scholarly journals Bayesian inference of agent-based models: a tool for studying kidney branching morphogenesis

2017 ◽  
Author(s):  
Ben Lambert ◽  
Adam L. MacLean ◽  
Alexander G. Fletcher ◽  
Alexander N. Combes ◽  
Melissa H. Little ◽  
...  
Keyword(s):  
Cell Division ◽  
Growth Factor ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Ex Vivo ◽  
Collecting Duct ◽  
Mesenchymal Cells ◽  
Ureteric Bud ◽  
Agent Based ◽  
Kidney Morphogenesis

AbstractThe adult mammalian kidney has a complex, highly-branched collecting duct epithelium that arises as a ureteric bud sidebranch from an epithelial tube known as the nephric duct. Subsequent branching of the ureteric bud to form the collecting duct tree is regulated by subcellular interactions between the epithelium and a population of mesenchymal cells that surround the tips of outgrowing branches. The mesenchymal cells produce glial cell-line derived neurotrophic factor (GDNF), that binds with RET receptors on the surface of the epithelial cells to stimulate several subcellular pathways in the epithelium. Such interactions are known to be a prerequisite for normal branching development, although competing theories exist for their role in morphogenesis. Here we introduce the first agent-based model of ex vivo kidney uretic branching. Through comparison with experimental data, we show that growth factor-regulated growth mechanisms can explain early epithelial cell branching, but only if epithelial cell division depends in a switch-like way on the local growth factor concentration; cell division occurring only if the driving growth factor level exceeds a threshold. We also show how a recently-developed method, “Approximate Approximate Bayesian Computation”, can be used to infer key model parameters, and reveal the dependency between the parameters controlling a growth factor-dependent growth switch. These results are consistent with a requirement for signals controlling proliferation and chemotaxis, both of which are previously identified roles for GDNF.Author SummaryA number of important congenital disorders arise due to incomplete development of the mammalian kidney. Elucidating the cause of these conditions requires an understanding of the mechanisms that contribute to kidney morphogenesis. Whilst experimental work has suggested several candidate mechanisms, their importance is still not well understood. Here we develop a computational model of kidney morphogenesis at the individual cell level to compare these different hypotheses. Guided by existing experimental evidence we propose that a generic growth factor, that we term “GDNF”, produced from the mesenchyme surrounding the epithelium, can drive a number of cellular responses. Simulations of our agent-based model reveal that diffusion of GDNF, coupled with GDNF-stimulated epithelial cell division, can generate the branching patterns seen in ex vivo kidney explant experiments. We also find that branching depends on the sensitivity of cell proliferation to changes in GDNF levels. In particular our model only generates realistic branching when there is significant variation in GDNF levels along the boundary of the epithelium, and most cells divide only if the local concentration of GDNF exceeds a threshold value. We conclude that feedback between mesenchymal cells that produce GDNF, and epithelial cells that consume it, is vital for normal kidney organogenesis.

scholarly journals Cellular Automaton for Kidney Branching Morphogenesis

2021 ◽  
Vol 18 ◽  
pp. 170-182
Author(s):  
Afshin Poorkhanalikoudehi ◽  
Karl-Heinz Zimmermann
Keyword(s):  
Experimental Data ◽  
Cell Division ◽  
Growth Factor ◽  
Cellular Automaton ◽  
Ex Vivo ◽  
Collecting Duct ◽  
Branching Morphogenesis ◽  
Mesenchymal Cells ◽  
Local Concentration ◽  
Ureteric Bud

Epithelium is a complex component in the mammalian kidney that has a highly branched duct system. Branching morphogenesis has a hierarchy structure in the ureteric bud and produces the collecting duct tree through repetitive processes. Epithelial and mesenchymal cells surround the tips of growing branches, and their cellular reactions adjust the ureteric bud branching. Mesenchymal cells produce a small protein called glial cellline derived neurotrophic factor (GDNF) that connects to te Rearranged in Transfection (RET) receptors on the surface of epithelial cells. The identified reactions are a necessity for the normal branching growth and their roles exist for using biological features in the proposed model. This paper presents an agent-based model based on cellular automaton for kidney branching in ex-vivo using the features that are expressed as artificial patterns in algorithms. This model extending the groundbreaking approach of Lambert et al. is flexible in features and high compatibility with experimental data. Mesenchymal cells and RET receptors are also expressed as mathematical patterns in the algorithms. The growth mechanism is determined by the growth factor, which indicates the epithelial cell branch when its cell division depends on the local concentration growth factor. Cell division occurs when the level of stimulus growth factor exceeds the threshold. Comparison shows that the model mimics experimental data with high consistency and reveals the dependence between growth factor parameters and features. Results indicate the superiority of compatibility with nature when compared with the model mentioned above.

