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PubMedDate not supplied

[Phospholipid composition, lipid peroxidation, and activity of enzymes of hepatocyte organoids in alcoholic intoxication].

During chronic ethanol intoxication phase alterations in phospholipid composition and in intensity of oxidation were observed in liver microsomes and mitochondria. The oxidative reactions were most pronounced within the first 15 and 30 days as shown by an increase in activity of malate- and isocitrate dehydrogenases from the mitochondrial fraction. Administration of ethanol within 15 days was accompanied by an increase in content of phospholipids and their separate fractions both in microsomes and in mitochondria. In microsomes content of lipid peroxides was distinctly increased but content of free phospholipid fractions was most distinctly lowered within 90 days.

Alcoholism↗
PubMed1975

[An electron microscopic study of the interaction between shigellae and cell cultures. II. Structuro-functional response of the chief cytoplasmic organoids of infected cells].

The initial mobilization of the protective power of amniotic cells under the influence of the intracellular parasite Shigellae Flexner was shown using qualitative and quantitative methods of electron microscopy. This mobilization is seen in the appearance and then concentration of membrane elements of the endoplasmic reticulum around the bacteria. The character of some degenerating changes confirms the opinion about the presence of an excreting endotoxin fraction in Shigellae Flexner.

Cell Line↗
PubMed2026

Endobronchial Ultrasound-Guided Biopsy-Derived Lung Cancer Models: A Platform for Precision Therapy.

BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration is used for clinical diagnosis and staging in patients with lung cancer. Nevertheless, establishing patient-derived preclinical models using needle biopsy samples remains challenging. This study describes the establishment and utility of patient-derived organoid (PDO) from endobronchial ultrasound-guided (EBUS) specimens and EBUS patient-derived xenograft (PDX). METHODS: A total of 175 EBUS specimens were used to establish PDO and PDX. "Stable establishment" organoids with passage numbers of 10 or greater were used for genomic, transcriptome, and pathologic assessment. Drug sensitivity of EBUS organoids and PDX tumors were compared with those of the matched patient. Drug screening was performed using stably established organoid models. RESULTS: We successfully established a total of 20 EBUS organoids: six EBUS-PDOs and 14 EBUS-xenograft derived organoids. These stable cancer organoid models were validated for cancer cell enrichment and pathologic assessment. Pathologic findings, exome, and transcriptome analysis found a high correlation between EBUS organoids and parental samples. EBUS organoids and PDX indicated consistent drug response patterns with their corresponding patients. A drug screening conducted on an EBUS organoid led to the discovery of potent activity of trametinib to a rare MAP2K1 K57N mutation. CONCLUSIONS: EBUS-PDO and -xenograft‒derived organoids are good options to generate stable organoids in patients with advanced stage lung cancer. The models were consistent with the genetic and pathologic features of patient tumors, and the patient's responses to treatment, supporting their utility for novel therapeutic research.

Humans↗
PubMed2000

Concept for organ engineering: a reconstruction method of rat liver for in vitro culture.

In the past decade, there have been remarkable advances in tissue engineering technology toward the goal of creating organoids in vitro from cells and cellular scaffolding. Indeed, tissue-engineered organoids such as skin and cartilage, each with comparatively simple architectures, are presently at the clinical stage. However, conventional tissue engineering techniques have not allowed for the reconstruction of an organoid that mimics an organ of complex architecture of abundant vascular networks. We established a method for organ engineering that can remodel a rat liver into a reconstructed organoid without separating the majority of liver cells by a continuous three-step perfusion. The liver was perfused through its vascular system with a buffered balanced salt solution to cleanse blood from the organ, with a collagenase/dispase medium to deconstruct cellular scaffolds, and with a culture medium containing collagen type I to reorganize the multicellular architecture. The reconstructed organoid was then prepared by excising the perfused liver from the rat and culturing it at 37 degrees C for 2 h. Histologically healthy parenchymal hepatocytes expressing albumin were observed in the excised organoid even after culture for 3 weeks. Furthermore, a fibroblast-implanted organoid was prepared by using a culture medium containing suspended fibroblasts in the third step of the perfusion procedure, demonstrating the efficacy of heterogeneous cells for the reconstruction of an organoid. This method may be applicable to the formation of organoids from other organs, such as kidney and spleen, each of which have abundant capillaries, and therefore the method provides a novel concept for the development of lab-grown organs, i. e., organ engineering.

Animals↗
PubMed1987

In vitro replication potential of serially passaged mammary parenchyma from mice with different reproductive histories.

