Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Cellular heterogeneity”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 55 records · Page 3Linked to original sources
PubMed2005

Heterogeneous cellular environments modulate one-hit neuronal death kinetics.

We recently demonstrated that cell loss kinetics in diverse forms of neurodegeneration (ND) suggests a universal death switch mechanism in which each cell is at a constant risk to initiate apoptosis. We proposed that mutant and injured neurons exist in a viable state typified by an increased risk of initiating death processes [Clarke, Collins, Leavitt, Andrews, Hayden, Lumsden, McInnes, A one-hit model of cell death in inherited neuronal degenerations, Nature 406 (2000) 195-199]. To date, however, measurements of cell death risk have been available only as averages across the affected cell population. Here we develop and apply a method of death kinetic analysis in which the risk factors vary across the neuronal population, as for example due to regional heterogeneities in the cellular microenvironment. We find that most cases of ND for which cell loss data has been obtained are better explained by death risks that vary from cell to cell, compared to death risk that is constant across the neuronal population. Strikingly, a common form of the frequency distribution defining the death risk heterogeneity is shared across most of these cases. This first characterization of the kinetic heterogeneity in one-hit neuronal death, therefore, suggests that the wide variety of ND now known may share mechanisms through which regional differences in the cellular microenvironment modulate the kinetics of cell loss.

Animals↗
PubMed1989

Ultrastructure of Amphiuma distal nephron: evidence for cellular heterogeneity.

To obtain more information on the ultrastructure of the distal nephron of the salamander, Amphiuma, we conducted freeze-fracture electron microscopy and morphometric experiments. In the early distal tubule, the organization of the tight junction is variable, containing from one to two strands in the proximal region and four strands in distal regions. The length density of the tight junction in this segment varies from greater than 60 m/cm2 of apical membrane surface to less than 10/cm2 of apical membrane surface. These observations agree with a previous study demonstrating that the junction of this segment exhibits considerable axial heterogeneity. The junctions of the late distal tubule and collecting tubule are more complex. In the late distal tubule, the tight junction is composed of 6-8 strands, whereas the tight junction of the collecting tubule is composed of 8-12 strands. The collecting tubule contains principal cells and two types of intercalated cells: alpha and beta. The alpha-cells contain a high density of rod-shaped particles in the apical plasma membrane and in membranes of apical cytoplasmic vesicles. The beta-cells contain rod-shaped particles only in the basolateral membrane. In principal cells, we observed a novel organization of intramembranous particles within the apical plasma membrane. A model describing the relationship of the two types of intramembranous particles within the membrane is presented. This study demonstrates that the amphibian and mammalian distal nephron share many morphological characteristics including cellular and axial heterogeneity.

Animals↗
PubMed1982

On the genesis and regulation of cellular heterogeneity in malignant tumors.

The growing body of evidence showing that malignant tumors are heterogeneous and contain diverse subpopulations of cells with different metastatic abilities is reviewed. The factors that may influence the evolution of cellular diversity at different stages in the progression of malignant neoplasms are discussed. Particular emphasis is given to the possibility that interactions occurring between the constituent subpopulations of a malignant tumor may influence the rate at which new variant subpopulations emerge. Metastatic heterogeneity poses significant problems for experimental efforts to identify the cellular features that correlate with metastatic behavior and for the therapy of metastatic disease.

Animals↗
PubMed2006

Kidney side population reveals multilineage potential and renal functional capacity but also cellular heterogeneity.

Side population (SP) cells in the adult kidney are proposed to represent a progenitor population. However, the size, origin, phenotype, and potential of the kidney SP has been controversial. In this study, the SP fraction of embryonic and adult kidneys represented 0.1 to 0.2% of the total viable cell population. The immunophenotype and the expression profile of kidney SP cells was distinct from that of bone marrow SP cells, suggesting that they are a resident nonhematopoietic cell population. Affymetrix expression profiling implicated a role for Notch signaling in kidney SP cells and was used to identify markers of kidney SP. Localization by in situ hybridization confirmed a primarily proximal tubule location, supporting the existence of a tubular "niche," but also revealed considerable heterogeneity, including the presence of renal macrophages. Adult kidney SP cells demonstrated multilineage differentiation in vitro, whereas microinjection into mouse metanephroi showed that SP cells had a 3.5- to 13-fold greater potential to contribute to developing kidney than non-SP main population cells. However, although reintroduction of SP cells into an Adriamycin-nephropathy model reduced albuminuria:creatinine ratios, this was without significant tubular integration, suggesting a humoral role for SP cells in renal repair. The heterogeneity of the renal SP highlights the need for further fractionation to distinguish the cellular subpopulations that are responsible for the observed multilineage capacity and transdifferentiative and humoral activities.