scholarly journals c-Src inactivation reduces renal epithelial cell-matrix adhesion, proliferation, and cyst formation

2011 ◽  
Vol 301 (2) ◽  
pp. C522-C529 ◽  
Author(s):  
Justine Elliott ◽  
Nadezhda N. Zheleznova ◽  
Patricia D. Wilson
Keyword(s):  
Cell Proliferation ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Collecting Duct ◽  
Specific Inhibitor ◽  
Cell Phenotype ◽  
Epithelial Cell Proliferation ◽  
Matrix Adhesion ◽  
Cyst Lining

c-Src is a non-receptor tyrosine kinase whose activity is induced by phosphorylation at Y418 and translocation from the cytoplasm to the cell membrane. Increased activity of c-Src has been associated with cell proliferation, matrix adhesion, motility, and apoptosis in tumors. Immunohistochemistry suggested that activated (pY418)-Src activity is increased in cyst-lining autosomal dominant polycystic kidney disease (ADPKD) epithelial cells in human and mouse ADPKD. Western blot analysis showed that SKI-606 (Wyeth) is a specific inhibitor of pY418-Src without demonstrable effects on epidermal growth factor receptor or ErbB2 activity in renal epithelia. In vitro studies on mouse inner medullary collecting duct (mIMCD) cells and human ADPKD cyst-lining epithelial cells showed that SKI-606 inhibited epithelial cell proliferation over a 24-h time frame. In addition, SKI-606 treatment caused a striking statistically significant decrease in adhesion of mIMCD and human ADPKD to extracellular collagen matrix. Retained viability of unattached cells was consistent with a primary effect on epithelial cell anchorage dependence mediated by the loss of extracellular matrix (ECM)-attachment due to α2β1-integrin function. SKI-606-mediated attenuation of the human ADPKD hyperproliferative and hyper-ECM-adhesive epithelial cell phenotype in vitro was paralleled by retardation of the renal cystic phenotype of Pkd1 orthologous ADPKD heterozygous mice in vivo. This suggests that SKI-606 has dual effects on cystic epithelial cell proliferation and ECM adhesion and may have therapeutic potential for ADPKD patients.

Insulin modulation of bronchial epithelial cell fibronectin in vitro

1995 ◽  
Vol 268 (2) ◽  
pp. L230-L238 ◽  
Author(s):  
D. J. Romberger ◽  
P. Pladsen ◽  
L. Claassen ◽  
M. Yoshida ◽  
J. D. Beckmann ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Bronchial Epithelial Cell ◽  
Chemotactic Factor ◽  
Tgf Beta ◽  
Bronchial Epithelial

Fibronectin (Fn) is involved in the migration of epithelial cells in re-epithelialization of wounds. Epithelial cell-derived Fn is particularly potent as a chemotactic factor for bronchial epithelial cells (BECs) in vitro. Thus modulation of airway epithelial cell Fn may be a key aspect of airway repair. Insulin is both an important growth factor and known chemotactic factor for cultured BECs. We postulated that insulin may modulate Fn production of cultured BECs. We examined this hypothesis utilizing bovine BECs in culture with serum-free media with and without insulin. BECs grown in media without insulin released more Fn into culture supernatants and contained more Fn in cell layers than cells grown with insulin. Labeling of cells with [35S]methionine demonstrated an increase in new protein production and Fn mRNA expression was increased. Increased Fn in BEC cultures without insulin was associated with an increase in active transforming growth factor-beta (TGF-beta) release as measured by a standard bioassay. Increased BEC Fn in cultures without insulin was partially inhibited by exposure of cultures to TGF-beta antibody. Thus insulin appears to modulate BEC Fn production in vitro in part through a TGF-beta-dependent mechanism. Insulin may be involved in airway repair mechanisms through modulation of epithelial cell Fn production.

scholarly journals Role of medullary progenitor cells in epithelial cell migration and proliferation

