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PubMed2004

Cytopenias in HIV infection: mechanisms and alleviation of hematopoietic inhibition.

Hematopoietic abnormalities including anemia, cytopenias, and alterations of the stem cell plasticity in the bone marrow microenvironment commonly occur in HIV infected patients. These observations suggest that HIV-1 infection may affect processes important during early stages of hematopoiesis or stem cell differentiation. Hematopoietic abnormalities may be caused by altered stem cell differentiation possibly due to abnormal lineage specific expression of certain cellular genes such as cytokines relevant to hematopoiesis. These cytokines could affect regulatory signals important in hematopoiesis. However, in HIV infected individuals, it is not only the virus but also the highly active antiretroviral therapy (HAART) that both contribute to persistent hematopoietic suppression and ensuing cytopenias. Even if a lowering of HIV replication by HAART were to occur in infected individuals, prolonged HAART by itself and/or appearance of drug resistant mutants can contribute to hematopoietic suppression and resulting cytopenias. However, confounding factors such as opportunistic infections, immune mediated effects, or the consequences of prolonged physiological stress, which could contribute to decreased hematopoiesis in patients or other individuals, make the causative role of HIV in vivo, uncertain. The severe combined immunodeficient mouse transplanted with human fetal thymus and liver tissues (SCID-hu) is a small animal model which mimics HIV infection in humans, and is useful to determine the mechanisms of HIV-1 induced hematopoietic inhibition and development of drug therapies for interventions of stem cell differentiation. Further, SCID mouse serves as a useful small animal recipient of human progenitor cells and also allows us to study the differentiation of these cells in vivo. Results from our studies are expected to provide relief for HIV infected individuals from hematopoietic inhibition and ensuing cytopenias.

Animals↗
PubMed2001

[Migration of neocortical neuroblasts in the rat embryo following multidose X-ray irradiation].

The study was designed to examine the process of neuroblast migration in rat embryonic neocortex after multi-dose X-ray irradiation in summary doses of 25, 50 and 75 cGy from the prenatal ontogenesis d 6 to d 18. Average content of nerve cells in the urinary bladder wall, thickness of cellular layers of developing cortex and the state of radial gliocyte processes were assessed by histological methods. Suppression of neuroblast migration not associated with structural disturbances of radial glia was found. The changes named are obviously the result of disorders of functional activity of cells of microenvironment and neuroblasts.

Animals↗
PubMed2005

Thimerosal induces neuronal cell apoptosis by causing cytochrome c and apoptosis-inducing factor release from mitochondria.

There is a worldwide increasing concern over the neurological risks of thimerosal (ethylmercury thiosalicylate) which is an organic mercury compound that is commonly used as an antimicrobial preservative. In this study, we show that thimerosal, at nanomolar concentrations, induces neuronal cell death through the mitochondrial pathway. Thimerosal, in a concentration- and time-dependent manner, decreased cell viability as assessed by calcein-ethidium staining and caused apoptosis detected by Hoechst 33258 dye. Thimerosal-induced apoptosis was associated with depolarization of mitochondrial membrane, generation of reactive oxygen species, and release of cytochrome c and apoptosis-inducing factor (AIF) from mitochondria to cytosol. Although thimerosal did not affect cellular expression of Bax at the protein level, we observed translocation of Bax from cytosol to mitochondria. Finally, caspase-9 and caspase-3 were activated in the absence of caspase-8 activation. Our data suggest that thimerosal causes apoptosis in neuroblastoma cells by changing the mitochondrial microenvironment.

Animals↗
PubMed1993

Novel interactions between dermal dendrocytes and mast cells in human skin. Implications for hemostasis and matrix repair.

