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PubMed1997

Effect of chemotherapy for acute myelogenous leukemia on hematopoietic and fibroblast marrow progenitors.

Since reduced marrow cellularity and prolonged pancytopenia following autologous bone marrow transplantation (ABMT) have been frequently observed in patients with acute myelogenous leukemia (AML) included in the AML10 GIMEMA/EORTC trial, the question was raised to what extent hematopoietic and microenvironmental progenitor cells were involved in these patients. Marrow hematopoietic progenitors were investigated by a short-term methylcellulose assay quantitating multipotent CFU-Mix, erythroid BFU-E and granulocyte-macrophage CFU-GM, as well as a long-term assay quantitating long-term culture-initiating cells (LTC-IC). The marrow microenvironment was studied by evaluating the incidence of fibroblastoid progenitors (CFU-F) and the capacity of stromal layers to support allogeneic hematopoietic progenitors. As compared to normal controls (n = 57), AML patients (n = 26) showed a statistically significant reduction of the mean (+/-s.e.m.) number of CFU-Mix (5.3 +/- 0.6 vs 0.8 +/- 0.2, P < or = 0.0001), BFU-E (68 +/- 5 vs 20 +/- 4, P < or = 0.0001), CFU-GM (198 +/- 11 vs 144 +/- 15, P < or = 0.008), and LTC-IC (302 +/- 46 vs 50 +/- 8, P < or = 0.001). The mean (+/-s.e.m.) incidence of marrow CFU-F was not significantly reduced as compared to normal controls (48 +/- 6 vs 52 +/- 7, P < or = 0.73). Seventeen AML stromal layers were tested for their capacity to support the growth of allogeneic hematopoietic progenitors. Seven samples failed to support any progenitor cell growth, seven had a significantly lower supportive activity as compared to normal stromal layers (13 +/- 5 vs 249 +/- 56, P < or = 0.002), whereas three cultures could not be analyzed due to contamination. In conclusion, induction and consolidation regimens used in AML patients of the AML10 protocol induce a markedly defective in vitro growth of primitive hematopoietic progenitors and a severe functional defect of marrow stroma. The association of hematopoietic with microenvironmental damage might play a key role in the delayed hematopoietic regeneration observed following ABMT in patients of the AML10 trial.

Adolescent↗
PubMed2003

GM-CSF-secreting melanoma vaccines.

The development of biochemical and genetic schemes to characterize cancer antigens led to the recognition that malignant melanoma frequently evokes a host response. While the generation of brisk T-cell infiltrates in early stage disease is correlated with prolonged survival, host reactions in most cases are insufficient to impede tumor progression. One variable that may limit the potency of the host response against nascent melanoma is the mixture of cytokines present in the tumor microenvironment. In a murine melanoma model, we identified granulocyte-macrophage colony stimulating factor (GM-CSF) as the most potent molecule for augmenting tumor immunity following gene transfer into melanoma cells. Vaccination with irradiated melanoma cells engineered to secrete GM-CSF enhances host responses through improved tumor antigen presentation by recruited dendritic cells and macrophages. Melanoma-specific CD4(+) and CD8(+) T-cells, CD1d-restricted NKT-cells, and antibodies mediate tumor rejection. Initial testing of this immunization strategy in patients with metastatic melanoma revealed the consistent induction of cellular and humoral antitumor responses that provoked the extensive necrosis of distant metastases without significant toxicity.

Adenosine Triphosphatases↗
PubMed2006

Photophysics of Clomeleon by FLIM: discriminating excited state reactions along neuronal development.

In this work, fluorescence lifetime imaging microscopy in the time domain was used to study the fluorescence dynamics of ECFP and of the ratiometric chloride sensor Clomeleon along neuronal development. The multiexponential analysis of fluorophores combined with the study of the contributions of the individual lifetimes (decay-associated spectra) was used to discriminate the presence of energy transfer from other excited state reactions. A characteristic change of sign of the pre-exponential factors of lifetimes from positive to negative near the acceptor emission maxima was observed in presence of energy transfer. By fluorescence lifetime imaging microscopy, we could show that the individual conformations of CFP display differential quenching properties depending on their microenvironment. Suitability of Clomeleon as an optical indicator to obtain a direct readout of the intracellular chloride concentrations in living cells was verified by steady-state and time-resolved spectroscopy. The simultaneous study of the photophysical properties of Clomeleon, the calcium indicator Cameleon, and ECFP with neuronal development provided a kinetic model for the mechanism when competitive quenching effects as well as energy transfer occur in the same molecule. Simultaneous analysis of donor and acceptor kinetics was necessary to discriminate Försters resonance energy transfer along neuronal development due to the different cellular effects involved.