Animals↗
PubMed1991

Regional cellular heterogeneity and DNA synthetic activity in rat ventral prostate during postnatal development.

Previous studies have provided evidence that the rat ventral prostate grows primarily, if not exclusively, at its distal tips. However, as yet there have been no analyses in which individual cells in defined regions of the prostatic ductal system have been resolved and quantified. Moreover, the possibility that the prostate might grow differently at different times of postnatal development has received little attention. Our objectives were to identify and quantify the proliferating epithelial and stromal cells in defined regions of the rat ventral prostate during its postnatal development. To this end, 3H-thymidine was administered in vivo to rats of ages 10-60 days. A dissection technique was then used by which the distal, intermediate, and proximal segments of the prostatic ductal system were physically isolated from each other without removing the stromal tissue. Longitudinal sections of these segments were examined for cellular composition and DNA synthetic activity. Regional heterogeneity with respect to cell composition and cell proliferation was seen. In rats of all ages, DNA synthetic activity was seen in epithelial and stromal cells throughout the prostate, rather than only in the distal segment. At Days 10 and 20, significantly higher percentages of epithelial and stromal cells were labeled in the distal than in the proximal segments; but at Days 45 and 60, the percentages of labeled epithelial and stromal cells in the distal, intermediate, and proximal segments were similar. Thus, in all segments, and at all ages, substantial labeling was seen throughout the prostate. These data suggest that the prostate grows in both length and width throughout postnatal development, reminiscent of the growth of a tree.

Animals↗
PubMed1989

Analysis of cellular heterogeneity in the response of human leukemic cells to photosensitization induced by pyrene-containing fatty acid.

Incubation of cells with 12-(1-pyrene) dodecanoic acid (P12) followed by irradiation with ultraviolet light at 366 nm (UVA) resulted in cytotoxicity. We compared the photosensitivity to UVA irradiation of various human myelo-monocytic leukemic cell lines, their intra- and inter-clonal variability and correlated their photosensitivity to P12-uptake and metabolism. The fluorescence properties of pyrene were utilized for flow cytometric analysis of cell distribution with respect to P12-uptake as well as for sorting subpopulations differing in their fluorescence. Spectrofluorometric analysis of the total cell-associated fluorescence and of the cellular lipids-associated fluorescence were also carried out. Considerable heterogeneity in P12-uptake and photosensitivity was found not only among cell lines, but also in the response of different clones and among the individual cells in specific clonal populations. Within a clone, photosensitivity was related to the amount of P12 taken up by the individual cells, while among different cell lines and their clones the photosensitivity was correlated with the proportion of cellular pyrene-linked phospholipids. The larger the fraction of pyrene-linked phospholipids within the cell--the more sensitive it was to UVA-irradiation. Photosensitivity could be affected by changing the proportion of cellular pyrene-linked phospholipids. Cells treated with cAMP showed an increase in total P12-uptake, but the proportion of pyrene-linked phospholipids was reduced, resulting in lower photosensitivity. These findings, demonstrating that by manipulating lipid metabolism photosensitivity can be modified, may prove useful in a clinical setting for selective photosensitization of malignant cells.

Cell Survival↗
PubMed1983

The experimental and clinical implications of cellular heterogeneity in malignant tumors.

The growing body of evidence showing that malignant tumors are heterogeneous and contain diverse subpopulations of tumor cells is reviewed, with particular emphasis being given to the presence of tumor-cell subpopulations with differing metastatic properties. The factors that may influence the evolution of cellular diversity at different stages in the progression of malignant neoplasms are discussed. Emphasis is given to the possibility that interactions occurring amongst the constituent subpopulations of a malignant tumor may influence the rate at which new variant subpopulations emerge. Metastatic heterogeneity poses significant problems for experimental efforts to identify features unique to metastatic cells and also for the therapy of metastatic disease.

Animals↗
PubMed2001

Aldolase C/zebrin II expression in the neonatal rat forebrain reveals cellular heterogeneity within the subventricular zone and early astrocyte differentiation.