2014 ◽  
Vol 307 (1) ◽  
pp. F64-F74 ◽  
Author(s):  
Dong Chen ◽  
Zhiyong Chen ◽  
Yuning Zhang ◽  
Chanyoung Park ◽  
Ahmed Al-Omari ◽  
...  
Keyword(s):  
Cell Migration ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Progenitor Cells ◽  
Conditioned Medium ◽  
Side Population ◽  
Collecting Duct ◽  
Tubular Epithelial Cell ◽  
Epithelial Cell Migration ◽  
Cell Migration And Proliferation

This study is aimed at characterizing medullary interstitial progenitor cells and to examine their capacity to induce tubular epithelial cell migration and proliferation. We have isolated a progenitor cell side population from a primary medullary interstitial cell line. We show that the medullary progenitor cells (MPCs) express CD24, CD44, CXCR7, CXCR4, nestin, and PAX7. MPCs are CD34 negative, which indicates that they are not bone marrow-derived stem cells. MPCs survive >50 passages, and when grown in epithelial differentiation medium develop phenotypic characteristics of epithelial cells. Inner medulla collecting duct (IMCD3) cells treated with conditioned medium from MPCs show significantly accelerated cell proliferation and migration. Conditioned medium from PGE2-treated MPCs induce tubule formation in IMCD3 cells grown in 3D Matrigel. Moreover, most of the MPCs express the pericyte marker PDGFR-b. Our study shows that the medullary interstitium harbors a side population of progenitor cells that can differentiate to epithelial cells and can stimulate tubular epithelial cell migration and proliferation. The findings of this study suggest that medullary pericyte/progenitor cells may play a critical role in collecting duct cell injury repair.

Fibroblasts of rabbit kidney in culture. II. Paracrine stimulation of papillary fibroblasts by PDGF

1991 ◽  
Vol 261 (2) ◽  
pp. F292-F299 ◽  
Author(s):  
A. Knecht ◽  
L. G. Fine ◽  
K. S. Kleinman ◽  
H. P. Rodemann ◽  
G. A. Muller ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epithelial Cells ◽  
Conditioned Medium ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Collecting Duct ◽  
Rabbit Kidney ◽  
Fibroblast Growth ◽  
Igf I

To examine the role of tubulointerstitial cell interaction in the regulation of fibroblast growth, fibroblasts from the rabbit renal cortex (CF) and papilla (PF) were cocultured with epithelial cells from the same tissue location. Inner medullary collecting duct epithelial cells (IMCDE) or IMCDE-conditioned medium stimulated DNA synthesis in PF, whereas proximal tubule epithelium (PTE) had no effect on the proliferation of CF. PF and CF showed a similar mitogenic response to exogenous epidermal growth factor and insulin-like growth factor 1 (IGF-I). Transforming growth factor-beta 1 inhibited growth of both cell types, and basic fibroblast growth factor (bFGF) had no effect on proliferation of either cell type. In contrast, platelet-derived growth factor (PDGF) was a potent mitogen for PF but was only weakly mitogenic for CF. Both CF and PF expressed a similar number of a single-affinity class of PDGF receptors (Kd, 2-4 x 10(-10) M). Assay for growth factor activity in conditioned medium from IMCDE and PTE showed that only IMCDE produced detectable PDGF. IMCDE-stimulated proliferation of PF was partially blocked by an antibody to PDGF, whereas antibodies to IGF-I had no neutralizing effect. The data suggest a role for PDGF in the regulation of interstitial fibroblast proliferation by IMCDE in the renal papilla. This paracrine system may be important in the pathogenesis of some forms of interstitial fibrosis of the kidney.

Fibronectin supports bronchial epithelial cell adhesion and survival in the absence of growth factors

1997 ◽  
Vol 273 (3) ◽  
pp. L684-L693 ◽  
Author(s):  
K. Aoshiba ◽  
S. I. Rennard ◽  
J. R. Spurzem
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Focal Adhesion ◽  
Bronchial Epithelial Cell ◽  
Bronchial Epithelial Cells ◽  
Peptide Sequence ◽  
Human Bronchial Epithelial Cells ◽  
Bronchial Epithelial

