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PubMed2006

Molecular characterization of retinal stem cells and their niches in adult zebrafish.

BACKGROUND: The persistence in adult teleost fish of retinal stem cells that exhibit all of the features of true 'adult stem cells'--self-renewal, multipotency, and the capacity to respond to injury by mitotic activation with the ability to regenerate differentiated tissues--has been known for several decades. However, the specialized cellular and molecular characteristics of these adult retinal stem cells and the microenvironmental niches that support their maintenance in the differentiated retina and regulate their activity during growth and regeneration have not yet been elucidated. RESULTS: Our data show that the zebrafish retina has two kinds of specialized niches that sustain retinal stem cells: 1) a neuroepithelial germinal zone at the interface between neural retina and ciliary epithelium, called the ciliary marginal zone (CMZ), a continuous annulus around the retinal circumference, and 2) the microenvironment around some Müller glia in the differentiated retina. In the uninjured retina, scattered Müller glia (more frequently those in peripheral retina) are associated with clusters of proliferating retinal progenitors that are restricted to the rod photoreceptor lineage, but following injury, the Müller-associated retinal progenitors can function as multipotent retinal stem cells to regenerate other types of retinal neurons. The CMZ has several features in common with the neurogenic niches in the adult mammalian brain, including access to the apical epithelial surface and a close association with blood vessels. Müller glia in the teleost retina have a complex response to local injury that includes some features of reactive gliosis (up-regulation of glial fibrillary acidic protein, GFAP, and re-entry into the cell cycle) together with dedifferentiation and re-acquisition of phenotypic and molecular characteristics of multipotent retinal progenitors in the CMZ (diffuse distribution of N-cadherin, activation of Notch-Delta signaling, and expression of rx1, vsx2/Chx10, and pax6a) along with characteristics associated with radial glia (expression of brain lipid binding protein, BLBP). We also describe a novel specific marker for Müller glia, apoE. CONCLUSION: The stem cell niches that support multi-lineage retinal progenitors in the intact, growing and regenerating teleost retina have properties characteristic of neuroepithelia and neurogenic radial glia. The regenerative capacity of the adult zebrafish retina with its ability to replace lost retinal neurons provides an opportunity to discover the molecular regulators that lead to functional repair of damaged neural tissue.

Aging↗
PubMed1989

[Interrelation of the osteogenic and hemopoietic tissues of the bone marrow during the development of estrogenic myelofibrosis].

By means of estrogenic myelofibrosis, using the method of heterotopic transplantation of the bone marrow, interrelations of osteogenic and hemopoietic tissues have been studied. Under estrone effect disorders in stromal microenvironment take place at the level of stem osteogenic cells of the bone marrow. Deficiency in cells of monocytic-macrophagal line, inhibiting proliferation of the bone marrow connective tissue cells, contributes to development of myelofibrosis. The hormone acts mainly in committed hemopoietic cells, singly launching them from G0- into S-period of the cycle, and then--into differentiation, accompanied with an enhanced discharge of cells from the bone marrow. There is neither direct, nor indirect dependence between the osteogenic mass and the cellularity of the hemopoietic tissue of the bone marrow. The changes, that take place in the bone marrow under estrone effect, are reversible.

Animals↗
PubMed1985

Lymphocyte traffic and the skin.