During late gestational and early postnatal development, proliferating cells in the subventricular zones of the lateral ventricles (SVZ) migrate into the gray and white matter of the forebrain and differentiate into astrocytes and oligodendrocytes. Because the cellular composition and structure of the neonatal SVZ is poorly understood, we performed a differential display PCR screen to identify genes preferentially expressed therein. One highly expressed gene encoded aldolase C. We used a specific monoclonal antibody, aldolase C/zebrin II (ALDC/ZII), in combination with markers of glial lineage and proliferation, to characterize the cells that express this gene. In the neonatal SVZ, ALDC/ZII-positive cells, which are generally polygonal and display several processes, have a nonuniform spatial distribution. They do not express vimentin, GFAP, or NG2. A subset of ALDC/ZII-positive cells incorporates bromodeoxyuridine, but progenitors identified by beta-galactosidase expression after infection with recombinant BAG virus do not show ALDC/ZII immunoreactivity. Outside of the SVZ, beta-galactosidase-positive/ALDC/ZII-positive cells have an astrocytic phenotype, suggesting that immunoreactivity was acquired after exit from the SVZ. These studies demonstrate that the neonatal SVZ is composed of different populations of cells that can be characterized by their antigenic phenotype, their proliferative capacity, and their spatial distributions. Nonrandom distributions of different cell types within the SVZ may permit the formation of microenvironments that stimulate the production of cells with specific potentials at appropriate points in development. Analysis of ALDC/ZII expression by astrocyte lineage cells in the neonatal cerebral cortex and white matter may reveal insights into the phenotype and behavior of undifferentiated astrocyte progenitors.

Animals↗
PubMed1992

Cellular heterogeneity in human transitional cell carcinoma: an analysis of optical properties and lectin binding.

Flow cytometry was used to measure the binding of a panel of ten fluorescein isothiocyanate(FITC)-conjugated lectins to fifteen samples of normal and neoplastic human urothelium. Concurrent measurement of light scattering and fluorescence permitted the quantification of lectin binding to cellular subpopulations defined by their light-scattering properties. In normal urothelium, we previously demonstrated levels of lectin binding to the cellular subpopulations derived from the superficial and intermediate cell layers which were higher than levels which bound to the subpopulation derived from the basal cell layer (Ward et al., 1987). This difference was most marked with Maclura pomifera agglutinin (MPA), Ricinus communis agglutinin (RCA) and Ulex europeus agglutinin (UEA). We now report a similar correlation between the degree of differentiation of a cellular subpopulation and the level of lectin binding in human transitional cell carcinomas (TCCs). Morphological differentiation in human TCCs is accompanied by alterations in cell-surface carbohydrates which are similar to those which accompany cellular differentiation in the corresponding normal tissue. No systematic difference in lectin binding was observed between the corresponding subpopulations of normal and neoplastic urothelial cells.

Carbohydrate Metabolism↗
PubMed1992

Immunolocalization, quantitation and cellular heterogeneity of apolipoprotein B in rat hepatocytes.

Hepatocyte autofluorescence represents a major problem in immunofluorescence studies with fluorescein conjugates because of significant spectral overlap. We describe a method for immunostaining hepatocytes with R-phycoerythrin (a fluorochrome with minimal overlap with autofluorescence) with paraformaldehyde fixation and Triton X-100 permeabilization for better antibody penetration. This method produced both perinuclear (presumed Golgi apparatus) and dispersed, reticular staining (presumed endoplasmic reticulum) in rat hepatocytes in culture stained with a monoclonal antibody to rat apolipoprotein B. Treatment with brefeldin A resulted in loss of apolipoprotein B perinuclear staining and increased reticular immunofluorescence consistent with known properties of brefeldin A (inhibition of protein transport within the secretory pathway by dissolution of Golgi bodies). This suggests that apolipoprotein B epitopes are present in both Golgi bodies and endoplasmic reticulum. To demonstrate the utility of the technique for quantitative studies, static cell cytofluorometry of brefeldin A-treated cells was performed, demonstrating increases in specific immunofluorescence of apolipoprotein B corresponding closely to results estimated by monoclonal antibody radioimmunoassays of cellular homogenates. The technique was then used with flow cytometry of single-cell suspensions of control rat hepatocytes derived from immunostained primary cultures to reveal cell-to-cell heterogeneity of apolipoprotein B epitope expression manifested as apolipoprotein B-negative and positive populations. Results for brefeldin A-treated cells revealed even clearer delineation of heterogeneity as indicated by frank bimodality of the populations, along with not only higher mean apolipoprotein B levels but also a significantly higher proportion of apolipoprotein B-positive cells than in the control.