BACKGROUND: Dermal dendrocytes are a newly-recognized cell type in human skin. They express coagulation Factor XIIIa (FXIIIa), also known as fibrin stabilizing factor, and their number is increased in certain inflammatory dermatoses. Current dogma suggests that these recently described cells may represent a subset of antigen-presenting macrophages. The present study therefore was undertaken to examine further the phenotype and potential function of these novel cells. EXPERIMENTAL DESIGN: Conventional ultrastructure, single and dual label immunofluorescence and immunocytochemistry, confocal laser scanning microscopy, and immunoelectron microscopy were used to define structure and potential heterogeneity among dermal dendrocytes. Human neonatal foreskin organ culture exposed to mast cell secretagogues, inhibitors, and relevant recombinant cytokines (tumor necrosis factors alpha) was employed to gain insight into functional characteristics of FXIIIa expression. RESULTS: We found that dermal dendrocytes are phenotypically unique dermal cells, separate from conventional macrophages, with antigenic heterogeneity of FXIIIa and CD34 expression related to their microanatomical location in the dermis. Moreover, they express specialized membrane-matrix plaques that may stabilize their placement in various dermal strata. Finally, superficial subpopulations of dermal dendrocytes are closely-associated with mast cells and show enhanced FXIIIa expression in response to mast cell degranulation, an event that appears to result from liberation of mast cell tumor necrosis factor in the dendrocyte microenvironment. CONCLUSIONS: These new insights establish dermal dendrocytes as distinctive fixed skin cells with potential functional capacity for mast cell-dependent facilitation of fibrin cross-linking and matrix remodeling. These previously unrecognized phenotypic and functional characteristics of dermal dendrocytes therefore may be relevant to cellular interactions responsible for cutaneous wound healing and hemostasis.

Cell Communication↗
PubMed2006

Prostate cancer metastasis: role of the host microenvironment in promoting epithelial to mesenchymal transition and increased bone and adrenal gland metastasis.

BACKGROUND: The ARCaP cell line was established from the ascites fluid of a patient with metastatic prostate cancer. This study characterized the host microenvironmental role in cancer progression, epithelial to mesenchymal transition (EMT), and bone and adrenal metastasis in parental ARCaP and its derived cell subclones. METHODS: Cytogenetic profiles, growth, migration, invasion, cellular interaction, drug sensitivities, and gene expression of ARCaP cell subclones were compared. In vivo gene expression, behavior, and metastasis of ARCaP subclones were analyzed by serial intracardiac injections into SCID mice. RESULTS: ARCaP(E) cells, with cobblestone morphology, underwent EMT through cellular interaction with host bone and adrenal gland. Lineage-derived ARCaP(M) cells, with spindle-shape fibroblastic morphology, exhibited decreased cell adhesion and increased metastasis to bone and adrenal gland. Cytogenetic analyses of parental and ARCaP subclones confirmed their clonality. CONCLUSIONS: ARCaP uniquely models the molecular basis of prostate cancer bone and adrenal metastases and epithelial to mesenchymal transition.

Adenocarcinoma↗
PubMed2003

Mycobacterium tuberculosis growth at the cavity surface: a microenvironment with failed immunity.

Protective immunity against pulmonary tuberculosis (TB) is characterized by the formation in the lungs of granulomas consisting of macrophages and activated T cells producing tumor necrosis factor alpha and gamma interferon, both required for the activation of the phagocytes. In 90% of immunocompetent humans, this response controls the infection. To understand why immunity fails in the other 10%, we studied the lungs of six patients who underwent surgery for incurable TB. Histologic examination of different lung lesions revealed heterogeneous morphology and distribution of acid-fast bacilli; only at the surface of cavities, i.e., in granulomas with a patent connection to the airways, were there numerous bacilli. The mutation profile of the isolates suggested that a single founder strain of Mycobacterium tuberculosis may undergo genetic changes during treatment, leading to acquisition of additional drug resistance independently in discrete physical locales. Additional drug resistance was preferentially observed at the cavity surface. Cytokine gene expression revealed that failure to control the bacilli was not associated with a generalized suppression of cellular immunity, since cytokine mRNA was up regulated in all lesions tested. Rather, a selective absence of CD4(+) and CD8(+) T cells was noted at the luminal surface of the cavity, preventing direct T-cell-macrophage interactions at this site, probably allowing luminal phagocytes to remain permissive for bacillary growth. In contrast, in the perinecrotic zone of the granulomas, the two cell types colocalized and bacillary numbers were substantially lower, suggesting that in this microenvironment an efficient bacteriostatic or bactericidal phagocyte population was generated.

