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BVES is required for maintenance of colonic epithelial integrity in experimental colitis by modifying intestinal permeability.
Choksi YA, Reddy VK, Singh K, Barrett CW, Short SP, Parang B, Keating CE, Thompson JJ, Verriere TG, Brown RE, Piazuelo MB, Bader DM, Washington MK, Mittal MK, Brand T, Gobert AP, Coburn LA, Wilson KT, Williams CS
(2018) Mucosal Immunol 11: 1363-1374
MeSH Terms: Adult, Animals, Caco-2 Cells, Cell Line, Cell Line, Tumor, Citrobacter rodentium, Coculture Techniques, Colitis, Ulcerative, Colon, Dextran Sulfate, Epithelial Cells, Escherichia coli, Female, HEK293 Cells, Humans, Intestinal Absorption, Intestinal Mucosa, Male, Membrane Proteins, Mice, Mice, Inbred C57BL, Middle Aged, Permeability, RNA, Messenger, Signal Transduction, Tight Junctions
Show Abstract · Added June 23, 2018
Blood vessel epicardial substance (BVES), or POPDC1, is a tight junction-associated transmembrane protein that modulates epithelial-to-mesenchymal transition (EMT) via junctional signaling pathways. There have been no in vivo studies investigating the role of BVES in colitis. We hypothesized that BVES is critical for maintaining colonic epithelial integrity. At baseline, Bves mouse colons demonstrate increased crypt height, elevated proliferation, decreased apoptosis, altered intestinal lineage allocation, and dysregulation of tight junctions with functional deficits in permeability and altered intestinal immunity. Bves mice inoculated with Citrobacter rodentium had greater colonic injury, increased colonic and mesenteric lymph node bacterial colonization, and altered immune responses after infection. We propose that increased bacterial colonization and translocation result in amplified immune responses and worsened injury. Similarly, dextran sodium sulfate (DSS) treatment resulted in greater histologic injury in Bves mice. Two different human cell lines (Caco2 and HEK293Ts) co-cultured with enteropathogenic E. coli showed increased attaching/effacing lesions in the absence of BVES. Finally, BVES mRNA levels were reduced in human ulcerative colitis (UC) biopsy specimens. Collectively, these studies suggest that BVES plays a protective role both in ulcerative and infectious colitis and identify BVES as a critical protector of colonic mucosal integrity.
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26 MeSH Terms
Successful Establishment of Primary Type II Alveolar Epithelium with 3D Organotypic Coculture.
Sucre JMS, Jetter CS, Loomans H, Williams J, Plosa EJ, Benjamin JT, Young LR, Kropski JA, Calvi CL, Kook S, Wang P, Gleaves L, Eskaros A, Goetzl L, Blackwell TS, Guttentag SH, Zijlstra A
(2018) Am J Respir Cell Mol Biol 59: 158-166
MeSH Terms: Cell Communication, Cells, Cultured, Coculture Techniques, Epithelial Cells, Fibroblasts, Humans, Lung, Lung Injury, Phenotype
Show Abstract · Added April 1, 2019
Alveolar type II (AT2) epithelial cells are uniquely specialized to produce surfactant in the lung and act as progenitor cells in the process of repair after lung injury. AT2 cell injury has been implicated in several lung diseases, including idiopathic pulmonary fibrosis and bronchopulmonary dysplasia. The inability to maintain primary AT2 cells in culture has been a significant barrier in the investigation of pulmonary biology. We have addressed this knowledge gap by developing a three-dimensional (3D) organotypic coculture using primary human fetal AT2 cells and pulmonary fibroblasts. Grown on top of matrix-embedded fibroblasts, the primary human AT2 cells establish a monolayer and have direct contact with the underlying pulmonary fibroblasts. Unlike conventional two-dimensional (2D) culture, the structural and functional phenotype of the AT2 cells in our 3D organotypic culture was preserved over 7 days of culture, as evidenced by the presence of lamellar bodies and by production of surfactant proteins B and C. Importantly, the AT2 cells in 3D cocultures maintained the ability to replicate, with approximately 60% of AT2 cells staining positive for the proliferation marker Ki67, whereas no such proliferation is evident in 2D cultures of the same primary AT2 cells. This organotypic culture system enables interrogation of AT2 epithelial biology by providing a reductionist in vitro model in which to investigate the response of AT2 epithelial cells and AT2 cell-fibroblast interactions during lung injury and repair.