Animals↗
PubMed1998

Cellular heterogeneity of CFTR expression and function in the lung: implications for gene therapy of cystic fibrosis.

Cystic fibrosis (CF) has become a paradigm disorder for the clinical testing of gene therapies in the treatment of inherited disease. In recent years, efforts directed at gene therapy of CF have concentrated on improving gene delivery systems to the airway. Surrogate endpoints for complementation of CFTR dysfunction in the lung have been primarily dependent on correction of chloride transport abnormalities. However, it is now clear that the pathophysiology of CF airways disease is far more complex than can be solely attributed to altered chloride permeability. For example, in addition to functioning as a chloride channel, CFTR also has been implicated in the regulation of other apical membrane conductance pathways through interactions with the amiloride sensitive epithelial sodium channel (ENaC) and the outwardly rectifying chloride channel (ORCC). Superimposed on this functional diversity of CFTR is a highly regulated pattern of CFTR expression in the lung. This heterogeneity occurs at both the level of CFTR protein expression within different cell types in the airway and the anatomical location of these cells in the lung. Potential targets for gene therapy of CF include ciliated, non-ciliated, and goblet cells in the surface airway epithelium as well as submucosal glands within the interstitium of the airways. Each of these distinct cellular compartments may have functionally distinct roles in processes which affect the pathogenesis of CF airways disease, such as fluid and electrolyte balance. However, it is presently unclear which of these cellular targets are most pathophysiologic relevant with regard to gene therapy. Elucidation of the underlying mechanisms of CFTR function in the airway will allow for the rational design of gene therapy approaches for CF lung diseases. This review will provide a summary of the field's current knowledge regarding CFTR functional diversity in the airway and the implications of such diversity for gene therapies of CF lung disease.

Cystic Fibrosis↗
PubMed2003

Analysis of the cellular heterogeneity in the basal layer of mouse ear epidermis: an approach from partial decomposition in vitro and retroviral cell marking in vivo.

In the thin epidermis, the existence of epidermal proliferation units was hypothesized. Each unit is supposed to be partitioned into each column of polygonal-shaped cornified plates, estimated to contain a central stem cell in its basal layer. We attempted to verify this hypothesis in vitro by analyzing the partially decomposed fragment of mouse ear epidermis and in vivo using retroviral cell marking. Partially decomposed fragments of the mouse ear epidermis, mostly composed of cytokeratin 14-expressing basal keratinocytes, formed multicellular colonies in vitro. They were composed of heterogeneously shaped cells, morphologically resembling the cells in each single cell-derived colony, including potential stem cells with great proliferative potency in vitro. The estimated frequency of the candidates of stem cells in the fragments was much lower than the prediction from the representative hypothesis. Retroviral cell marking with nuclear localizing LacZ protein in vivo suggested the existence of a large clonal cellular unit for epidermal renewal. From these in vitro and in vivo observations, we propose a new model for the epidermal proliferation unit.

Animals↗
PubMed2004

Scale-free neurodegeneration: cellular heterogeneity and the stretched exponential kinetics of cell death.

Neurodegenerative disorders are an insidious group of diseases characterized by severe physical and cognitive effects that often have devastating consequences for the lives of affected individuals and their families. One feature common to a significant proportion of these diseases is that affected neurons commit to undergoing an active form of degeneration known as programmed cell death, or apoptosis. Although intense effort over the past several years has resulted is a remarkable increase in our understanding of the molecular events involved in neurodegeneration, our knowledge regarding the cellular and tissue properties that determine the temporal patterns of neuronal attrition is limited. We recently demonstrated that neurodegenerative kinetics in various diseases fit well to exponential decay functions, and proposed a universal one-hit switch mechanism in which mutant and injured neurons exist in a viable state characterized by an increased but constant risk of initiating apoptosis (Nature, 406, p. 195). Here we show that a heavy-tailed stretched exponential function is better able to account for neurodegenerative kinetic data. Moreover, normalization of all available data according to their corresponding best-fit stretched exponential parameters suggest that the generalized model is consistent with a universal mechanism of neuronal cell death that is greatly improved over the constant risk model. In contrast to the original model in which all cells exhibit an identical risk of initiating apoptosis, the stretched exponential model is consistent with each neuron experiencing a constant risk that is different from that experienced by other cells in the degenerating population, perhaps due to spatial differences in the cellular microenvironment. Intriguingly, the predicted distribution of risk across the cell population can be fit by a power-law function, further suggesting that scale-free properties of degenerating neuronal tissues might act as potent regulators of the kinetics of cell death in neural tissue.

