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PubMed2006

Signaling pathways in self-renewing hematopoietic and leukemic stem cells: do all stem cells need a niche?

Many adult tissue stem cells, such as the cells of the hematopoietic system, gastrointestinal epithelium, brain, epidermis, mammary gland and lung have now been identified, all of them fulfilling a crucial role in supplying organisms with mature cells during normal homeostasis as well as in times of tissue generation or repair. Two unique features characterize adult stem cells: the ability to generate new pluripotent stem cells (to self-renew) and the ability to give rise to differentiated progeny that has lost its self-renewal capacity. Our understanding of the mechanisms that determine whether, where and when a stem cell will self-renew or differentiate is still limited, but recent advances have indicated that the stem cell microenvironment, or niche, provides essential cues that direct these cell fate decisions. Moreover, loss of control over these cell fate decisions might lead to cellular transformation and cancer. This review addresses the current understandings of the molecular mechanisms that regulate hematopoietic stem cell self-renewal in the niche and how leukemic transformation might change the dependency of leukemic stem cells on their microenvironment for self-renewal and survival.

Animals↗

PubMedDate not supplied

On the origin of intracellular compartmentation and organized metabolic systems.

The history of the development of the ideas and research of organized metabolic systems during last three decades is shortly reviewed. The cell cytoplasm is crowded with solutes, soluble macromolecules such as enzymes, nucleic acids, structural proteins and membranes. The high protein density within the large compartments of the cells predominantly determines the major characteristics of cellular environment such as viscosity, diffusion and inhomogeneity. The fact that the solvent viscosity of cytoplasm is not substantially different from the water is explained by intracellular structural heterogeneity: the intrinsic macromolecular density is relatively low within the interstitial voids in the cell because many soluble enzymes are apparently integral parts of the insoluble cytomatrix and are not distributed homogeneously. The molecular crowding and sieving restrict the mobility of very large solutes, binding severely restrict the mobility of smaller solutes. One of consequence of molecular crowding and hindered diffusion is the need to compartmentalize metabolic pathway to overcome diffusive barriers. Although the movement of small molecules is slowed down in the cytoplasm, the metabolism can successfully proceed and even be facilitated by metabolite channeling which directly transfers the intermediate from one enzyme to an adjacent enzyme without the need of free aqueous-phase diffusion. The enhanced probability for intermediates to be transferred from one active site to the other by sequential enzymes requires stable or transient interactions of the relevant enzymes, which associate physically in non-dissociable, static multienzyme complexes--metabolones, particles containing enzymes of a part or whole metabolic systems. Therefore, within the living cell the metabolism depends on the structural organization of enzymes forming microcompartments. Since cells contain many compartments and microenvironments, the measurement of the concentration of metabolites in whole cells or tissues gives an average cellular concentration and not that which is actually sensed by the active site of a specific enzyme. Thus, the microcompartmentation could provide a mechanism which can control metabolic pathways. Independently and in parallel to the developments described above, the ideas of compartmentation came into existence from the necessity to explain important physiological phenomena, in particular in heart research and in cardiac electrophysiology. These phenomena demonstrated the physiological importance of the biophysical and biochemical mechanisms described in this review.

Cell Compartmentation↗

PubMed1993

Elevated levels of heme oxygenase-1 activity and mRNA in peripheral blood adherent cells of acquired immunodeficiency syndrome patients.

Patients with the acquired immunodeficiency syndrome (AIDS) commonly develop hematological abnormalities, including anemia, leukopenia, and thrombocytopenia. Heme synthesis and heme degradation are critical to the maintenance of cellular heme homeostasis and to hematopoietic differentiation. We examined heme oxygenase activity and expression of the heme oxygenase gene in adherent cells (monocytes-macrophages) obtained from the peripheral blood of AIDS patients and normal controls. Heme oxygenase activity in normal control cells was 43 +/- 16 pmol bilirubin formed/4 x 10(5) cells/hr as compared to 133 +/- 30 pmol bilirubin formed/4 x 10(5) cells/hr in the AIDS patients. Via blot hybridization analysis with human heme oxygenase cDNA, heme oxygenase mRNA levels in cells of the normal and the AIDS patients were compared. Total RNA from normal cells displayed only weak hybridization with the cDNA probe. In contrast, cells from peripheral blood of the AIDS patients displayed marked increases over normal levels in heme oxygenase mRNA. Heme oxygenase activity could be substantially suppressed by the competitive inhibitor of the enzyme, Sn-mesoporphyrin. Elevated heme oxygenase activity in cells of AIDS patients could produce a decrease in cellular heme needed for transductional signalling for the growth factor network, which regulates the hematopoietic microenvironment, and for other metabolic purposes. Suppression of heme catabolism by inhibitors of this enzyme may thus be useful in potentiating erythropoietic responses in this disorder.