Adolescent↗
PubMed2003

Effects of membrane lipids on ion channel structure and function.

Biologic membranes are not simply inert physical barriers, but complex and dynamic environments that affect membrane protein structure and function. Residing within these environments, ion channels control the flux of ions across the membrane through conformational changes that allow transient ion flux through a central pore. These conformational changes may be modulated by changes in transmembrane electrochemical potential, the binding of small ligands or other proteins, or changes in the local lipid environment. Ion channels play fundamental roles in cellular function and, in higher eukaryotes, are the primary means of intercellular signaling, especially between excitable cells such as neurons. The focus of this review is to examine how the composition of the bilayer affects ion channel structure and function. This is an important consideration because the bilayer composition varies greatly in different cell types and in different organellar membranes. Even within a membrane, the lipid composition differs between the inner and outer leaflets, and the composition within a given leaflet is both heterogeneous and highly dynamic. Differential packing of lipids (and proteins) leads to the formation of microdomains, and lateral diffusion of these microdomains or "lipid rafts" serve as mobile platforms for the clustering and organization of bilayer constituents including ion channels. The structure and function of these channels are sensitive to specific chemical interactions with neighboring components of the membrane and also to the biophysical properties of their membrane microenvironment (e.g., fluidity, lateral pressure profile, and bilayer thickness). As specific examples, we have focused on the K+ ion channels and the ligand-gated nicotinicoid receptors, two classes of ion channels that have been well-characterized structurally and functionally. The responsiveness of these ion channels to changes in the lipid environment illustrate how ion channels, and more generally, any membrane protein, may be regulated via cellular control of membrane composition.

Ion Channels↗
PubMed2006

Cell labeling for magnetic resonance imaging with the T1 agent manganese chloride.

There is growing interest in using MRI to track cellular migration. To date, most work in this area has been performed using ultra-small particles of iron oxide. Immune cells are difficult to label with iron oxide particles. The ability of adoptively infused tumor specific T cells and N cells to traffic to the tumor microenvironment may be a critical determinant of their therapeutic efficacy. We tested the hypothesis that lymphocytes and B cells would label with MnCl2 to a level that would allow their detection by T1-weighted MRI. Significant signal enhancement was observed in human lymphocytes after a 1 h incubation with 0.05-1.0 mM MnCl2. A flow cytometry-based evaluation using propidium iodide and Annexin V staining showed that lymphocytes did not undergo apoptosis or necrosis immediately after and 24 h following a 1 h incubation with up to 1.0 mM MnCl2. Importantly, NK cells and cytotoxic T cells maintained their in vitro killing capacity after being incubated with up to 0.5 mM MnCl2. This is the first report to describe the use of MnCl2 to label lymphocytes. Our data suggests MnCl2 might be an alternative to iron oxide cell labeling for MRI-based cell migration studies.

Cell Movement↗
PubMed2005

Cell and tissue autofluorescence research and diagnostic applications.

Cells contain molecules, which become fluorescent when excited by UV/Vis radiation of suitable wavelength. This fluorescence emission, arising from endogenous fluorophores, is an intrinsic property of cells and is called auto-fluorescence to be distinguished from fluorescent signals obtained by adding exogenous markers. The majority of cell auto-fluorescence originates from mitochondria and lysosomes. Together with aromatic amino acids and lipo-pigments, the most important endogenous fluorophores are pyridinic (NADPH) and flavin coenzymes. In tissues, the extracellular matrix often contributes to the auto-fluorescence emission more than the cellular component, because collagen and elastin have, among the endogenous fluorophores, a relatively high quantum yield. Changes occurring in the cell and tissue state during physiological and/or pathological processes result in modifications of the amount and distribution of endogenous fluorophores and chemical-physical properties of their microenvironment. Therefore, analytical techniques based on auto-fluorescence monitoring can be utilized in order to obtain information about morphological and physiological state of cells and tissues. Moreover, auto-fluorescence analysis can be performed in real time because it does not require any treatment of fixing or staining of the specimens. In the past few years spectroscopic and imaging techniques have been developed for many different applications both in basic research and diagnostics.