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9 MeSH Terms
Cancer-associated fibroblasts promote directional cancer cell migration by aligning fibronectin.
Erdogan B, Ao M, White LM, Means AL, Brewer BM, Yang L, Washington MK, Shi C, Franco OE, Weaver AM, Hayward SW, Li D, Webb DJ
(2017) J Cell Biol 216: 3799-3816
MeSH Terms: Cancer-Associated Fibroblasts, Cell Communication, Cell Line, Tumor, Cell Movement, Coculture Techniques, Extracellular Matrix, Fibronectins, Humans, Integrin alpha5beta1, Male, Mechanotransduction, Cellular, Neoplasm Invasiveness, Nonmuscle Myosin Type IIA, Prostatic Neoplasms, RNA Interference, Receptor, Platelet-Derived Growth Factor alpha, Time Factors, Transfection, Tumor Cells, Cultured, Tumor Microenvironment
Show Abstract · Added March 14, 2018
Cancer-associated fibroblasts (CAFs) are major components of the carcinoma microenvironment that promote tumor progression. However, the mechanisms by which CAFs regulate cancer cell migration are poorly understood. In this study, we show that fibronectin (Fn) assembled by CAFs mediates CAF-cancer cell association and directional migration. Compared with normal fibroblasts, CAFs produce an Fn-rich extracellular matrix with anisotropic fiber orientation, which guides the cancer cells to migrate directionally. CAFs align the Fn matrix by increasing nonmuscle myosin II- and platelet-derived growth factor receptor α-mediated contractility and traction forces, which are transduced to Fn through α5β1 integrin. We further show that prostate cancer cells use αv integrin to migrate efficiently and directionally on CAF-derived matrices. We demonstrate that aligned Fn is a prominent feature of invasion sites in human prostatic and pancreatic carcinoma samples. Collectively, we present a new mechanism by which CAFs organize the Fn matrix and promote directional cancer cell migration.
© 2017 Erdogan et al.
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20 MeSH Terms
Endoglin Mediates Vascular Maturation by Promoting Vascular Smooth Muscle Cell Migration and Spreading.
Tian H, Ketova T, Hardy D, Xu X, Gao X, Zijlstra A, Blobe GC
(2017) Arterioscler Thromb Vasc Biol 37: 1115-1126
MeSH Terms: Animals, CRISPR-Cas Systems, Cell Movement, Cell Shape, Cells, Cultured, Coculture Techniques, Endoglin, Endothelial Cells, Focal Adhesion Kinase 1, Gene Expression Regulation, Humans, Integrins, Mice, Inbred C57BL, Muscle, Smooth, Vascular, Myocytes, Smooth Muscle, Phenotype, RNA Interference, Signal Transduction, Transfection
Show Abstract · Added March 22, 2018
OBJECTIVE - Endoglin, a transforming growth factor-β superfamily coreceptor, is predominantly expressed in endothelial cells and has essential roles in vascular development. However, whether endoglin is also expressed in vascular smooth muscle cells (VSMCs), especially in vivo, remains controversial. Furthermore, the roles of endoglin in VSMC biology remain largely unknown. Our objective was to examine the expression and determine the function of endoglin in VSMCs during angiogenesis.