Acquired Immunodeficiency Syndrome↗

PubMed1993

Metabolism of different adipose tissues in vivo in the rat.

To explore regional differences in triglyceride retention in white adipose tissues of growing male rats, the mass of adipocytes from epididymal, retroperitoneal, inguinal, and mesenteric tissues were followed with time. In order to attempt to explain regional differences, adipose tissue metabolism was studied in vivo and in vitro. (U-14C) oleic acid in sesame oil was given by gastric gavage to conscious male and female rats, and accumulation and half-life of radioactivity measured. Lipoprotein lipase activity and lipolysis were studied in vitro. Adipocyte triglyceride mass increased linearly in all the depots during 4 months of observation.The increase in mass was more pronounced in retroperitoneal (0.31 microg) and epididymal (0.30 microg) than in mesenteric (0.11 microg) or inguinal (0.05 microg) adipocytes. In the fed state label from (U-14C) oleic acid first increased with time in liver, muscle, and adipose tissues. In the liver radioactivity peaked at 4 hours, and was not measurable in either liver or muscle after a time point between 24 hours to 1 week. In contrast label continued to increase in adipose tissues up to about 16 hours to 24 hours, suggesting transfer of label by recirculation from liver and muscle to adipose tissues. Thereafter the radioactivity decreased. When expressed per adipocyte uptake of label was not significantly different between white adipose tissues. The rate of decrease between 7 days and 4 months was, however, more rapid in mesenteric and inguinal than, particularly, epididymal, and, probably, retroperitoneal adipocytes. These results were partly parallel to in vitro data on lipoprotein lipase activity, which was not different between depots, and the rate of lipolysis, which was higher in mesenteric than other adipocytes. These results suggest that differences in weight increase of adipose tissue regions are due mainly to differences in the rate of mobilization of adipocyte triglycerides. When expressed per gram triglyceride, uptake and mobilization of label were clearly more rapid in mesenteric than other white adipose tissues. This is probably explained by a combination of a higher adipocyte density plus the metabolic characteristics of adipocytes in this depot. Since mesenteric adipose tissue is smaller than the other depots studied, the absolute contribution of this tissue to the energy supply of the body is probably not different from that of other adipose tissues, however. A large uptake and short half life was observed in interscapular adipose tissue. This region contains brown adipocytes, and the results therefore suggest that lipid uptake for thermogenic purposes is of a considerable magnitude. It was concluded that among white adipose tissues, the mesenteric tissue has a rapid turnover of triglyceride. This is probably due to a combination of a high density and specific metabolic characteristics of these adipocytes. Factors in the microenvironment of adipocytes probably contribute to the high turnover either directly, or by modification of cellular characteristics.

Abdomen↗

PubMed2003

Adrenomedullin--a regulator of bone formation.

Bone growth and maintenance are highly regulated processes. Throughout life, bone constantly undergoes remodelling, maintaining a balance between bone formation by osteoblasts and bone resorption by osteoclasts. This balance depends on the coordinated activities of many systemic hormones and locally acting factors in the bone microenvironment. Understanding the mechanisms of action of these factors provides a better appreciation of the cellular and molecular basis of bone remodelling. Adrenomedullin has recently been found to stimulate the proliferation of osteoblasts in vitro, and to increase indices of bone formation when administered either locally or systemically in vivo. Adrenomedullin receptors, as well as adrenomedullin itself, are expressed in primary osteoblasts and in osteoblast-like cell lines. In this paper we discuss the anabolic effect of adrenomedullin in bone, and present new evidence for a possible role of adrenomedullin in the regulation of cartilage cells. We show that adrenomedullin stimulates proliferation of primary chondrocytes in culture and that mRNA for adrenomedullin and for adrenomedullin receptors are expressed in these cells. Studies of structure-activity relationships have demonstrated that osteotropic effects of adrenomedullin can be retained in peptide fragments of the molecule which lack the parent molecule's vasodilatory properties. Thus, these small peptides, or their analogues, are attractive candidates as anabolic therapies for osteoporosis.