Animals↗
PubMed1995

Heparan sulfate initiates signals in murine macrophages leading to divergent biologic outcomes.

We have previously shown that the interaction of heparan sulfate (HS), a constituent of cell surfaces and extracellular matrices, with murine macrophages causes activation of the macrophages leading to the production of cytokines and PGE2 and profound changes in the cellular immune responses triggered by the macrophages. Here we describe the molecular mechanisms that underlie these immunoregulatory changes. We demonstrate that HS delivers signals to macrophages through at least two pathways, one involving the activation of a tyrosine kinase and of nuclear factor-KB, and the other involving the activation of protein kinase C and the elevation of intracellular calcium. The former pathway is associated with the production of IL-6, and the latter pathway is associated with the production of PGE2. Our findings suggest a model in which components of the microenvironment, such as HS, may determine the functional state of an APC, thereby modifying immune responses.

Animals↗
PubMed2006

A transient microenvironment loaded mainly with macrophages in the early developing human pancreas.

We have previously shown that the human developing pancreas, as a tissue under construction and remodeling, is composed of epithelial ducts and differentiated endocrine cells surrounded by mesenchyme. The physiologic importance of resident tissue leukocytes, expected to enter through the mesenchyme in remodeling functions, prompted us to investigate human developing pancreases for the presence of leukocyte lineages and for expression of cytokines and receptors involved in their recruitment and differentiation. Immunohistochemistry studies were performed on 69 human, paraffin-embedded pancreases at 6-12 weeks of development (WD). Cytokines and receptor transcripts were monitored by reverse transcription (RT)-PCR, by immunohistochemistry when antibodies were available or by in situ hybridization (ISH). We show that numerous cells expressing CD45RA, HLADR and CD68 antigens are cellular components of the mesenchyme of all the pancreases at 6-12 WD. So-called constitutive chemokines (SLC (CCL19), stromal-derived factor 1 (SDF1) (CXCL12)) and a macrophage-specific growth/survival factor, colony-stimulating factor 1 (CSF1), were detected in epithelial duct cells. Both epithelial and mesenchymal cells expressed chemokine receptors, suggesting a role in leukocyte recruitment and possibly in early pancreatic development. In conclusion, we demonstrated the presence of CD45RA resident leukocyte-derived lineages, mostly macrophages, in the early human pancreatic mesenchyme. These cells may have migrated in the tissue through the vascular system, attracted by constitutively expressed chemokines, and locally surviving through CSF1 signaling. The role of macrophages in epithelium/mesenchyme interaction-mediated pancreatic development remains to be demonstrated.

Biomarkers↗
PubMed2006

New weapons in the war on worms: identification of putative mechanisms of immune-mediated expulsion of gastrointestinal nematodes.

Parasitic nematode infections of humans and livestock continue to impose a significant public health and economic burden worldwide. Murine models of intestinal nematode infection have proved to be relevant and tractable systems to define the cellular and molecular basis of how the host immune system regulates resistance and susceptibility to infection. While susceptibility to chronic infection is propagated by T helper cell type 1 cytokine responses (characterised by production of IL-12, IL-18 and interferon-gamma), immunity to intestinal-dwelling adult nematode worms is critically dependent on a type 2 cytokine response (controlled by CD4+T helper type 2 cells that secrete the cytokines IL-4, IL-5, IL-9 and IL-13). However, the immune effector mechanisms elicited by type 2 cytokines in the gut microenvironment that precipitate worm expulsion have remained elusive. This review focuses on new studies that implicate host intestinal epithelial cells as one of the dominant immune effector cells against this group of pathogens. Specifically, three recently identified type 2 cytokine-dependent pathways that could offer insights into the mechanisms of expulsion of parasitic nematodes will be discussed: (i) the intelectins, a new family of galactose-binding lectins implicated in innate immunity, (ii) the resistin-like molecules, a family of small cysteine-rich proteins expressed by multiple cell types, and (iii) cytokine regulation of intestinal epithelial cell turnover. Identifying how the mammalian immune response fights gastrointestinal nematode infections is providing new insights into host protective immunity. Harnessing these discoveries, coupled with identifying what the targets of these responses are within parasitic nematodes, offers promise in the design of a new generation of anti-parasitic drugs and vaccines.

