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Principal Investigator: Gregory H Underhill
Organization: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
Fiscal Year: 2024
Award: $446,688
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Project Summary
The bipotential differentiation of liver progenitor cells to hepatocytes and biliary epithelial cells (cholangiocytes)
is integral to liver development, regeneration, and diseases including bile duct paucity and liver cancer. In
particular, the most common congenital liver diseases are associated with bile duct dysfunction. In addition to
the developmental processes during embryogenesis, duct morphogenesis also occurs in the adult liver in
response to severe and chronic injury. These so-called ductular reactions exhibit highly variable differentiation
patterns, and although these reactions significantly contribute to the proliferative responses in the liver, they
remain poorly characterized. Notably, ductular proliferations in the adult liver are concentrated near the portal
vein region, similar to the formation of bile ducts during development. Despite substantial research efforts, the
structural complexity and dynamic nature of liver development and regeneration has limited the comprehensive
understanding of disease mechanisms as well as the advancement of new therapeutic options. The long-term
goal of this project is to develop complementary two-dimensional and three-dimensional engineered tissue
platforms that can be applied towards the investigation of liver progenitor cell differentiation mechanisms that
are presently inaccessible with current cell culture systems and animal models. Towards this end, we will
pursue the following research objectives, which are specifically targeted towards deconstructing the combined
influence of biochemical and biomechanical signals in liver progenitor cell fate specification. In Aim 1, we will
utilize a cell microarray platform to investigate the influence of spatial gradients of Notch signaling and cell
mechanical stresses in progenitor cell differentiation. Our approach will enable the independent control of cell-
cell interactions, defined by multicellular geometry, and specific exogenous microenvironmental signals
presented within the array platform. In Aim 2, we will develop and utilize a three-dimensional microtissue
culture platform to systematically investigate the effects of three-dimensional geometry and determine how
distinct multicellular geometries regulate differentiation patterns. These research efforts will establish
microscale tissue engineering tools that enable the controlled presentation and systematic perturbation of a
range of microenvironmental signals. In Aim 3, we will extend our studies towards the direct analysis of human
liver differentiation mechanisms through the integration of human induced pluripotent stem (iPS) cell-derived
liver progenitor cells. Collectively, our approach will allow for novel studies into the mechanisms of liver
progenitor cell differentiation, including the unique examination of the combinatorial influence of cell
mechanical stress gradients and Notch signaling. Further, we envision that these platforms are generalizable,
and could be implemented as enabling technologies for fundamental biological investigation and therapeutic
development efforts for a broad range of cell and tissue contexts.
Terms: <2-dimensional><21+ years old><3-D><3-Dimensional><3D><Address><Adult><Adult Human><Anatomic Sites><Anatomic structures><Anatomy><Animal Model><Animal Models and Related Studies><Biliary><Biochemical><Biologic Models><Biological><Biological Models><Biomechanics><Body Tissues><Cancers><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Culture System><Cell Culture Techniques><Cell Differentiation><Cell Differentiation process><Cell Interaction><Cell Signaling><Cell-to-Cell Interaction><Cells><Chronic><Communication><Cues><Degenerative Disorder><Development><Developmental Process><Disease><Disorder><Duct><Duct (organ) structure><Dysfunction><Embryo Development><Embryogenesis><Embryonic Development><Engineering><Epithelial Cells><Exhibits><Functional disorder><Geometry><Goals><Hepatic Cancer><Hepatic Cells><Hepatic Disorder><Hepatic Parenchymal Cell><Hepatocyte><Human><Individual><Injury><Intracellular Communication and Signaling><Intrahepatic bile duct><Investigation><Investigators><Ligands><Link><Liver><Liver Cells><Liver Regeneration><Liver Stem Cell><Liver diseases><Malignant Neoplasms><Malignant Tumor><Malignant neoplasm of liver><Maps><Mechanical Stress><Mechanics><Mesenchymas><Mesenchyme><Model System><Modeling><Modern Man><Morphogenesis><Natural regeneration><Nature><Notch Signaling Pathway><Pattern><Physiopathology><Play><Portal Vein><Portal vein structure><Process><Progenitor Cells><Proliferating><Proteolysis and Signaling Pathway of Notch><Reaction><Regeneration><Regulation><Research><Research Personnel><Researchers><Role><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Specific qualifier value><Specified><Structure><Technology><Testing><Tissue Engineering><Tissues><Work><adulthood><bile duct><bile ductule><bile formation><bioengineered tissue><biologic><biological signal transduction><biomechanical><cell culture><cell cultures><cell fate specification><cellular differentiation><cholangiocyte><combinatorial><degenerative condition><degenerative disease><design><designing><developmental><differentiation protocol><disease mechanisms study><drug detection><drug testing><engineered tissue><experience><experiment><experimental research><experimental study><experiments><hepatic body system><hepatic disease><hepatic organ system><hepatopathy><hiPSC><human iPS><human iPSC><human induced pluripotent cell><human induced pluripotent stem cells><human inducible stem cells><in vitro Model><induced human pluripotent stem cells><injuries><insight><jagged-1><jagged1 protein><liver cancer><liver development><liver disorder><liver malignancy><liver progenitor><malignancy><malignant liver tumor><mechanic><mechanical><mechanical cue><mechanical signal><model of animal><morphogenetic process><neoplasm/cancer><new approaches><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><notch><notch protein><notch receptors><novel><novel approaches><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel strategies><novel strategy><novel therapeutics><novel therapy><pathophysiology><progenitor cell differentiation><progenitor cell fate><progenitor cell fate specification><progenitor cell function><progenitor differentiation><progenitor fate><progenitor fate specification><progenitor function><progenitor specification><regenerate><response><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 fate><stem and progenitor cell function><stem and progenitor differentiation><stem and progenitor function><stem cell differentiation><stem cell fate><stem cell fate specification><stem cell function><stem cell specification><stem cells><therapeutic agent development><therapeutic development><three dimensional><tissue culture><tool><two-dimensional>