A5047162229- Pancreatic function and diabetes
- Diabetes and associated disorders
- Congenital heart defects research
- Pluripotent Stem Cells Research
- Diabetes Management and Research
- Developmental Biology and Gene Regulation
- Diet, Metabolism, and Disease
- Epigenetics and DNA Methylation
- Muscle Physiology and Disorders
- Metabolism, Diabetes, and Cancer
- 3D Printing in Biomedical Research
- Genetics and Neurodevelopmental Disorders
- MicroRNA in disease regulation
- Renal and related cancers
- CRISPR and Genetic Engineering
- Pancreatic and Hepatic Oncology Research
- Genomics and Chromatin Dynamics
- Cancer-related molecular mechanisms research
- Neuroendocrine Tumor Research Advances
- dental development and anomalies
- Caveolin-1 and cellular processes
- Phagocytosis and Immune Regulation
- Cancer-related gene regulation
- Genetic and Kidney Cyst Diseases
- Cancer Cells and Metastasis
City of Hope
2015-2025
City Of Hope National Medical Center
2023
Beckman Research Institute
2015-2023
University of California, San Diego
2011-2019
Sanford Consortium for Regenerative Medicine
2014-2019
Pediatrics and Genetics
2012
University of California, Irvine
2008-2012
Oregon State University
2006-2007
One major unresolved question in the field of pancreas biology is whether ductal cells have ability to generate insulin-producing β-cells. Conclusive examination this has been limited by lack appropriate tools efficiently and specifically label vivo. We generated Sox9CreER(T2) mice, which, during adulthood, allow for labeling an average 70% pancreatic cells, including terminal duct/centroacinar cells. Fate-mapping studies Sox9(+) domain revealed endocrine acinar cell neogenesis from...
Significance Human mutations in SOX9 lead to several congenital disorders, including campomelic dysplasia. Babies born with this condition often die of respiratory distress; however, defects lung development have thus far not been reported mouse models. Here, we report that epithelial-specific deletion Sox9 leads developmental abnormalities the during branching morphogenesis. We demonstrate plays multiple roles epithelium, balancing proliferation and differentiation regulating extracellular...
In the pancreas, Notch signaling is thought to prevent cell differentiation, thereby maintaining progenitors in an undifferentiated state. Here, we show that renders competent differentiate into ductal and endocrine cells by inducing activators of differentiation. promotes expression Sox9, which cell-autonomously activates pro-endocrine gene Ngn3. However, at high activity differentiation blocked, as also induces Ngn3 repressor Hes1. At transition from intermediate activity, only but not...
All mature pancreatic cell types arise from organ-specific multipotent progenitor cells. Although previous studies have identified cell-intrinsic and -extrinsic cues for expansion, it is unclear how these are integrated within the niche of developing organ. Here, we present genetic evidence in mice that transcription factor Sox9 forms centerpiece a gene regulatory network crucial proper organ growth maintenance identity. We show progenitor-specific ablation during early pancreas development...
The study of hematopoietic colony-forming units using semisolid culture media has greatly advanced the knowledge hematopoiesis. Here we report that similar methods can be used to pancreatic units. We have developed two colony assays enable quantitative and functional analyses progenitor-like cells isolated from dissociated adult (2-4 mo old) murine pancreas. find a methylcellulose-based medium containing Matrigel allows growth duct-like "Ring/Dense" colonies rare (∼1%) population total...
The generation of pancreas, liver, and intestine from a common pool progenitors in the foregut endoderm requires establishment organ boundaries. How dorsal activate pancreatic genes evade intestinal lineage choice remains unclear. Here, we identify Pdx1 Sox9 as cooperative inducers gene regulatory network that distinguishes lineage. Genetic studies demonstrate dual functions for induction repression choice. bind to sequences near differentiation jointly regulate their expression, revealing...
Pitx2 expression is observed during all states of the myogenic progression in embryonic muscle anlagen and persists adult muscle. mutant mice form but a few anlagen. Loss or degeneration could generally be attributed to loss attachment site induced by some other aspect phenotype. Muscles derived from first branchial arch were absent, whereas muscles second merely distorted mutants at midgestation. was expressed well before, required for, initiation first, not second, mesoderm. also for...
During pancreas development, epithelial buds undergo branching morphogenesis to form an exocrine and endocrine gland. Proper is necessary for correct lineage allocation of pancreatic progenitors; however, the cellular events underlying are unknown. Here, we employed time-lapse microscopy fluorescent labeling cells analyze cell behaviors associated with morphogenesis. We observed that outer bud adjacent basement membrane pleomorphic rearrange frequently; additionally, they largely remain in...