APPROACH AND RESULTS - Here, we determine that endoglin is robustly expressed in VSMCs. Using CRISPR/CAS9 knockout and short hairpin RNA knockdown in the VSMC/endothelial coculture model system, we determine that endoglin in VSMCs, but not in endothelial cells, promotes VSMCs recruitment by the endothelial cells both in vitro and in vivo. Using an unbiased bioinformatics analysis of RNA sequencing data and further study, we determine that, mechanistically, endoglin mediates VSMC recruitment by promoting VSMC migration and spreading on endothelial cells via increasing integrin/FAK pathway signaling, whereas endoglin has minimal effects on VSMC adhesion to endothelial cells. In addition, we further determine that loss of endoglin in VSMCs inhibits VSMC recruitment in vivo.
CONCLUSIONS - These studies demonstrate that endoglin has an important role in VSMC recruitment and blood vessel maturation during angiogenesis and also provide novel insights into how discordant endoglin function in endothelial and VSMCs may regulate vascular maturation and angiogenesis.
© 2017 The Authors.
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19 MeSH Terms
Skeletal Colonization by Breast Cancer Cells Is Stimulated by an Osteoblast and β2AR-Dependent Neo-Angiogenic Switch.
Mulcrone PL, Campbell JP, Clément-Demange L, Anbinder AL, Merkel AR, Brekken RA, Sterling JA, Elefteriou F
(2017) J Bone Miner Res 32: 1442-1454
MeSH Terms: Animals, Bone and Bones, Breast Neoplasms, Cell Line, Tumor, Coculture Techniques, Female, Humans, Mice, Mice, Knockout, Neoplasm Metastasis, Neoplasm Proteins, Neovascularization, Pathologic, Osteoblasts, Receptors, Adrenergic, beta-2, Vascular Endothelial Growth Factor A
Show Abstract · Added April 26, 2017
The skeleton is a common site for breast cancer metastasis. Although significant progress has been made to manage osteolytic bone lesions, the mechanisms driving the early steps of the bone metastatic process are still not sufficiently understood to design efficacious strategies needed to inhibit this process and offer preventative therapeutic options. Progression and recurrence of breast cancer, as well as reduced survival of patients with breast cancer, are associated with chronic stress, a condition known to stimulate sympathetic nerve outflow. In this study, we show that stimulation of the beta 2-adrenergic receptor (β2AR) by isoproterenol, used as a pharmacological surrogate of sympathetic nerve activation, led to increased blood vessel density and Vegf-a expression in bone. It also raised levels of secreted Vegf-a in osteoblast cultures, and accordingly, the conditioned media from isoproterenol-treated osteoblast cultures promoted new vessel formation in two ex vivo models of angiogenesis. Blocking the interaction between Vegf-a and its receptor, Vegfr2, blunted the increase in vessel density induced by isoproterenol. Genetic loss of the β2AR globally, or specifically in type 1 collagen-expressing osteoblasts, diminished the increase in Vegf-positive osteoblast number and bone vessel density induced by isoproterenol, and reduced the higher incidence of bone metastatic lesions induced by isoproterenol after intracardiac injection of an osteotropic variant of MDA-MB-231 breast cancer cells. Inhibition of the interaction between Vegf-a and Vegfr2 with the blocking antibody mcr84 also prevented the increase in bone vascular density and bone metastasis triggered by isoproterenol. Together, these results indicate that stimulation of the β2AR in osteoblasts triggers a Vegf-dependent neo-angiogenic switch that promotes bone vascular density and the colonization of the bone microenvironment by metastatic breast cancer cells. © 2017 American Society for Bone and Mineral Research.
© 2017 American Society for Bone and Mineral Research.
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15 MeSH Terms
Fms-like tyrosine kinase-3 ligand increases resistance to burn wound infection through effects on plasmacytoid dendritic cells.