Animals↗
PubMed2006

Structures of biologically active oxysterols determine their differential effects on phospholipid membranes.

Oxysterols, derivatives of cholesterol that contain a second oxygen moiety, are intermediates in cholesterol catabolism, regulators of lipid metabolism, and toxic sterols with proatherogenic effects. In model membranes, cholesterol and eight selected oxysterols were compared by fluorescence probe techniques that measure changes in bilayer order and phase behavior and by the formation of detergent-resistant membranes (DRM). The oxysterols were modified on the sterol nucleus or on the isooctyl side chain. The model membranes consisted of dipalmitoyl phosphatidylcholine (DPPC) and mixtures of dioleoyl phosphatidylcholine with DPPC and with sphingomyelin. The different oxysterols induced changes in membrane properties according to the differences in their structures. Whereas the effects of some oxysterols on membrane order, fluorescence probe microenvironment, and DRM formation were similar to those of cholesterol, others had little or no effect. An empirical correlation ranking the oxysterols by their ability to modify membrane biophysical properties when compared to cholesterol led to a significant structure/function relationship between the biophysical measurements and an important cellular phenomenon, apoptosis. 7beta-Hydroxycholesterol, which is the most cytotoxic of the eight selected oxysterols, was one of the least cholesterol-like with respect to modification of membrane properties. The results suggest that an underlying mechanism for oxysterol-induced apoptosis in cells, e.g., monocyte/macrophages, should include their biophysical effects on membranes, such as the regulation of the formation and composition of sterol-rich membrane domains.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed2004

Attenuation of the p53 response to DNA damage by high cell density.

The p53 tumor suppressor is critical for preventing cancer progression. Numerous observations suggest that p53 function can be modulated by the cells' microenvironment. We addressed specifically the impact of cell crowding on the induction of p53 by DNA damage. We report that cell crowding attenuates markedly p53 upregulation, transcriptional activation and subsequent p53-dependent apoptosis following exposure to genotoxic stress. The p53 protein remains short-lived in confluent cultures regardless of the extent of DNA damage, even though it undergoes efficient phosphorylation on the mouse equivalent of human p53 serine 15. This inhibitory effect of cell crowding is not a secondary consequence of density-dependent cell cycle arrest (contact inhibition). Microscopic examination indicates that dense cultures display prominent cadherin-mediated cell-cell junctions, and only poor cell-matrix focal adhesions, whereas sparse cells possess conspicuous matrix adhesions and essentially no cell-cell contacts. High-density cell culture might recapitulate the microenvironment of cells in a living organism, where the response of p53 to DNA damage is reported to be low in some organs and ages. The impact of cell density on p53 activation may have important bearings on the involvement of p53 in tumor suppression and the cellular response to anticancer therapy.

Animals↗
PubMed2006

Mammary stem cells and mammopoiesis.

The isolation and characterization of mammary stem cells is fundamental to understanding mammary gland development and tissue homeostasis as well as breast oncogenesis. Recent studies have led to the prospective isolation of pluripotential stem cells from the mouse mammary gland through the identification of specific cell-surface markers and transplantation of cells into the mammary stromal microenvironment. A single cell was sufficient to reconstitute a fully developed mammary gland in vivo, indicating that combinatorial activity between independent stem cells is not essential to generate an outgrowth. Here we review the characteristics of mouse mammary stem cells, their estrogen receptor status, and the potential cellular hierarchy that exists within the mammary gland.

Animals↗
PubMed2004

Distinct gene expression profiles in different B-cell compartments in human peripheral lymphoid organs.