The molecular and functional heterogeneity of pancreatic β-cells is well recognized, but the underlying mechanisms remain unclear. Pancreatic islets harbor a subset that co-express tyrosine hydroxylase (TH), an enzyme involved in synthesis catecholamines repress insulin secretion. Restriction TH+ within essential for appropriate function mice, such higher proportion these cells corresponds to reduced Here, we use as model dissect developmental control β-cell heterogeneity. We define specific...
Loss of functional β-cell mass is a major cause diabetes. Thus, identifying regulators health crucial for treating this disease. The We evaluated Lgr4 expression in mouse and human islets response to acute (proinflammatory cytokines), or chronic (high fat fed mice, db/db aging) stress. To determine the role LGR4 we employed vitro loss gain function primary rodent β-cells examined its mechanism action INS1 cell line. Using was reduced by multiple stressors. In vitro, knockdown decreased...
Abstract Developmental progression depends on temporally defined changes in gene expression mediated by transient exposure of lineage intermediates to signals the progenitor niche. To determine whether cell-intrinsic epigenetic mechanisms contribute signal-induced transcriptional responses, here we manipulate signalling environment and activity histone demethylase LSD1 during differentiation hESC-gut tube into pancreatic endocrine cells. We identify a requirement for cell spanning short...
The transplantation of pancreatic endocrine islet cells from cadaveric donors is a promising treatment for type 1 diabetes (T1D), which chronic autoimmune disease that affects approximately nine million people worldwide. However, the demand donor islets outstrips supply. This problem could be solved by differentiating stem and progenitor to cells. many current culture methods used coax differentiate into require Matrigel, matrix composed extracellular (ECM) proteins secreted mouse sarcoma...
Pancreatic islets are three-dimensional cell aggregates consisting of unique cellular composition, cell-to-cell contacts, and interactions with blood vessels. Cell aggregation is essential for islet endocrine function; however, it remains unclear how developing establish aggregation. By combining genetic animal models, imaging tools, gene expression profiling, we demonstrate that regulated by extracellular matrix signaling cell-cell adhesion. Islet cell-specific inactivation receptor...
The HMG box transcription factor Sox9 plays a critical role in progenitor cell expansion during pancreas organogenesis and is required for proper endocrine development the embryo. Based on vitro studies it has been suggested that controls expression of network important developmental regulators, including Tcf2/MODY5, Hnf6, Foxa2, pancreatic cells. Here, we sought to: 1) determine whether regulates this transcriptional vivo 2) investigate reduced gene dosage leads to impaired glucose...
Progenitor cells in the adult pancreas are potential sources of endocrine beta for treating type 1 diabetes. Previously, we identified tri-potent progenitor (2-4month-old) murine that were capable self-renewal and differentiation into duct, acinar, vitro. These named pancreatic colony-forming units (PCFUs). However, because PCFUs a minor population (~1%) they difficult to study. To enrich PCFUs, strategies using cell-surface marker analyses fluorescence-activated cell sorting developed. We...
To maximize the translational utility of human induced pluripotent stem cells (iPSCs), ability to precisely modulate differentiation iPSCs target phenotypes is critical. Although effects physical cell niche on are well documented, current approaches direct step-wise have been typically limited optimization soluble factors. In this regard, we investigated how temporally varied substrate stiffness affects towards various lineages/phenotypes. Electrospun nanofibrous substrates with different...
Pancreatic endocrine cell differentiation is orchestrated by the action of transcription factors that operate in a gene regulatory network to activate lineage genes and repress lineage-inappropriate genes. MicroRNAs (miRNAs) are important modulators expression, yet their role has not been systematically explored. Here we characterize miRNA-regulatory networks active human combining small RNA sequencing, miRNA over-expression, modeling approaches. Our analysis identified Let-7g, Let-7a,...
The five-year survival rate of patients diagnosed with advanced pancreatic ductal adenocarcinoma (PDAC) has remained static at <5% despite decades research. With the exception erlotinib, clinical trials have failed to demonstrate benefit any targeted therapy for PDAC promising results in preclinical animal studies. development more refined mouse models which recapitulate carcinogenic progression from non-neoplastic, adult exocrine subsets cells invasive carcinoma humans are needed facilitate...
Abstract Cadherin-mediated cell-cell adhesion plays an important role in organ development and changes cadherin expression are often linked to morphogenetic pathogenic events. Cadherins interact with other intracellular components form adherens junctions (AJs) provide mechanical attachments between adjacent cells. E-cadherin (Cdh1) represents integral component of these intercellular junctions. To elucidate the function developing pancreas, we generated studied pancreas-specific Cdh1...
Cells of the ventrolateral dermomyotome delaminate and migrate into limb buds where they give rise to all muscles limbs. The migratory cells proliferate form myoblasts, which withdraw from cell cycle become terminally differentiated myocytes. myogenic lineage colonizes pre-patterned regions muscle anlagen as fibers are assembled. regulatory mechanisms that control later steps this program not well understood. homeodomain transcription factor Pitx2 is expressed specifically in migration...