cell Physiology><Cell Process><Cell Shape><Cell Signaling><Cells><Cellular Function><Cellular Physiology><Cellular Process><Chromatin><Chromatin Structure><Chronic><Clinical><Community Medicine><Data><Dental><Devices><Engineering / Architecture><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epithelium><Exhibits><Force Microscopy><Future><Gene Down-Regulation><Gene Expression><Gene Transcription><Genetic Transcription><Geometry><Goals><HOX gene><Heterochromatin><Homeo Box Genes><Homeobox Family Gene><Homeobox Genes><Homeodoamin Gene><Homeotic Genes><Human><Image><In Situ><Incisor><Intracellular Communication and Signaling><Investigators><Knowledge><Lamin A><Lamin Type A><Laser Electromagnetic><Laser Radiation><Lasers><Life Style><Lifestyle><Load Bearing><Magnetism><Maps><Measures><Mechanics><Mediating><Medicine><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Mice><Mice Mammals><Micro-tubule><Microscopy><Microtubules><Model System><Modern Man><Molecular><Murine><Mus><Nuclear><Nuclear Envelope><Nuclear Import><Nuclear Membrane><Nuclear Pore><Nuclear Protein><Nucleus><Oils><Organ><Pattern><Phenotype><Polycomb><Process><Progenitor Cells><Proteins><Public Health><RNA Expression><Regenerating teeth><Regenerating tooth><Regenerative Medicine><Regulation><Repression><Research Personnel><Researchers><Role><Scanning Force Microscopy><Shapes><Signal Transduction><Signal Transduction Systems><Signaling><Stress><Subcellular Process><Surface Proteins><System><Teeth regeneration><Testing><Time><Tissues><Tooth><Tooth Loss><Tooth regeneration><Tooth structure><Transcription><Transcription Regulation><Transcription Repression><Transcriptional Control><Transcriptional Regulation><Transcriptional Repression><Weight Bearing><Weight-Bearing state><Work><adult progenitor><adult stem cell><adulthood><bio-engineered><bio-engineers><bioengineering><biological engineering><biological signal transduction><biomechanical><cellular differentiation><cofactor><differential expression><differentially expressed><epigenetically><epithelial progenitor><epithelial progenitor cell><epithelial stem cell><experiment><experimental research><experimental study><experiments><force sensor><gene repression><imaging><in vivo><injury and repair><interest><loss of function><magnetic><mechanic><mechanical><mechanical cue><mechanical force><mechanical signal><mouse genetics><mouse model><murine model><novel><physical property><progenitor><progenitor biology><progenitor cell based therapy><progenitor cell biology><progenitor cell fate><progenitor cell function><progenitor cell model><progenitor cell niche><progenitor cell proliferation><progenitor cell therapy><progenitor cell treatment><progenitor fate><progenitor function><progenitor model><progenitor niche><progenitor proliferation><progenitor therapy><progenitor treatment><protein expression><regeneration based therapy><regeneration potential><regeneration therapy><regenerative potential><regenerative therapeutics><regenerative therapy><response><social role><somatic progenitor><somatic stem cell><stem and progenitor biology><stem and progenitor cell fate><stem and progenitor cell function><stem and progenitor cell model><stem and progenitor cell niche><stem and progenitor cell proliferation><stem and progenitor cell therapy><stem and progenitor function><stem cell based model><stem cell based therapy><stem cell biology><stem cell derived model><stem cell fate><stem cell function><stem cell mediated therapy><stem cell model><stem cell niche><stem cell proliferation><stem cell therapeutics><stem cell therapy><stem cell treatment><stem cell-based therapeutic><stem cell-based treatment><stem cells><teeth><theories><three dimensional><transcriptional differences>