Bae L, Bohannon JK, Cui W, Vinish M, Toliver-Kinsky T
(2017) BMC Immunol 18: 9
MeSH Terms: Animals, Burns, Cell Differentiation, Cell Movement, Cells, Cultured, Coculture Techniques, Dendritic Cells, Disease Models, Animal, Humans, Male, Membrane Proteins, Mice, Mice, Inbred BALB C, Neutrophil Activation, Neutrophils, Pseudomonas Infections, Pseudomonas aeruginosa, Sepsis
Show Abstract · Added May 10, 2017
BACKGROUND - Patients experiencing large thermal injuries are susceptible to opportunistic infections that can delay recovery and lead to sepsis. Dendritic cells (DC) are important for the detection of pathogens and activation of the innate and acquired immune responses. DCs are significantly decreased in burn patients early after injury, and the development of sepsis is associated with persistent DC depletion. In a murine model of burn wound infection, the enhancement of DCs after injury by treatment with the DC growth factor Fms-like tyrosine kinase-3 ligand (FL) enhances neutrophil migration to infection, improves bacterial clearance, and increases survival in a DC-dependent manner. FL expands the production of both conventional DCs (cDC) and plasmacytoid DCs (pDC). It has been established that cDCs are required for some of the protective effects of FL after burn injury. This study was designed to determine the contribution of the pDC subset.
METHODS - Mice were subjected to full-thickness scald burns under deep anesthesia and were provided analgesia. pDCs were depleted by injection of anti-plasmacytoid dendritic cell antigen-1 antibodies. Survival, bacterial clearance, and neutrophil responses in vivo and in vitro were measured.
RESULTS - Depletion of preexisting pDCs, but not FL-expanded pDCs, abrogated the beneficial effects of FL on survival, bacterial clearance, and neutrophil migration in response to burn wound infection. This requisite role of pDCs for FL-mediated enhancement of neutrophil migratory capacity is not due to direct effects of pDCs on neutrophils. cDCs, but not pDCs, directly increased neutrophil migratory capacity after co-culture.
CONCLUSIONS - The protective effects of FL treatment after burn injury are mediated by both pDCs and cDCs. Pharmacological enhancement of both DC subtypes by FL is a potential therapeutic intervention to enhance immune responses to infection and improve outcome after burn injury.
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18 MeSH Terms
The Yin/Yan of CCL2: a minor role in neutrophil anti-tumor activity in vitro but a major role on the outgrowth of metastatic breast cancer lesions in the lung in vivo.
Lavender N, Yang J, Chen SC, Sai J, Johnson CA, Owens P, Ayers GD, Richmond A
(2017) BMC Cancer 17: 88
MeSH Terms: Animals, Breast Neoplasms, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Chemokine CCL2, Coculture Techniques, Disease Models, Animal, Disease Progression, Disease-Free Survival, Female, Humans, Leukocytes, Lung, Lung Neoplasms, Macrophages, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Neutrophils
Show Abstract · Added March 14, 2017
BACKGROUND - The role of the chemokine CCL2 in breast cancer is controversial. While CCL2 recruits and activates pro-tumor macrophages, it is also reported to enhance neutrophil-mediated anti-tumor activity. Moreover, loss of CCL2 in early development enhances breast cancer progression.
METHODS - To clarify these conflicting findings, we examined the ability of CCL2 to alter naïve and tumor entrained neutrophil production of ROS, release of granzyme-B, and killing of tumor cells in multiple mouse models of breast cancer. CCL2 was delivered intranasally in mice to elevate CCL2 levels in the lung and effects on seeding and growth of breast tumor cells were evaluated. The TCGA data base was queried for relationship between CCL2 expression and relapse free survival of breast cancer patients and compared to subsets of breast cancer patients.