Animals↗
PubMed2005

Tuberculosis - metabolism and respiration in the absence of growth.

Human tuberculosis is a complex disease caused by bacterial populations that are located in discrete lesions (microenvironments) in a single host. Some of these microenvironments are conducive to replication, whereas others restrict bacterial growth without necessarily sterilizing the infecting microorganisms. The physical and biochemical milieu in these lesions is poorly defined. None of the existing animal models for tuberculosis (except perhaps non-human primates) reproduce the diversity of disease progression that is seen in humans. Nonetheless, transcriptomics and studies using bacterial mutants have led to testable hypotheses about metabolic functions that are essential for viability in the absence of replication. A complete picture of bacterial metabolism must balance reducing equivalents while maintaining an energized membrane and basic cellular processes.

Adaptation, Physiological↗
PubMed2001

Topics in bone marrow biopsy pathology: role of marrow topography in myelodysplastic syndromes and evaluation of post-treatment and post-bone marrow transplant biopsies.

The role of bone marrow biopsy is expanding. Bone marrow biopsy is considered a "gold standard" for assessing cellularity and infiltrative process. More recently, biopsies are increasingly used for immunohistochemical stains and molecular studies such as in situ hybridization and laser microdissection, further augmenting morphologic interpretation. Biopsies are playing a greater role in early diagnosis of myelodysplastic syndromes (MDS). Both primary and secondary MDS are increasing (5% to 12%), and can present a significant challenge in early diagnosis. Present MDS diagnostic criteria are based purely on marrow aspirate smears, peripheral blood smears, and ancillary studies, and may not be adequate in some instances. With the current understanding of marrow topography and hematopoietic microenvironment, bone marrow biopsies are greatly useful in early diagnosis and grading of MDS. Marrow biopsies also are helpful in evaluation of postchemotherapy and post-bone marrow transplant patients. Assessment of topographic alteration and certain corroborating immunohistochemical and molecular studies can only be performed on bone marrow biopsies, and these ancillary studies will contribute significantly to the understanding of hematopoietic disorders. Bone marrow biopsy, in conjunction with other modalities such as flow cytometry, will play a significant role in diagnostic hematopathology. Ann Diagn Pathol 5:110-120, 2001.

Biopsy↗
PubMed2001

Induction of TAK (cyclin T1/P-TEFb) in purified resting CD4(+) T lymphocytes by combination of cytokines.

Combinations of cytokines are known to reactivate transcription and replication of latent human immunodeficiency virus type 1 (HIV-1) proviruses in resting CD4(+) T lymphocytes isolated from infected individuals. Transcription of the HIV-1 provirus by RNA polymerase II is strongly stimulated by the viral Tat protein. Tat function is mediated by a cellular protein kinase known as TAK (cyclin T1/P-TEFb) that is composed of Cdk9 and cyclin T1. We have found that treatment of peripheral blood lymphocytes and purified resting CD4(+) T lymphocytes with the combination of interleukin-2 (IL-2), IL-6, and tumor necrosis factor alpha resulted in an increase in Cdk9 and cyclin T1 protein levels and an increase in TAK enzymatic activity. The cytokine induction of TAK in resting CD4(+) T lymphocytes did not appear to require proliferation of lymphocytes. These results suggest that induction of TAK by cytokines secreted in the microenvironment of lymphoid tissue may be involved in the reactivation of HIV-1 in CD4(+) T lymphocytes harboring a latent provirus.

CD4-Positive T-Lymphocytes↗
PubMed2006

Inhibition of transforming growth factor-beta1 signaling attenuates ataxia telangiectasia mutated activity in response to genotoxic stress.