Lymphocyte migration patterns into and within lymphoid organs and nonlymphoid organs such as the skin as highly regulated and controlled by a variety of factors, some of which we are beginning to understand at a basic cellular and molecular level. In the case of lymphocyte migration into lymphoid organs, recirculatory patterns and preferences appear to be mediated by selective recognition via lymphocyte membrane receptors of distinctive determinants expressed by specialized endothelial cells in different organ sites. A similar model in which endothelial cells in the skin share common determinants with endothelial cells in peripheral lymph nodes can be developed to explain the migration patterns of lymphocytes from the blood into the skin. Cells that have undergone blast transformation in the microenvironment of the skin or peripheral lymph nodes, or both, appear to recirculate selectively within this particular sphere of immunologic influence, whereas other cells that undergo this transformation in the microenvironment of the gastrointestinal tract and its draining mesenteric lymph nodes selectively recirculate within that sphere of immunologic influence. This preferential recirculation increases the probability that the immunologic defense needs of a given region or tissue such as the skin will be met efficiently and appropriately. Finally, some of the phenotypic characteristics favoring the movement of lymphocytes from the bloodstream into the dermis (such as recent stimulation and the presence of T-cell surface markers) also seem to favor lymphocyte migration into or retention in the epidermis. However, under appropriate circumstances, epidermotropism can be exhibited by both major subsets of T cells as well as a variety of non-T cells.

Animals↗
PubMed2002

Epithelial carcinogenesis: dynamic interplay between neoplastic cells and their microenvironment.

Matrix metalloproteinases (MMPs) have long been thought of as critical factors regulating matrix degradation associated with cell invasion into ectopic tissue compartments during primary tumor growth and metastasis. One member of the MMP family historically linked to these invasive processes is MMP-9/gelatinase B. By studying a transgenic mouse model of de novo epithelial carcinogenesis, new roles for MMP-9 have emerged that broaden the view of its functional contribution to malignant progression. The combined implication of these studies suggest that MMP-9 functionally contributes to cancer development; however, its major regulatory role may be in its ability to activate poorly diffusible and/or matrix-sequestered growth factors that regulate epithelial and/or endothelial cell growth as opposed to regulating cellular invasion across basement membranes.

Animals↗
PubMed1994

Transient expression of the cytochrome P450 aromatase gene in elongating porcine blastocysts is correlated with uterine insulin-like growth factor levels during peri-implantation development.

The insulin-like growth factors (IGFs-I and -II) are mediators of cellular growth and differentiation. The expression of these growth factor genes is temporally and hormonally regulated in the uterus during pregnancy, suggesting potentially important roles in embryonic development, implantation, and successful progression of pregnancy. A known regulator of uterine IGF-I secretion is estrogen, which is produced by pre-implantation mammalian embryos of several species and whose amounts may be influenced by growth factors via their effects on the transcriptional activities of steroidogenic enzyme genes. We have previously proposed that within the uterine microenvironment, a positive feedback loop may link uterine secretion of IGFs with embryonic production of estrogens to maintain and coordinate the timing of biological signals essential for embryo development. The present study examined the temporal relationships between the levels of conceptus cytochrome P450 aromatase mRNA and protein and concentrations of IGF-I and -II in uterine luminal fluids of pigs. A DNA fragment encoding a highly conserved region among mammalian aromatase P450 proteins was isolated by hybridization screening of a porcine genomic DNA library with a human aromatase P450 cDNA fragment as probe. A synthetic oligopeptide DDVIDGYPVKKGTNI within this highly conserved region was used to generate an antiserum in sheep that recognized a protein of M(r) 49,000 in Western blot analysis of porcine ovarian, placental, endometrial, and conceptus extracts. A radioimmunoassay (RIA) for aromatase P450 was established and validated using this antiserum. RIA demonstrated highest levels of aromatase P450 protein in extracts of days 10, 11, and 12 porcine conceptuses with significantly diminished levels in elongated conceptuses at days 15 and 18. In the conceptus, aromatase P450 was localized to the inner cell layer (hypoblast) of the trophectoderm. A major mRNA transcript of approximately 3 kb in length was demonstrated by Northern blot analysis of conceptus RNA with a porcine aromatase P450 antisense RNA probe. The relative levels of aromatase P450 mRNA were higher in conceptuses at day 12 than at days 15 and 18, in parallel with the levels of aromatase P450 protein. RIA of uterine luminal fluids demonstrated maximal concentrations of IGF-I at day 12, which were significantly decreased by day 15, and increased concentrations of IGF-II by day 12, which were maintained until day 18 of pregnancy. These results demonstrate that the transient expression of conceptus aromatase P450 mRNA and protein in elongating pig blastocysts is coincident with their capacity to secrete estrogens and with the rapidly changing concentrations of IGFs within the uterine microenvironment.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed2003

Cell adhesion molecule regulation of nucleocytoplasmic trafficking.