Growth properties of multicellular units (organoids) of mouse mammary parenchyma have been analyzed. These intact units grew differently in collagen-matrix cultures than did dispersed cells prepared from them. The latter actively migrated in the collagen matrix and reorganized themselves into multicellular structures before producing three-dimensional protuberances in gel. Terminal unit (end-bud/alveoli)-enriched fractions grew more extensively than did ducts, as predicted from growth patterns in vivo. To assess the growth potential and the relationships between replication history in vivo and replication potential in vitro in mammary parenchyma, intact terminal units from mammary glands of mice of different ages and with different reproductive histories were isolated and their growth characteristics compared. Terminal-unit organoids were cultured in collagen gel matrix and passaged weekly for up to 5 weeks. Morphology, growth rates, and growth fractions were compared among organoids from young virgin, old virgin, monoparous, and multiparous mice. Morphologies observed in various passages of organoids from the groups of mice were similar. Organoids from old virgin and multiparous mice declined in growth rate for four passages and then growth rate increased again during the fifth passage. (However, fifth-passage organoids failed to form tumors if implanted in syngeneic mice in vivo.) Growth of organoids from either old or young virgin mice was less at any given passage than tissue from multiparous mice of similar age. Growth fractions of organoids from old parous mice were the same as those from old virgin mice but reached the same maximum fraction faster. Later passage organoids from the different mouse groups responded morphologically to the hormone combination of estrogen, progesterone, prolactin, and cortisone but not respond to cholera toxin. These results suggest that an animal's hormonal history (altered profoundly by pregnancy and lactation) may be as important as chronological age in determining subsequent growth potentials of mammary epithelium.

Aging↗
PubMed1995

Endothelium-modulated proliferation of medial smooth muscle cells: influence of angiotensin II and converting enzyme inhibition.

This study investigated the role of the endothelium and angiotensin II (Ang II) in regulating medial smooth muscle cell (SMC) proliferation. [3H]-thymidine incorporation into medial SMC of rat arteries was examined in vivo, using ballooned rat carotid arteries, as well as in vitro, using cultures of aortic tissue rings (organoids). In vivo, maximal medial [3H]-thymidine incorporation occurred within 3 days post-ballooning. In endothelium-denuded organoids, maximum medial DNA synthesis was achieved after 7 days of culture. [3H]-thymidine-labelling of SMC in intact organoids (with endothelium) increased minimally during culture, indicating that the endothelium provided protection with respect to medial proliferation under basal conditions (culture in the presence of 1% plasma-derived serum). Inclusion of 10(-7) M Ang II significantly elevated medial [3H]-thymidine incorporation above that in control cultures. The stimulatory effect of Ang II was much more pronounced in intact organoids that in endothelium-denuded organoids, indicating synergistic growth regulation by Ang II and endothelium-derived factors. When organoids were cultured in the combined presence of Ang II and the ACE inhibitor cilazaprilat, labelling indices of intact organoids were also significantly increased above control, but to a lower level than those obtained in the presence of Ang II alone. However, for endothelium-denuded organoids, medial [3H]-thymidine incorporation in the combined presence of Ang II and cilazaprilat was not significantly different from that in untreated controls. Thus, cilazaprilat exerts both endothelium-dependent and endothelium-independent negative regulatory effects on medial SMC proliferation.

Angiotensin II↗
PubMed2005

A three-dimensional tissue culture model for the study of attach and efface lesion formation by enteropathogenic and enterohaemorrhagic Escherichia coli.

We sought to develop a practical and representative model to study the interactions of enteropathogenic and enterohaemorrhagic Escherichia coli (EPEC and EHEC, respectively) with human intestinal tissue. For this purpose, human intestinal epithelial HCT-8 cells were cultured under low-shear microgravity conditions in a rotating cell culture system. After 10 days, layered cell aggregates, or 'organoids', developed. Three lines of evidence indicated that these organoids exhibited traits characteristic of normal tissue. First, the organoids expressed normal intestinal tissue markers in patterns that suggested greater cellular differentiation in the organoids than conventionally grown monolayers. Second, the organoids produced higher levels of intestinally expressed disaccharidases and alkaline phosphatase on a cell basis than did conventionally cultured monolayers. Third, HCT-8 organoid tissue developed microvilli and desmosomes characteristic of normal tissue, as revealed by electron microscopy. Because the low-shear microgravity condition is proposed by modelling studies to more closely approximate conditions in the intestinal microvilli, we also tested the impact of microgravity of bacterial growth and virulence gene expression. No influence on growth rates was observed but intimin expression by EHEC was elevated during culture in microgravity as compared with normal gravity. That the responses of HCT-8 organoids to infection with wild-type EPEC or EHEC under microgravitational conditions approximated infection of normal tissue was demonstrated by the classical appearance of the resultant attaching and effacing lesions. We concluded that the low shear microgravity environment promoted growth of intestinal cell organoids with greater differentiation than was seen in HCT-8 cells maintained in conventional tissue culture and provided a reduced gravity environment for study of bacterial-host cell interactions.

Adhesins, Bacterial↗
PubMed1992

Patterns of growth and differentiation in the colon carcinoma cell line LIM 1863.