RESULTS - Even though each of the tumor cell lines studied produced approximately equal amounts of CCL2, exogenous delivery of CCL2 to co-cultures of breast tumor cells and neutrophils enhanced the ability of tumor-entrained neutrophils (TEN) to kill the less aggressive 67NR variant of 4T1 breast cancer cells. However, exogenous CCL2 did not enhance naïve or TEN neutrophil killing of more aggressive 4T1 or PyMT breast tumor cells. Moreover, this anti-tumor activity was not observed in vivo. Intranasal delivery of CCL2 to BALB/c mice markedly enhanced seeding and outgrowth of 67NR cells in the lung and increased the recruitment of CD4+ T cells and CD8+ central memory T cells into lungs of tumor bearing mice. There was no significant increase in the recruitment of CD19+ B cells, or F4/80+, Ly6G+ and CD11c + myeloid cells. CCL2 had an equal effect on CD206+ and MHCII+ populations of macrophages, thus balancing the pro- and anti-tumor macrophage cell population. Analysis of the relationship between CCL2 levels and relapse free survival in humans revealed that overall survival is not significantly different between high CCL2 expressing and low CCL2 expressing breast cancer patients grouped together. However, examination of the relationship between high CCL2 expressing basal-like, HER2+ and luminal B breast cancer patients revealed that higher CCL2 expressing tumors in these subgroups have a significantly higher probability of surviving longer than those expressing low CCL2.
CONCLUSIONS - While our in vitro data support a potential anti-tumor role for CCL2 in TEN neutrophil- mediated tumor killing in poorly aggressive tumors, intranasal delivery of CCL2 increased CD4+ T cell recruitment to the pre-metastatic niche of the lung and this correlated with enhanced seeding and growth of tumor cells. These data indicate that effects of CCL2/CCR2 antagonists on the intratumoral leukocyte content should be monitored in ongoing clinical trials using these agents.
2 Communities
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20 MeSH Terms
Sustained Administration of β-cell Mitogens to Intact Mouse Islets Ex Vivo Using Biodegradable Poly(lactic-co-glycolic acid) Microspheres.
Pasek RC, Kavanaugh TE, Duvall CL, Gannon MA
(2016) J Vis Exp :
MeSH Terms: Animals, Biocompatible Materials, Coculture Techniques, Drug Delivery Systems, Glycols, Humans, Insulin-Secreting Cells, Islets of Langerhans, Lactic Acid, Mice, Microspheres, Mitogens, Polyglycolic Acid
Show Abstract · Added March 14, 2018
The development of biomaterials has significantly increased the potential for targeted drug delivery to a variety of cell and tissue types, including the pancreatic β-cells. In addition, biomaterial particles, hydrogels, and scaffolds also provide a unique opportunity to administer sustained, controllable drug delivery to β-cells in culture and in transplanted tissue models. These technologies allow the study of candidate β-cell proliferation factors using intact islets and a translationally relevant system. Moreover, determining the effectiveness and feasibility of candidate factors for stimulating β-cell proliferation in a culture system is critical before moving forward to in vivo models. Herein, we describe a method to co-culture intact mouse islets with biodegradable compound of interest (COI)-loaded poly(lactic-co-glycolic acid) (PLGA) microspheres for the purpose of assessing the effects of sustained in situ release of mitogenic factors on β-cell proliferation. This technique describes in detail how to generate PLGA microspheres containing a desired cargo using commercially available reagents. While the described technique uses recombinant human Connective tissue growth factor (rhCTGF) as an example, a wide variety of COI could readily be used. Additionally, this method utilizes 96-well plates to minimize the amount of reagents necessary to assess β-cell proliferation. This protocol can be readily adapted to use alternative biomaterials and other endocrine cell characteristics such as cell survival and differentiation status.
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13 MeSH Terms
Epithelial Coculture and l-Lactate Promote Growth of Helicobacter cinaedi under H2-Free Aerobic Conditions.