Cells undergo processes such as proliferation, differentiation, and survival based upon cues that they receive from their microenvironment. Extracellular matrix adhesion molecules, such as integrins and syndecans, and cell-cell adhesion molecules, including cadherins and Ig superfamily members, convey information about the environment to the cell. It is evident that cell adhesion molecules (CAMs) regulate a variety of signaling events. An emerging theme is that one level of CAM signaling control is through regulated nucleocytoplasmic distribution of molecules that either phosphorylate or co-activate transcription factors. In this manner, CAMs control transcription events that ultimately have a strong impact on cellular processes.

Animals↗
PubMed1994

Mechanisms of immune-mediated myocyte injury.

Much progress has been made in defining the mechanisms by which altered systolic and diastolic function of the heart may be produced by components of the immune system activated during allograft rejection and myocarditis and in patients with dilated cardiomyopathy. It is clear that injury of the vascular bed can occur via both humoral and cellular mediators and probably accounts for the acute alterations in ventricular compliance that occur during allograft rejection, as well as the accelerated development of graft atherosclerosis. Altered myocyte function and lysis can be produced by CTL in vitro, but the importance of this injury process in vivo remains uncertain. Other cells present in the inflammatory infiltrate can also affect myocyte function and survival. Neutrophils may cause lysis of myocytes, and cytokines produced by infiltrating macrophages and HtL may reach a sufficient concentration in the interstitial microenvironment to decrease myocyte catecholamine responsiveness and/or directly depress myocyte contractility. Humoral antibodies to myocyte cell surface antigens may cause cell damage by an antibody-dependent cytotoxic cell mechanism or by directly binding to and altering sarcolemmal receptor and/or ion channel function. Further elucidation of the extent of involvement of these different mechanisms in specific clinical settings may provide a basis for improved therapy of immune-mediated cardiac injury and dysfunction.

Animals↗
PubMed1996

Protein kinase C, interleukin-1 beta, and corticosteroids regulate shedding of the type I, 55 kDa TNF receptor from human airway epithelial cells.

Tumor necrosis factor (TNF) may contribute to the pathogenesis of inflammatory airway disorders via the regulation of inflammatory and cellular immune responses. Shed cell surface TNF receptors can act as soluble TNF binding proteins and modulate TNF biological activity. We report that normal human airway epithelial cells, as well as two human airway epithelial cell lines, shed soluble type I TNF receptors (sTNF-RI) in a concentration-dependent fashion following protein kinase C (PKC) activation by PMA. Interleukin (IL)-1beta also induced concentration-dependent sTNF-RI shedding from NCI-H292 cells, which could be inhibited by the PKC inhibitor calphostin C. Since corticosteroids are commonly utilized as antiinflammatory agents in airway disorders, the effect of dexamethasone on sTNF-RI release was assessed. Dexamethasone inhibited constitutive, as well as PMA- and IL-1beta-mediated sTNF-RI release from NCI-H292 cells in a concentration-dependent fashion. Furthermore, dexamethasone increased while PMA decreased total cellular 55 kDa TNF-RI protein as detected by immunoblotting. These changes in total cellular 55kDa TNF-RI protein did not appear to be mediated at the mRNA level, as assessed by ribonuclease protection assays. This suggests that sTNF-RI shedding represents a mechanism by which airway epithelial cells can actively participate in local cytokine networks and modulate TNF-mediated inflammation. Furthermore, since corticosteroids inhibit sTNF-RI release and are known to downregulate TNF synthesis, this may represent a mechanism by which equilibrium between TNF ligand and soluble binding protein is maintained in the airway microenvironment.