Ionizing radiation causes DNA damage that elicits a cellular program of damage control coordinated by the kinase activity of ataxia telangiectasia mutated protein (ATM). Transforming growth factor beta (TGFbeta)-1, which is activated by radiation, is a potent and pleiotropic mediator of physiologic and pathologic processes. Here we show that TGFbeta inhibition impedes the canonical cellular DNA damage stress response. Irradiated Tgfbeta1 null murine epithelial cells or human epithelial cells treated with a small-molecule inhibitor of TGFbeta type I receptor kinase exhibit decreased phosphorylation of Chk2, Rad17, and p53; reduced gammaH2AX radiation-induced foci; and increased radiosensitivity compared with TGFbeta competent cells. We determined that loss of TGFbeta signaling in epithelial cells truncated ATM autophosphorylation and significantly reduced its kinase activity, without affecting protein abundance. Addition of TGFbeta restored functional ATM and downstream DNA damage responses. These data reveal a heretofore undetected critical link between the microenvironment and ATM, which directs epithelial cell stress responses, cell fate, and tissue integrity. Thus, Tgfbeta1, in addition to its role in homoeostatic growth control, plays a complex role in regulating responses to genotoxic stress, the failure of which would contribute to the development of cancer; conversely, inhibiting TGFbeta may be used to advantage in cancer therapy.

Activin Receptors, Type I↗
PubMed2006

Indirect effects of leptin receptor deficiency on lymphocyte populations and immune response in db/db mice.

Leptin-deficient ob/ob and leptin receptor (Ob-rb)-deficient db/db mice display a marked thymic atrophy and exhibit defective immune responses. Lymphocytes express leptin receptors and leptin exerts direct effects on T cells in vitro. In addition, ob/ob and db/db mice display multiple neuroendocrine and metabolic defects, through which leptin deficiency may indirectly affect the immune system in vivo. To study the relative contributions of direct and indirect effects of leptin on the immune system in a normal environment, we generated bone marrow chimeras (BMCs) by transplantation of leptin receptor-deficient db/db, or control db/+, bone marrow cells into wild-type (WT) recipients. The size and cellularity of the thymus, as well as cellular and humoral immune responses, were similar in db/db to WT and db/+ to WT BMCs. The immune phenotype of db/db mice is thus not explained by a cell autonomous defect of db/db lymphocytes. Conversely, thymus weight and cell number were decreased in the reverse graft setting in WT to db/db BMCs, indicating that expression of the leptin receptor in the environment is important for T cell development. Finally, normal thymocyte development occurred in fetal db/db thymi transplanted into WT hosts, indicating that direct effects of leptin are not required locally in the thymic microenvironment. In conclusion, direct effects of leptin on bone marrow-derived cells and on thymic stromal cells are not necessary for T lymphocyte maturation in normal mice. In contrast, leptin receptor deficiency affects the immune system indirectly via changes in the systemic environment.

Animals↗
PubMed2007

S100B expression defines a state in which GFAP-expressing cells lose their neural stem cell potential and acquire a more mature developmental stage.

During the postnatal development, astrocytic cells in the neocortex progressively lose their neural stem cell (NSC) potential, whereas this peculiar attribute is preserved in the adult subventricular zone (SVZ). To understand this fundamental difference, many reports suggest that adult subventricular GFAP-expressing cells might be maintained in immature developmental stage. Here, we show that S100B, a marker of glial cells, is absent from GFAP-expressing cells of the SVZ and that its onset of expression characterizes a terminal maturation stage of cortical astrocytic cells. Nevertheless, when cultured in vitro, SVZ astrocytic cells developed as S100B expressing cells, as do cortical astrocytic cells, suggesting that SVZ microenvironment represses S100B expression. Using transgenic s100b-EGFP cells, we then demonstrated that S100B expression coincides with the loss of neurosphere forming abilities of GFAP expressing cells. By doing grafting experiments with cells derived from beta-actin-GFP mice, we next found that S100B expression in astrocytic cells is repressed in the SVZ, but not in the striatal parenchyma. Furthermore, we showed that treatment with epidermal growth factor represses S100B expression in GFAP-expressing cells in vitro as well as in vivo. Altogether, our results indicate that the S100B expression defines a late developmental stage after which GFAP-expressing cells lose their NSC potential and suggest that S100B expression is repressed by adult SVZ microenvironment.

Animals↗
PubMedDate not supplied

Thrombospondin-1 as an endogenous inhibitor of angiogenesis and tumor growth.