Schmitz JE, Taniguchi T, Misawa N, Cover TL
(2016) Appl Environ Microbiol 82: 6701-6714
MeSH Terms: Aerobiosis, Caco-2 Cells, Coculture Techniques, Epithelial Cells, HeLa Cells, Helicobacter, Helicobacter Infections, Humans, Hydrogen, Lactic Acid
Show Abstract · Added April 9, 2017
Helicobacter cinaedi is an emerging opportunistic pathogen associated with infections of diverse anatomic sites. Nevertheless, the species demonstrates fastidious axenic growth; it has been described as requiring a microaerobic atmosphere, along with a strong preference for supplemental H gas. In this context, we examined the hypothesis that in vitro growth of H. cinaedi could be enhanced by coculture with human epithelial cells. When inoculated (in Ham's F12 medium) over Caco-2 monolayers, the type strain (ATCC BAA-847) gained the ability to proliferate under H-free aerobic conditions. Identical results were observed during coculture with several other monolayer types (LS-174T, AGS, and HeLa). Under chemically defined conditions, 40 amino acids and carboxylates were screened for their effect on the organism's atmospheric requirements. Several molecules promoted H-free aerobic proliferation, although it occurred most prominently with millimolar concentrations of l-lactate. The growth response of H. cinaedi to Caco-2 cells and l-lactate was confirmed with a collection of 12 human-derived clinical strains. mRNA sequencing was next performed on the type strain under various growth conditions. In addition to providing a whole-transcriptome profile of H. cinaedi, this analysis demonstrated strong constitutive expression of the l-lactate utilization locus, as well as differential transcription of terminal respiratory proteins as a function of Caco-2 coculture and l-lactate supplementation. Overall, these findings challenge traditional views of H. cinaedi as an obligate microaerophile.
IMPORTANCE - H. cinaedi is an increasingly recognized pathogen in people with compromised immune systems. Atypical among other members of its bacterial class, H. cinaedi has been associated with infections of diverse anatomic sites. Growing H. cineadi in the laboratory is quite difficult, due in large part to the need for a specialized atmosphere. The suboptimal growth of H. cinaedi is an obstacle to clinical diagnosis, and it also limits investigation into the organism's biology. The current work shows that H. cinaedi has more flexible atmospheric requirements in the presence of host cells and a common host-derived molecule. This nutritional interplay raises new questions about how the organism behaves during human infections and provides insights for how to optimize its laboratory cultivation.
Copyright © 2016, American Society for Microbiology. All Rights Reserved.
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10 MeSH Terms
Androgen receptor differentially regulates the proliferation of prostatic epithelial cells in vitro and in vivo.
Yang S, Jiang M, Grabowska MM, Li J, Connelly ZM, Zhang J, Hayward SW, Cates JM, Han G, Yu X
(2016) Oncotarget 7: 70404-70419
MeSH Terms: Androgens, Animals, Cell Differentiation, Cell Line, Cell Proliferation, Coculture Techniques, Epithelial Cells, Humans, Male, Mice, Nude, Prostate, Proto-Oncogene Proteins c-myc, Rats, Receptors, Androgen, Stromal Cells
Show Abstract · Added November 1, 2018
Androgens regulate the proliferation and differentiation of prostatic epithelial cells, including prostate cancer (PCa) cells in a context-dependent manner. Androgens and androgen receptor (AR) do not invariably promote cell proliferation; in the normal adult, endogenous stromal and epithelial AR activation maintains differentiation and inhibits organ growth. In the current study, we report that activation of AR differentially regulates the proliferation of human prostate epithelial progenitor cells, NHPrE1, in vitro and in vivo. Inducing AR signaling in NHPrE1 cells suppressed cell proliferation in vitro, concomitant with a reduction in MYC expression. However, ectopic expression of AR in vivo stimulated cell proliferation and induced development of invasive PCa in tissue recombinants consisting of NHPrE1/AR cells and rat urogenital mesenchymal (UGM) cells, engrafted under renal capsule of adult male athymic mice. Expression of MYC increased in the NHPrE1/AR recombinant tissues, in contrast to the reduction seen in vitro. The inhibitory effect of AR signaling on cell proliferation in vitro were reduced by co-culturing NHPrE1/AR epithelial cells with prostatic stromal cells. In conclusion, these studies revealed that AR signaling differentially regulates proliferation of human prostatic epithelia cells in vitro and in vivo through mechanisms involving stromal/epithelial interactions.
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MeSH Terms