Apoptosis↗
PubMed1994

Cellular heterogeneity in DNA damage and growth inhibition induced by ICI D1694, thymidylate synthase inhibitor, using single cell assays.

Heterogeneity in the response of the HCT-8 (human ileocecal adenocarcinoma) tumor cell line to a new thymidylate synthase inhibitor, ICI D1694, was investigated in terms of induction of DNA single-strand breaks and cytotoxicity, applying the single cell alkaline gel (SCG) electrophoresis assay and the individual colony formation assay (iCFA), respectively. ICI D1694 induced maximal total DNA single-strand breaks 24 hr after a 2-hr drug exposure with incomplete repair by 72 hr. The level of DNA damage was concentration dependent and paralleled cellular growth inhibition in vitro. The proportion of cells with DNA damage and the extent of DNA single-strand breaks increased with drug concentration. At 1 microM ICI D1694 (IC95), a significant level of DNA damage was detected in 58% of the cells; however, 25% of the cells had little or no damage. Using the iCFA system, it was observed that with 1 microM ICI D1694, only 2.6% of the seeded cells maintained a colony growth rate similar to that of the control colonies, and 22% of the cells were growing significantly more slowly. In conclusion, the SCG assay and the iCFA identified subpopulations of cells that were unaffected by ICI D1694. Although these cells represented only a small proportion of the total cell population, this phenomenon of heterogeneity in response to ICI D1694 might limit its therapeutic efficacy.

Cell Division↗
PubMedDate not supplied

Cellular heterogeneity in normal human urothelium: quantitative studies of lectin binding.

A panel of 10 FITC-labelled lectins (MPA, PNA, ConA, DBA, SBA, RCA-120, WGA, UEA, GS-I, GS-II+) was applied to cryosections of seven specimens of normal urothelium. Seven of the lectins (MPA, ConA, RCA, WGA, UEA, GS-I and GS-II) showed a pattern of increasing fluorescence intensity from basal to superficial cells of the urothelium whereas PNA, DBA and SBA showed more uniform binding throughout the urothelium. Urothelial cell suspensions labelled with FITC-lectins were studied by flow cytometry to quantify the variation in binding to different cells types. Three cellular subpopulations were identified in normal urothelium on the basis of their optical properties. Fluorescence intensity due to specific lectin binding was then measured separately for each subpopulation. Although there was some variation among individual cases, a general pattern emerged in this small series. WGA, RCA, and GS-II bind in large quantities to all urothelial cells while PNA, SBA, ConA and DBA show little binding. MPA, RCA, UEA and GS-I showed the most marked increase in fluorescence intensity from basal to superficial cells as observed microscopically and quantified by flow cytometry.

Adult↗
PubMed1997

Actin isoform expression, cellular heterogeneity, and contractile function in smooth muscle.

Smooth muscles express four isoforms of actin: two smooth muscle specific and two cytoplasmic isoforms typically associated with the cytoskeleton of nonmuscle cells. The relative amounts of each isoform expressed and the total actin content vary with smooth muscle type, with development, in cell culture, pathologically, and potentially between cells within tissues. Our objective was to determine whether actin isoforms contribute to contractile diversity. Functional diversity may be the result of differences in the kinetics of the cross-bridge interaction with thin filaments consisting of different actin isoforms or of the fraction of cross-bridges developing force in series or in parallel resulting from thin filaments of different lengths. Our hypothesis was that functionally significant differences in actin isoform properties (i.e., myosin interactions or properties affecting thin filament lengths) would require isoform segregation into distinct populations of thin filaments within cellular domains (e.g., cytoskeletal and contractile) or in phenotypically different cells. We tested this hypothesis by determining the smooth muscle alpha- and gamma-actin and cytoplasmic beta-actin isoform composition of native thin filaments isolated from swine stomach using isoform-specific antibodies linked to colloidal gold beads with protein A (the cytoplasmic lambda-isoactin content was below the detection limit). The lengths of individual thin filaments were also estimated from electron micrographs. A statistically uniform population of thin filaments was observed consisting of randomly copolymerized isoactins in each filament with the same isoform proportions as the tissue. The average thin filament length was 1.35 +/- 0.06 (SEM) microns. These results, together with other studies, suggest that actin isoforms are functionally equivalent. The data imply that the high stress-generating and shortening capacities of smooth muscles are not primarily due to long thin filament to thick filament length ratios compared with striated muscles.

Actins↗