Adrenomedullin↗

PubMed1988

Analysis of early lymphocyte activation events by fluorescence polarization flow cytometry.

After short-term (up to 4 h) stimulation with mitogen or antigen, lymphocytes were incubated with fluorescein diacetate and the polarization of fluorescence from intracellular fluorescein was measured on a specially adapted FACS II. This flow cytofluorimetric method to assay early changes in activated lymphocytes gave a reproducible response to the mitogens phytohaemagglutinin (PHA), concanavalin-A and the monoclonal antibody OKT3, recognized at 1 h by decreased polarization. A response by immune spleen cells to the antigen dinitrophenyl-ovalbumin was revealed at 4 h. The calcium ionophore A23187 induced an increase in polarization after only 10 min. The PHA polarization response was shown to be dependent on PHA binding, PHA dose, T cells, calcium ions and an intact cytoskeleton. The cellular events monitored by the polarization change are presumably altered fluidity of the probe's microenvironment due to conformational change in macromolecules to which the probe has bound or to dissociation of the probe into the aqueous phase. The fluorescein fluorescence polarization assay is a reliable and sensitive monitor of early lymphocyte activation events and, coupled with the use of a flow cytometer, permits study of particular subpopulations of responding cells.

Acetylgalactosamine↗

PubMed1986

Axonal caliber and neurofilaments are proportionately decreased in galactose neuropathy.

Feeding galactose to rats induces nerve conduction abnormalities, increased levels of nerve galactitol, endoneurial edema, elevated pressure and hypoxia of endoneurial fluid, and pathological abnormalities of nerve fibers. To investigate the cellular mechanisms of the fiber lesions and their possible relationship to alterations in the nerve microenvironment, rat peroneal nerves were morphometrically evaluated eight months after the commencement of galactose feeding. Whereas the density of neurofilaments (NF/micron2) in the transverse axonal area of myelinated fibers was not significantly different between the nerves of galactose-fed and control rats, axonal areas and the number of NF/axon, when related to myelin spiral length, were significantly less in nerves of galactose-fed rats. Myelin alterations, characteristic of axonal atrophy, were also significantly increased. The present data provide evidence of a proportionate decrease in axonal caliber and the number of NF/axon in myelinated fibers in experimental galactose neuropathy, suggesting that galactose induces fibers in experimental galactose neuropathy, suggesting that galactose induces either decreased NF synthesis, assembly or transport. The possible role of microenvironmental alterations, including endoneurial hypoxia and hyperosmolarity, in the production of this axonal atrophy is discussed.

Animals↗

PubMed2006

E11/gp38 selective expression in osteocytes: regulation by mechanical strain and role in dendrite elongation.

Within mineralized bone, osteocytes form dendritic processes that travel through canaliculi to make contact with other osteocytes and cells on the bone surface. This three-dimensional syncytium is thought to be necessary to maintain viability, cell-to-cell communication, and mechanosensation. E11/gp38 is the earliest osteocyte-selective protein to be expressed as the osteoblast differentiates into an osteoid cell or osteocyte, first appearing on the forming dendritic processes of these cells. Bone extracts contain large amounts of E11, but immunostaining only shows its presence in early osteocytes compared to more deeply embedded cells, suggesting epitope masking by mineral. Freshly isolated primary osteoblasts are negative for E11 expression but begin to express this protein in culture, and expression increases with time, suggesting differentiation into the osteocyte phenotype. Osteoblast-like cell lines 2T3 and Oct-1 also show increased expression of E11 with differentiation and mineralization. E11 is highly expressed in MLO-Y4 osteocyte-like cells compared to osteoblast cell lines and primary osteoblasts. Differentiated, mineralized 2T3 cells and MLO-Y4 cells subjected to fluid flow shear stress show an increase in mRNA for E11. MLO-Y4 cells show an increase in dendricity and elongation of dendrites in response to shear stress that is blocked by small interfering RNA specific to E11. In vivo, E11 expression is also increased by a mechanical load, not only in osteocytes near the bone surface but also in osteocytes more deeply embedded in bone. Maximal expression is observed not in regions of maximal strain but in a region of potential bone remodeling, suggesting that dendrite elongation may be occurring during this process. These data suggest that osteocytes may be able to extend their cellular processes after embedment in mineralized matrix and have implications for osteocytic modification of their microenvironment.