BACKGROUND: There are three major B-cell compartments in peripheral lymphoid organs: the germinal center (GC), the mantle zone (MNZ) and the marginal zone (MGZ). Unique sets of B-cells reside in these compartments, and they have specific functional roles in humoral immune response. MNZ B cells are naive cells in a quiescent state and may participate in GC reactions upon proper stimulation. The adult splenic MGZ contains mostly memory B cells and is also known to provide a rapid response to particulate antigens. The GC B-cells proliferate rapidly and undergo selection and affinity maturation. The B-cell maturational process is accompanied by changes in the expression of cell-surface and intracellular proteins and requires signals from the specialized microenvironments. RESULTS: We performed laser microdissection of the three compartments for gene expression profiling by cDNA microarray. The transcriptional program of the GC was dominated by upregulation of genes associated with proliferation and DNA repair or recombination. The MNZ and MGZ showed increased expression of genes promoting cellular quiescence. The three compartments also revealed distinct repertoires of apoptosis-associated genes, chemokines and chemokine receptors. The MNZ and GC showed upregulation of CCL20 and CCL18 respectively. The MGZ was characterized by high expression of many chemokines genes e.g. CXCL12, CCL3, CCL14 and IFN-associated genes, consistent with its role in rapid response to infections. A stromal signature was identified including genes associated with macrophages or with synthesis of extracellular matrix and genes that influenced lymphocyte migration and survival. Differentially expressed genes that did not belong to the above categories include the well characterized BCL6 and CD10 and many others whose function is not known. CONCLUSIONS: Transcriptional profiling of B-cell compartments has identified groups of genes involved in critical molecular and cellular events that affect proliferation, survival migration, and differentiation of the cells. The gene expression study of normal B-cell compartments may additionally contribute to our understanding of the molecular abnormalities of the corresponding lymphoid tumors.

Apoptosis↗
PubMed2005

Asymmetric stem cell division and function of the niche in the Drosophila male germ line.

The balance between stem cell and differentiating cell populations is critical for the long-term maintenance of tissue renewal for cell types derived from adult stem cell lineages such as blood, skin, intestinal epithelium, and sperm. To keep this balance, stem cells have the potential to divide asymmetrically, producing one daughter cell that maintains stem cell identity and one daughter cell that initiates differentiation. In many adult stem cell systems, the maintenance, proliferation, and number of stem cells appear to be controlled by the microenvironment, or niche. The Drosophila male and female germ line provide excellent model systems in which to study asymmetric stem cell divisions within the stem cell niche. In addition to signals from the niche that specify stem cell self-renewal, the stem cells themselves have elaborate cellular mechanisms to ensure the asymmetric outcome of cell division.

Animals↗
PubMed2026

Spatial analysis reveals the evolving organization of IDH-mutant glioma.

Adult diffuse gliomas are composed of malignant cell states interwoven with the non-malignant brain microenvironment. Here, we combine spatial transcriptomics and spatial proteomics of isocitrate dehydrogenase (IDH)-mutant gliomas to define organizational principles across histological grades. In low-grade tumors, spatial organization is shaped by underlying brain anatomy. We identify a functional white-gray matter junction that restricts cortical invasion and is associated with marked changes in tumor composition and cellular phenotypes. This junction is preferentially traversed by oligodendrocyte progenitor (OPC)-like malignant cells, suggesting a role in tumor expansion. In contrast, tumors with intermediate histological features are largely disorganized, with few recurring interactions between cancer cell states and microenvironmental cell types. In high-grade tumors, hypoxia-associated structure emerges, resembling IDH-wild-type glioblastoma. Together, these findings reveal two independent axes of spatial organization-from anatomy-driven structure in low-grade tumors to hypoxia-driven organization in high-grade tumors-and establish a framework linking tumor grade to recurrent spatial interactions.

Isocitrate Dehydrogenase↗
PubMed2003

Tumor necrosis factor-alpha: molecular and cellular mechanisms in skeletal pathology.