Cell-extracellular matrix interactions support the ability of cells to migrate into areas of inflammation and injury. The present study evaluated the ability of different matrix proteins to support bronchial epithelial cell attachment and survival. Collagens were able to support attachment and survival of normal cultured human bronchial epithelial cells but only in the presence of added soluble growth factors such as insulin, epidermal growth factor, platelet-derived growth factor, and bovine pituitary extract. In contrast, fibronectin was able to support attachment and survival of normal human bronchial epithelial cells in growth factor-deficient medium. In addition, fibronectin, in the absence of added growth factors, was able to induce integrin clustering, focal adhesion formation, and phosphorylation of focal adhesion kinase. A 120-kDa chymotryptic fragment of fibronectin containing the Arg-Gly-Asp peptide sequence was able to reproduce the effects of the whole fibronectin molecule. This study supports the concept that fibronectin has specialized roles in injury and repair.

Establishment of a bovine rumen epithelial cell line

2021 ◽  
Author(s):  
Xu Ji ◽  
Huili Tong ◽  
Robert Settlage ◽  
Wen Yao ◽  
Honglin Jiang
Keyword(s):  
Growth Factor ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Cell Line ◽  
Rna Sequencing ◽  
T Antigen ◽  
Short Chain ◽  
Epithelial Cell Line ◽  
Rumen Epithelium ◽  
Rumen Epithelial Cells

Abstract Rumen epithelium plays an essential role in absorption, transport, and metabolism of short-chain fatty acids, the main products of rumen fermentation, and in preventing microbes and other potentially harmful rumen contents from entering the systemic circulation. The objective of this study was to generate an immortal rumen epithelial cell line that can be used as a convenient model of rumen epithelial cells in vitro. We isolated primary rumen epithelial cells from a steer through trypsin digestion and transduced them with lentiviruses expressing the Simian Virus (SV) 40 T antigen. We cloned the transduced cells by limiting dilution. Western blotting analysis confirmed the expression of the SV40 T antigen in two single-cell clones. Cells from one clone, named bovine rumen epithelial clone 1 (BREC1), displayed a flat and squamous morphology in culture. RNA sequencing revealed that BREC1 cells expressed many markers of epithelial cells, including keratins, the epidermal growth factor receptor, and the short-chain fatty acid transporters monocarboxylic acid transporter 1 (MCT-1) and MCT-4. RNA sequencing revealed that BREC1 cells expressed key enzymes such as 3-hydroxymethyl-3-methylglutaryl-CoA lyase and 3-hydroxy-3-methylglutaryl-CoA synthase 1 involved in ketogenesis, a unique function of rumen epithelial cells. RNA sequencing also revealed the expression of genes encoding tight junctions, desmosomes, anchoring junctions, and polarized plasma membranes, structures typical of epithelial cells, in BREC1 cells. Cell proliferation assays indicated that BREC1 cells were similar to primary rumen epithelial cells in response to insulin-like growth factor 1, insulin, and butyrate. In conclusion, BREC1 is not only a convenient but an appropriate model for studying the factors and mechanisms that control proliferation, apoptosis, differentiation, nutrient transport, metabolism, and barrier function in rumen epithelium.

scholarly journals Keratinocyte Growth Factor Expression in the Mesenchymal Cells of Human Amnion*

1997 ◽  
Vol 82 (10) ◽  
pp. 3319-3323 ◽  
Author(s):  
M. Linette Casey ◽  
Paul C. MacDonald
Keyword(s):  
Growth Factor ◽  
Epithelial Cells ◽  
Transforming Growth Factor ◽  
Keratinocyte Growth Factor ◽  
Transforming Growth Factor Β ◽  
Mesenchymal Cells ◽  
Cell Replication ◽  
Human Amnion ◽  
Tetradecanoyl Phorbol Acetate ◽  
Amnion Epithelial Cells