Animals↗

PubMed2001

Mesenchymal stem cells.

Within the bone marrow stroma there exists a subset of nonhematopoietic cells referred to as mesenchymal stem or mesenchymal progenitor cells. These cells can be ex vivo expanded and induced, either in vitro or in vivo, to terminally differentiate into osteoblasts, chondrocytes, adipocytes, tenocytes, myotubes, neural cells, and hematopoietic-supporting stroma. The multipotential of these cells, their easy isolation and culture, as well as their high ex vivo expansive potential make these cells an attractive therapeutic tool. In this work we will review the information dealing with the biology of mesenchymal progenitors as it has been revealed mainly by ex vivo studies performed with bone marrow-derived cells. The discussed topics include, among others, characteristics of mesenchymal progenitors, evidence for the existence of a vast repertoire of uncommitted and committed progenitors both in the bone marrow and in mesenchymal tissues, a diagram for their proliferative hierarchy, and comments on mobilization, microenvironment, and clinical use of mesenchymal progenitors. Despite the enormous data available at molecular and cellular levels, it is evident that a number of fundamental questions still need to be resolved before mesenchymal progenitors can be used for safe and effective clinical applications in the context of both cell and gene therapies.

Animals↗

PubMed2006

Tumor antigen targets and tumor immunotherapy.

Tumor immunology and immunotherapy attempt to use the exquisite specificity and lytic capability of the immune system to treat malignant disease with a minimum of damage to normal tissue. Increasing knowledge of the identity of tumor antigens should point the way to effective therapeutic vaccines or more specific immunotherapeutic strategies. Tumors, however, have evolved mechanisms to inactivate cytolytic T-cells and other immune responses targeting tumor antigens. The current goal of immunotherapy research is to use contemporary advances in cellular and molecular immunology to develop strategies to overcome the disabling effects of the tumor microenvironment on the immune system attack against tumor antigen targets. This review will summarize our current knowledge of the spectrum of tumor antigen targets available for immune recognition in cancer, the obstacles to tumor immunotherapy, the use of adoptive immunotherapy to overcome some of these obstacles, the use of monoclonal antibodies to target tumor antigens for immunotherapy, and finally the potential use of heat shock proteins as targets for cancer immunotherapy.

Animals↗

PubMed2000

Regulation and functions of c-Jun N-terminal kinase/stress-activated protein kinase.

The cell uses a complex signal transduction network both to respond to changes in its microenvironment and to integrate all of its intracellular signals. Actions of various signals in the cellular signal transduction network converge at the mitogen-activated protein kinase (MAPK) cascades, which lead to and activate transcription factors in the nucleus and other effectors throughout the cell. Extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinases/stress-activated protein kinases (JNK/SAPK), and p38 are some of the better characterized members of the MAPK family. Unlike ERK mainly responding to mitogens, JNK/SAPK was originally identified as a stress-related kinase and it has been extensively demonstrated to be associated with apoptosis. However, recent studies have further indicated that JNK/SAPK also has many functions other than the promotion of apoptosis. The repertoire of the JNK/SAPK pathway is wide-ranging, and its functions can vary, and even oppose each other, depending on the cell types and stimuli. It remains a challenge for biomedical scientists to elucidate the distinct role of JNK/SAPK in each model system.

Animals↗

PubMed1988

Purified lymphocyte function-associated antigen-3 (LFA-3) activates human thymocytes via the CD2 pathway.