Thrombospondin-1 (TSP-1) is a matricellular glycoprotein that influences cellular phenotype and the structure of the extracellular matrix. These effects are important components of the tissue remodeling that is associated with angiogenesis and neoplasia. The genetic mutations in oncogenes and tumor suppressor genes that occur within tumor cells are frequently associated with decreased expression of TSP-1. However, the TSP-1 that is produced by stromal fibroblasts, endothelial cells and immune cells suppresses tumor progression. TSP-1 inhibits angiogenesis through direct effects on endothelial cell migration and survival and through indirect effects on growth factor mobilization. TSP-1 that is present in the tumor microenvironment also acts to suppress tumor cell growth through activation of transforming growth factor beta in those tumor cells that are responsive to TGF beta. In this review, the molecular basis for the role of TSP-1 in the inhibition of tumor growth and angiogenesis is summarized.

Amino Acid Sequence↗
PubMed1987

Determination and morphogenesis in the sea urchin embryo.

The study of the sea urchin embryo has contributed importantly to our ideas about embryogenesis. This essay re-examines some issues where the concerns of classical experimental embryology and cell and molecular biology converge. The sea urchin egg has an inherent animal-vegetal polarity. An egg fragment that contains both animal and vegetal material will produce a fairly normal larva. However, it is not clear to what extent the oral-aboral axis is specified in embryos developing from meridional fragments. Newly available markers of the oral-aboral axis allow this issue to be settled. When equatorial halves, in which animal and vegetal hemispheres are separated, are allowed to develop, the animal half forms a ciliated hollow ball. The vegetal half, however, often forms a complete embryo. This result is not in accord with the double gradient model of animal and vegetal characteristics that has been used to interpret almost all defect, isolation and transplantation experiments using sea urchin embryos. The effects of agents used to animalize and vegetalize embryos are also due for re-examination. The classical animalizing agent, Zn2+, causes developmental arrest, not expression of animal characters. On the other hand, Li+, a vegetalizing agent, probably changes the determination of animal cells. The stability of these early determinative steps may be examined in dissociation-reaggregation experiments, but this technique has not been exploited extensively. The morphogenetic movements of primary mesenchyme are complex and involve a number of interactions. It is curious that primary mesenchyme is dispensable in skeleton formation since in embryos devoid of primary mesenchyme, the secondary mesenchyme cells will form skeletal elements. It is likely that during its differentiation the primary mesenchyme provides some of its own extracellular microenvironment in the form of collagen and proteoglycans. The detailed form of spicules made by primary mesenchyme is determined by cooperation between the epithelial body wall, the extracellular material and the inherent properties of primary mesenchyme cells. Gastrulation in sea urchins is a two-step process. The first invagination is a buckling, the mechanism of which is not understood. The secondary phase in which the archenteron elongates across the blastocoel is probably driven primarily by active cell repacking. The extracellular matrix is important for this repacking to occur, but the basis of the cellular-environmental interaction is not understood.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

Regulatory role of osteogenic growth peptide in proliferation, osteogenesis, and hemopoiesis.

Bone marrow regeneration after injury is preceded by local and systemic osteogenic reactions. Recently, an osteogenic growth peptide was characterized in the regenerating marrow. The osteogenic growth peptide also is abundant in normal serum where it is markedly and transiently increased after marrow injury. This increase and the osteogenic growth peptide-induced stimulation of bone formation in vivo suggest a role for this peptide in mediating the systemic osteogenic response. In vitro, the osteogenic growth peptide is an autocrine mitogen for osteoblastic and fibroblastic cells. It also stimulates alkaline phosphatase activity and matrix mineralization. The serum osteogenic growth peptide is downregulated in osteoporotic ovariectomized mice. The osteogenic growth peptide levels as well as the bone loss, tetracycline uptake, and serum osteocalcin are reversed by exogenously administered osteogenic growth peptide. In normal mice, the osteogenic growth peptide increases white blood cell counts and total femoral bone marrow cellularity. These increases include all the hemopoietic lineages. When given to mice for 1 week before ablative radiotherapy and bone marrow transplantation, synthetic osteogenic growth peptide stimulates the bone marrow transplant engraftment; optimal osteogenic growth peptide doses doubled the survival rate. These data indicate that osteogenic growth peptide has an important role in the pathogenesis and treatment of systemic bone loss and provide a basis for further development of an antiosteoporotic osteogenic growth peptide therapy. It is suggested also that the osteogenic growth peptide promotes hemopoiesis secondary to the stimulation of the stromal (particularly osseous) microenvironment.