The LIM 1863 colon carcinoma cell line grows in the form of morphologically and functionally organized organoids. Cells are arranged around a central lumen with a brush border and nuclei are polarized to the periphery. The organoids contain 3 morphological cell types (columnar, goblet and caveolated cells). By agar cloning it has been possible to isolate 29 subclones of the cell line, all of which display the same phenotype and percentage of morphological cell types as the parent line. Cell-sorting experiments showed that precursor cells of LIM 1863 cultures could express either mucin (large-intestinal-mucus antigen) or a brush-border enzyme (sucrase-isomaltase). Proliferating cells were predominantly found near the outer periphery of organoids with cell maturation towards the internal lumen. Dead cells were continuously shed from the organoids but terminal non-cycling cells were not observed within the organoids. The organoid structure was calcium-dependent and promoted cell survival. Suspension cultures of disaggregated cells could be grown in medium containing less than 100 microM calcium. No decrease in differentiation antigens was observed in the low-calcium cultures, although polarization of the cells was lost. The organoid cultures formed by this cell line represent a unique in vitro model for colonic crypt growth and organization.

Calcium↗
PubMed1988

Transplantation of human breast epithelia to mammary-gland-free fat-pads of athymic nude mice: influence of mammotrophic hormones on growth of breast epithelia.

Normal human breast tissue was enzymatically dissociated and the cells were injected into the gland-free fat-pads of athymic nude mice. Within 30 days, small, spherical, duct-like epithelial elements (organoids) formed in 68% of the fat-pads inoculated (0-23 organoids/fat-pad). Short-term (30-day) treatment of the host mice with mammotrophic hormones [secretions from a chorionic, soamto-mammotrophin-secreting transplantable human choriocarcinoma (JEG-3), secretions from a prolactin- and growth-hormone-secreting transplantable rat pituitary tumor (GH3), estrogen and/or progesterone] and/or cAMP inducers (cholera toxin) significantly (p less than 0.05) increased the size of the human breast organoids but did not increase organoid number or induce extensive and expansive growth (extensive duct elongation and branching) of these structures. Such treatments induced intense proliferation of the host mouse mammae resembling that which occurs during late pregnancy. The results of this study, therefore, provide evidence that normal human breast epithelium can be readily accepted by and maintained in the gland-free fat-pad of the athymic nude mouse, and the epithelium, within 30 days, forms spherical duct-like structures (organoids). The human breast organoids are hormone-responsive, as they respond to a mammotrophic growth stimulus by an increase in size. The failure of the human breast organoids to grow expansively in the gland-free fat-pad of this immunologically deficient mouse does not appear to be due to the absence of an appropriate hormonal growth stimulus.

Adipose Tissue↗
PubMed1988

Effects of calcium on synthesis and secretion of parathyroid hormone and secretory protein I.

Bovine parathyroid organoids were cultured for up to 3 wk in medium containing 1.4 or 1.8 mM calcium. Steady-state secretion of parathyroid hormone and secretory protein I was two- to fourfold greater at 1.4 mM. At the end of culture, organoids were incubated 3.5 h in 1 or 2 mM calcium to examine maximum and minimum acute secretory rates. Relative to organoids cultured at 1.8 mM calcium, culture at 1.4 mM induced a hypersecretory state, i.e., both the maximum and minimum acute secretory rates of organoids previously cultured at 1.4 mM calcium were up to threefold greater than those of organoids previously at 1.8 mM calcium. Proparathyroid hormone synthesis was up to 50% greater in organoids cultured at 1.4 mM calcium, whereas secretory protein I and total protein synthesis were unaltered. The results showed that parathyroid hypersecretion can be induced by chronic hypocalcemic conditions in vitro. We conclude that the secretory adaptation to chronic hypocalcemia in vitro involves alterations in both synthesis and degradation of parathyroid hormone.

Animals↗
PubMed1991

Effects of insulin on the synthesis, intracellular degradation, and secretion of parathormone.

Bovine parathyroid organoids were maintained for up to 12 days of culture in the presence or absence of insulin. Insulin-treated organoids secreted more PTH and secretory protein-I (SP-I) than did untreated organoids at both 1.4 and 1.8 mM Ca, concentrations chosen to promote partially elevated and suppressed secretion rates, respectively. The insulin effect was dose dependent and reversible. To determine whether insulin might increase secretion by reducing degradation of cellular PTH, its effects on several parameters related to degradative processes were examined. Compared to control cultures maintained at either 1.4 or 1.8 mM Ca, insulin did not induce changes in the relative levels of intact hormone and COOH-terminal peptide fragments secreted into culture medium, nor did it decrease the total cellular levels of three lysosomal enzymes or mute the effects of 3-methyladenine (an agent that decreases formation of autophagosomes) to increase PTH secretion. Thus, insulin did not appear to increase PTH secretion by reducing the latter's cellular degradation. Synthesis of total proteins and of the secreted proteins SP-I and PTH was examined using short incubations of control and insulin-treated organoids with [3H] leucine. Incorporation of 3H into total acid-precipitable proteins was not elevated in insulin-treated organoids; that into PTH/pro-PTH and SP-I, however, was significantly greater in insulin-treated than in control organoids. The results suggested that the insulin-mediated increase in PTH and SP-I secretion is largely due to its regulation of PTH and SP-I biosynthesis.

Acid Phosphatase↗