Defining the cellular and molecular mechanisms of interaction of developing thymocytes with nonlymphoid cells of the thymic microenvironment is critical for understanding normal thymus function. We have previously shown that the CD2/LFA-3 adhesion pathway is important in the interaction of thymocytes with a variety of LFA-3+ nonlymphoid thymic microenvironment cell types. Moreover, T cell activation via the CD2 (alternative, Ag independent) pathway is considered an important mechanism for intrathymic T cell proliferation. To study the relevance of CD2/LFA-3 interactions to human thymocyte activation, we have used purified LFA-3 Ag in several in vitro assays of thymocyte proliferation. Whereas LFA-3 Ag alone did not induce thymocyte proliferation, LFA-3 Ag in combination with the anti-CD2 antibody, CD2.1, and rIL-2 induced marked thymocyte proliferation. Additionally, the anti-CD28 antibody, Kolt2, could substitute for rIL-2, resulting in thymocyte activation induced by LFA-3 Ag in combination with antibodies CD2.1 and Kolt2. In both triggering systems, LFA-3 induced thymocyte activation was dependent upon the concentration of LFA-3 Ag. LFA-3 Ag-dependent thymocyte activation was directed primarily toward CD1-, mature thymocytes. Finally, intact SRBC that express the sheep homolog of LFA-3, T11TS, in combination with antibody CD2.1 and rIL-2 could also induce thymocyte activation. These data suggest that interaction of LFA-3 molecules with thymocyte CD2 molecules may provide a component of the stimulus for normal intrathymic thymocyte activation leading to thymocyte proliferation.

Animals↗

PubMed1980

Hemopoietic bone culture in diffusion chambers.

Many experimental arguments make some cellular elements which are present in the hemopoietic bone cavities responsible for the bone marrow microenvironment. Diaphyseal fragments of previously curetted rat femurs were cultivated in vivo in diffusion chambers. Histological examination of the chamber membranes showed the presence of fibroblast-like cells. Their osseous origin was demonstrated by the study of the sexual chromatin. A morphological similarity seems to occur between these cells obtained in vivo and those described in in vitro cultures of hempoietic bone or bone marrow.

Animals↗

PubMed1997

Infection of human marrow stroma by human immunodeficiency virus-1 (HIV-1) is both required and sufficient for HIV-1-induced hematopoietic suppression in vitro: demonstration by gene modification of primary human stroma.

Patients with human immunodeficiency virus-1 (HIV-1) infection often present with bone marrow (BM) failure that may affect all hematopoietic lineages. It is presently unclear whether this failure reflects a direct viral impairment of the CD34+ hematopoietic progenitor cells or whether the virus affects the BM microenvironment. To study the effects of HIV-1 on the BM microenvironment, we examined the stromal cell monolayers in long-term BM culture (LTBMC), which are the in vitro equivalent of the hematopoietic microenvironment. We assessed the hematopoietic support function (HSF) of human stromal layers by determining the cellular proliferation and colony-forming ability of hematopoietic progenitors from BM cells grown on the stromal layers. We show that the HSF is reduced by in vitro infection of the human stromal cell layer by a monocytotropic isolate of HIV-1 (JR-FL). There is no loss of HSF when the stromal cell layer is resistant to HIV-1 replication, either using murine stromal cell layers that are innately resistant to HIV-1 infection or using human stromal cells genetically modified to express a gene that inhibits HIV-1 replication (an RRE decoy). Decreased HSF was seen using either human or murine hematopoietic cells, if the stromal cells were human cells that were susceptible to HIV-1 infection. These in vitro studies implicate HIV-1 replication in the stroma as the essential component causing decreased hematopoietic cell production in HIV-1 infection.

Bone Marrow↗

PubMed2004

Aminopeptidase N/CD13 regulates the fetal liver microenvironment of hematopoiesis.

Fetal liver (FL) hematopoiesis is thought to be important for expanding the cell number during ontogeny. In order to investigate the cellular interaction molecules among FL stromal and hematopoietic cells, we established a monoclonal antibody, Ndk-10, that reacts with FL stromal cells but not with dish non-adherent cells. When Ndk-10 was added to an FL stromal and hematopoietic cell-coculture, it inhibited the survival of c-kit+ cells. The inhibitory activity of Ndk-10 was also observed in the fetal liver organ culture. The Ndk-10 recognized a 150 kD molecule in the adherent cells of FL and kidney, and the N-terminal amino acid sequence was identical to that of mouse aminopeptidase N/CD13. The peptidase activity of CD13 was inhibited by Ndk-10, and addition of its specific inhibitor resulted in the same inhibitory activity as Ndk-10. We propose that aminopeptidase N/CD13 is a critical molecule that regulates the survival of c-kit+ cells in the FL microenvironment.