Animals↗
PubMed1990

Cellular expression of lymphocyte function associated antigens and the intercellular adhesion molecule-1 in normal tissue.

A detailed immunohistological analysis of normal tissues for the distribution of lymphocyte function-associated antigens (LFA) and the intercellular adhesion molecule-1 (ICAM-1) showed several hitherto unrecognised patterns of LFA-3 and ICAM-1 expression. The widespread, but not ubiquitous, distribution of LFA-3 contrasted with the more restricted distribution of ICAM-1. Among epithelial cells, all tissues which were ICAM-1 positive were also LFA-3 positive with the single exception that thymic cortical epithelium, in contrast to previous reports, expressed only ICAM-1. It was striking that LFA-3 molecules were absent in some tissues which are considered to be sites of immunological privilege (such as brain and testis), suggesting an additional mechanism by which these microenvironments maintain immunological autonomy. Furthermore, the unexpected finding that LFA-3 is strongly expressed on intercalated discs of cardiac muscle may possibly be related to a non-immune function, or indicate a structurally similar epitope expressed by an unrelated molecule within this tissue.

Antigens, Surface↗
PubMed2000

Flow cytometry analysis of atherosclerotic plaque cells from human carotids: a validation study.

BACKGROUND: Atherosclerotic plaques are heterogeneous vascular lesions. Changes in cell plaque composition are fundamental events inside the plaque microenvironment that are strictly related to the clinical outcome of these lesions (organ damage). The knowledge of these modifications may help to better understand the pathophysiological mechanisms of atherosclerosis. METHODS: We report on a flow cytometry method to characterize and quantify the cell subpopulations in human atherosclerotic plaques. Cells were obtained from endarterectomy specimens after collagenase digestion. Both surface and intracytoplasmic antigens were labeled. RESULTS: Our data demonstrated that the method we described allowed the characterization of cell populations that compose the atherosclerotic plaque, avoiding contamination by tunica media smooth muscle cells and the noise of cellular debris. Moreover this validation study showed that about 50% of cells in the atherosclerotic plaques are inflammatory mononuclear cells (T lymphocytes and monocytes/macrophages). CONCLUSIONS: Reproducible quantitative methods for cell population characterization may increase the understanding of pathophysiological mechanisms responsible for plaque progression. The methodology herein described gave us the possibility of quickly calculating the relative amount of each cell population and studying both surface and intracellular markers to analyze the functional stage of the cells. The clinical correlation was not assessed in the present study, because we used a small patient group to validate the method, but should be the subject of further analyses in a larger patient population.

Actins↗
PubMed1997

Factors affecting aminolaevulinic acid-induced generation of protoporphyrin IX.

Photodynamic therapy (PDT) may cause tumour cell destruction by direct toxicity or by inducing cellular hypoxia as a result of microcirculatory shutdown. Aminolaevulinic acid (ALA) causes cellular accumulation of protoporphyrin IX (PPIX) in cells exposed to it in excess. PPIX can be used as a photosensitizer for PDT. Microcirculatory shutdown may be induced by toxicity to the endothelial and vascular smooth muscle (VSM) cells or by release of vasoactive substances. We have studied whether PPIX is produced by endothelial, VSM and tumour cells on exposure to ALA and whether these cell lines are directly damaged by PDT in vitro. Tumour endothelial cells are angiogenic and we have, therefore, investigated the effect of cellular proliferation rates on PPIX generation. Tumour cells generate more PPIX intracellularly than the non-neoplastic cell lines studied and are correspondingly more sensitive to PDT-induced cytotoxicity. Endothelial cells are sensitive to PDT-induced cytotoxicity and accumulate between 1.5 and four times more PPIX when proliferating (as during tumour-induced angiogenesis) than when quiescent. We conclude that PPIX-mediated PDT may exert some of its effects on the microcirculation of treated tissues by direct toxicity to endothelial and VSM cells, and that this toxicity may be enhanced in the tumour microenvironment.

Aminolevulinic Acid↗