Tumor necrosis factor-alpha (TNF) is one member of a large family of inflammatory cytokines that share common signal pathways, including activation of the transcription factor nuclear factor kappa B (Nf-kappa B) and stimulation of the apoptotic pathway. Data derived from early work supported a role for TNF as a skeletal catabolic agent that stimulates osteoclastogenesis while simultaneously inhibiting osteoblast function. The finding that estrogen deficiency was associated with increased production of cytokines led to a barrage of studies and lively debate on the relative contributions of TNF and other cytokines on bone loss, on the potential cell sources of TNF in the bone microenvironment, and on the mechanism of TNF action. TNF has a central role in bone pathophysiology. TNF is necessary for stimulation of osteoclastogenesis along with the receptor activator of Nf-kappa B ligand (RANKL). TNF also stimulates osteoblasts in a manner that hinders their bone-formative action. TNF suppresses recruitment of osteoblasts from progenitor cells, inhibits the expression of matrix protein genes, and stimulates expression of genes that amplify osteoclastogenesis. TNF may also affect skeletal metabolism by inducing resistance to 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) by a mechanism that extends to other members of the steroid hormone nuclear receptor family. Thus, TNF assails bone at many levels. This review will focus on the cellular and molecular mechanisms of TNF action in the skeleton that result in increased bone resorption and impaired formation. TNF and its signal pathway remains an important target for the development of new therapies for bone loss from osteoporosis and inflammatory arthritis.

Animals↗
PubMed2006

In vitro models of intestinal epithelial cell differentiation.

The intestinal epithelium is a particularly interesting tissue as (1) it is in a constant cell renewal from a stem cell pool located in the crypts which form, with the underlying fibroblasts, a stem cell niche and (2) the pluripotent stem cells give rise to four main cell types: enterocytes, mucus, endocrine, and Paneth cells. The mechanisms leading to the determination of phenotype commitment and cell-specific expressions are still poorly understood. Although transgenic mouse models are powerful tools for elucidating the molecular cascades implicated in these processes, cell culture approaches bring easy and elegant ways to study cellular behavior, cell interactions, and cell signaling pathways for example. In the present review, we will describe the major tissue culture technologies that allow differentiation of epithelial cells from undifferentiated embryonic or crypt cells. We will point to the necessity of the re-creation of a complex microenvironment that allows full differentiation process to occur. We will also summarize the characteristics and interesting properties of the cell lines established from human colorectal tumors.

Animal Testing Alternatives↗
PubMed2003

Axis of evil: molecular mechanisms of cancer metastasis.

Although the genetic basis of tumorigenesis may vary greatly between different cancer types, the cellular and molecular steps required for metastasis are similar for all cancer cells. Not surprisingly, the molecular mechanisms that propel invasive growth and metastasis are also found in embryonic development, and to a less perpetual extent, in adult tissue repair processes. It is increasingly apparent that the stromal microenvironment, in which neoplastic cells develop, profoundly influences many steps of cancer progression, including the ability of tumor cells to metastasize. In carcinomas, the influences of the microenvironment are mediated, in large part, by bidirectional interactions (adhesion, survival, proteolysis, migration, immune escape mechanisms lymph-/angiogenesis, and homing on target organs) between epithelial tumor cells and neighboring stromal cells, such as fibroblasts as well as endothelial and immune cells. In this review, we summarize recent advances in understanding the molecular mechanisms that govern this frequently lethal metastatic progression along an axis from primary tumor to regional lymph nodes to distant organ sites. Affected proteins include growth factor signaling molecules, chemokines, cell-cell adhesion molecules (cadherins, integrins) as well as extracellular proteases (matrix metalloproteinases). We then discuss promising new therapeutic approaches targeting the microenvironment. We note, however, that there is still too little knowledge of how the many events are coordinated and integrated by the cancer cell, with conspiratorial help by the stromal component of the host. Before drug development can proceed with a legitimate chance of success, significant gaps in basic knowledge need to be filled.

Cell Adhesion Molecules↗