Animals↗

PubMed1995

Human tumor gangliosides inhibit murine immune responses in vivo.

Gangliosides which are shed by tumor cells clearly inhibit cellular immune responses in vitro. However, the immunosuppressive activity of these molecules have been more difficult to ascertain in vivo. Here we have adapted a murine model to determine the effects of tumor gangliosides in an in vivo microenvironment, the lymph node draining the site of stimulation by allogeneic cells. In this model, allogeneic splenocytes (BALB/c) are s.c. injected into C3H mice. The cellular immune response in the draining popliteal lymph nodes 4 days later is evidenced as an increase in lymph node mass (2-fold), lymphocyte number (6-fold), and lymphocyte DNA synthesis (6-fold). Purified human neuroblastoma gangliosides (10 nmol) coinjected with the stimulating allogeneic cells significantly suppressed this in vivo immune response. The increase in the lymph node mass was reduced by 65% (0.66 versus 1.89 mg), the increase in lymphocyte number (4.0 x 10(6) cells/node) was almost completely inhibited (1.1 x 10(6) cells/node), and in vitro [3H]thymidine uptake by the lymphocytes recovered in vivo was reduced by 80%. In contrast to the inhibition by tumor gangliosides, liposomes of cholesterol:lecithin were not inhibitory. Thus, tumor gangliosides, specifically, modulate cellular immune responses in vivo, which may contribute to the observed enhancement of tumor formation by these molecules.

Animals↗

PubMed2007

Role of the tumor microenvironment in the activity and expression of the p-glycoprotein in human colon carcinoma cells.

The metabolic microenvironment of solid tumors is characterized by an oxygen deficiency and increased anaerobic glycolysis leading to extracellular acidosis and ATP depletion, which in turn may affect other energy-dependent cellular pathways. Since many tumors overexpress active drug transporters (e.g. the p-glycoprotein) leading to a multidrug-resistant phenotype, this study analyzes the impact of the different aspects of the extracellular microenvironment (hypoxia and acidosis) on the activity and expression of the p-glycoprotein (pGP) in the human colon carcinoma cell line LS513. For up to 24 h cells were exposed to hypoxia (pO2<0.5 mmHg), an acidic extracellular environment (pH 6.6), or the combination of hypoxia and acidosis. Under hypoxic conditions (at a normal pH), the pGP activity (measured by the daunorubicin efflux) and the pGP expression were not markedly altered. Under acidic conditions, however, the pGP-mediated drug efflux was increased, an effect which was even more pronounced when the cells were exposed to hypoxia and acidosis simultaneously (increasing the pGP-activity by 70%). The cellular pGP expression remained almost constant under these conditions, indicating that the increased transport rate results from a functional modulation. The findings of the present study indicate that the parameters of the tumor microenviroment (especially extracellular acidosis) can increase the pGP-mediated drug efflux, an effect which may explain the reduced cytotoxicity of chemotherapeutic agents in hypoxic/acidic tumors.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1998

Cellular interactions in the thymus regulate the protein kinase C signaling pathway.

We provide evidence that thymocytes receive signals from the thymic microenvironment which regulate the protein kinase C (PKC) signaling pathway. Thus, phorbol 12-myristate 13-acetate (PMA) causes a PKC-dependent down-regulation of CD4 expression and induces apoptosis in isolated thymocytes but has little effect on thymocytes maintained within intact thymic lobes or in reaggregate lobes containing purified thymocytes with either thymic or non-thymic stromal cells. Moreover, compact pellets of thymocytes alone are protected from the effects of PMA. This protection is maintained when the compacted thymocytes are rigorously depleted of MHC class II-expressing cells. We conclude that signals arising from thymocyte-thymocyte contact control the utilization of the PKC cascade. These observations have implications for thymocyte signaling in general as well as for the interpretation of studies carried out on thymocyte suspensions.

Animals↗