Abstract Amnion epithelial and mesenchymal cells were separated by differential protease treatment, and the separated cells were maintained in monolayer culture. Keratinocyte growth factor (KGF) messenger RNA (mRNA) was readily detected by Northern analysis of amnion mesenchymal cell total RNA (10 μg) but not in amnion epithelial cells. Treatment of the amnion mesenchymal cells in serum-free medium with tetradecanoyl phorbol acetate (1 nm) caused an increase in the level of KGF mRNA. Forskolin treatment also caused an increase in KGF mRNA but not to the levels attained with tetradecanoyl phorbol acetate treatment. Dexamethasone (1 nm) treatment of these cells effected a reduction in the level of KGF mRNA. Prolonged maintenance of mesenchymal cells in serum-free medium also was associated with an increase in the level of KGF mRNA. Treatment with a variety of other agents, viz., interleukin (IL)-1, IL-6 plus or minus IL-6 soluble receptor, IL-11, oncostatin M , epidermal growth factor (EGF), and transforming growth factor-β did not modify the level of KGF mRNA. Treatment of amnion epithelial cells with KGF caused an increase in the rate of [3H]thymidine incorporation, but the rate of cell replication induced by KGF was less than that induced by treatment with EGF. Transforming growth factor-β treatment inhibited basal and EGF- and KGF-stimulated amnion epithelial cell replication. The findings of this study are indicative that KGF is expressed in human amnion mesenchymal cells, and that KGF may act on the epithelial cells of this tissue.

scholarly journals Regulation of proliferation of prostate epithelial cells by 1,25-dihydroxyvitamin D3 is accompanied by an increase in insulin-like growth factor binding protein-3

2001 ◽  
Vol 170 (3) ◽  
pp. 609-618 ◽  
Author(s):  
CC Sprenger ◽  
A Peterson ◽  
R Lance ◽  
JL Ware ◽  
RH Drivdahl ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Human Prostate ◽  
Dihydroxyvitamin D3 ◽  
Prostate Epithelial Cell ◽  
Igf System ◽  
Prostate Epithelial Cells ◽  
Igf I ◽  
Igfbp 3

The biologically active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) has been shown to regulate the proliferation of human prostate epithelial cell lines. Since the insulin-like growth factor (IGF) system is involved in the transformation process of epithelial cells, the following study was undertaken to determine if the IGF system, in particular IGF binding protein-3 (IGFBP-3), is altered by 1,25-(OH)2D3 in normal prostate epithelial cells as part of a mechanism for inhibition of transformation. Two cell systems were used in this study: (1) primary cultures of benign human prostate epithelial cells (PECs) and (2) an SV40-T immortalized prostate epithelial cell line (P153) that is non-tumorigenic. 1,25-(OH)2D3 was added to parallel sets of PECs and P153 cells in addition to the presence or absence of IGF-I or des(1-3)IGF-I. Treatment with 1,25-(OH)2D3 resulted in significant growth inhibition of both PECs and P153 cells. Furthermore, 1,25-(OH)2D3 inhibited IGF-induced proliferation, but this was partially reversed by high concentrations of IGF-I. Western ligand blots of condition media demonstrated a significant increase in IGFBP-3; likewise Northern blots demonstrated an increase in mRNA for IGFBP-3. Proliferation assays using an antibody designed to block the IGF-independent effects of IGFBP-3 failed to reverse the inhibitory effect of 1,25-(OH)2D3. Thus, IGFBP-3 acts in an IGF-dependent manner to inhibit cell growth of benign prostate epithelial cells.

scholarly journals STRUCTURAL VARIATIONS DURING MITOSIS IN THE CHICK EMBRYO

1967 ◽  
Vol 33 (1) ◽  
pp. 179-196 ◽  
Author(s):  
Allan L. Allenspach ◽  
L. E. Roth
Keyword(s):  
Free Surface ◽  
Cell Division ◽  
Epithelial Cells ◽  
Chick Embryo ◽  
Mesenchymal Cells ◽  
Cleavage Furrow ◽  
Chick Embryos ◽  
Structural Variations ◽  
Spindle Elongation ◽  
Elongation Process

Selected tissues from chick embryos were fixed in 2% glutaraldehyde and 1% OsO4, both buffered at pH 7.6 with Veronal-acetate, and were embedded in Maraglas or Araldite. Two types of cell division have been noted. Generally, epithelial cells divide predominantly by a shortening of the chromosome-to-pole distance rather than by spindle elongation; mesenchymal cells undergo extensive spindle elongation. The presence of numerous continuous microtubules in cells that undergo extensive spindle elongation functionally implicates these tubules in the elongation process. In most embryonic epithelia, the cleavage furrow converges to a fixed site forming a mid-body near the anchoring desmosomes at the free surface; symmetrical furrow formation is typical of mesenchymal cells which lack desmosomes. The hypothesis of cleavage furrow formation and the fate of the mid-body that is formed during cytokinesis are discussed.

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