Antigens, CD↗
PubMed1995

Defect of stromal microenvironment in long term bone marrow cultures of patients with acute and chronic myelogenous leukemias.

Inhibition of normal hemopoiesis is a regular finding in acute (AML) and chronic (CML) myelogenous leukemias and functional abnormalities of the hemopoietic microenvironment may be involved in this regard. In order to evaluate this possibility we studied the formation of adherent stromal cell layers (ASCL) in long term bone marrow cultures (LTBMC) of 7 patients with CML and 7 patients with AML and examined the ability of these ASCLs to support hemopoiesis after irradiation and a second inoculation of bone marrow cells. The formation of ASCLs was significantly impaired in CML and AML. These CML patients and 3 AML patients did not form typical ASCLs and the cellularity of these layers was greatly reduced. Colony forming unit granulocyte-macrophage (CFU-GM) production from bone marrow cells seeded on normal irradiated ASCLs peaked at week 3 and then gradually decreased by week 8. In CML and AML cocultures CFU-GM numbers decreased rapidly to zero by weeks 4-6 and did not differ significantly from the control cultures which did not contain preestablished ASCLs beginning from week 3. It is suggested that there may be a functional microenvironmental defect in CML and AML that may play a role in the pathogenesis of inhibition of normal hemopoiesis in these diseases.

Bone Marrow↗
PubMed2004

Lymphocyte development and function in the absence of retinoic acid-related orphan receptor alpha.

The orphan nuclear receptor, retinoid acid-related orphan receptor (ROR)alpha, is essential for the development of cerebellar Purkinje cells and bone tissue. RORalpha may also play a critical role in lymphocyte development and function because staggerer mice, a natural mutant strain with a disrupted expression of RORalpha, have reduced thymic and splenic cellularity. In this report, we analyzed the role of RORalpha in lymphocyte development by examining lymphoid compartments in RORalpha(-/-) mice and Rag-2(-/-) mice reconstituted with RORalpha(-/-) bone marrow. We found that T and B cell development was severely defective in RORalpha(-/-) mice, but not in Rag-2(-/-)/RORalpha(-/-) chimeric mice. We also analyzed cellular and humoral immune responses in Rag-2(-/-)/RORalpha(-/-) chimeric mice. Our results show that serum IgG levels were elevated in Rag-2(-/-)/RORalpha(-/-) chimeric mice after immunization with a T-dependent Ag compared with control chimeras. IFN-gamma production by RORalpha(-/-) CD8(+) T cells after TCR stimulation was also increased. Furthermore, RORalpha(-/-) mast cells and macrophages produced an increased amount of TNF-alpha and IL-6 upon activation. These results indicate that RORalpha indirectly regulates lymphocyte development by providing an appropriate microenvironment and controls immune responses by negatively regulating cytokine production in innate immune cells and lymphocytes.

Animals↗
PubMed2004

Targeting K+ channels for cancer therapy.

A number of experimental evidences in cellular biology and pharmacology demonstrate that K+ channels are involved in the regulatory mechanisms of neoplastic cell proliferation and survival. Among the various types of K+ channels known so far, those that express an inwardly rectifying current (mainly the types named Kir, EAG and HERG) appear of peculiar importance in favoring cancer progression in vivo. In fact, besides helping to maintain a constantly depolarized value of the resting potential required for deregulated tumor growth, they can confer selective advantages to cancer cells in an hypoxic microenvironment, such as that of tumor masses. Inhibitors and modulators of K+ channels have been demonstrated to have the ability to impair cancer cell proliferation in vitro and to counteract cancer progression in vivo. A process of rigorous scientific verification at a pre-clinical level of the anticancer potential of K+ channels inhibitors and modulators have never been rationally performed thus far, but would appear opportune in the light of the data here discussed.

Antineoplastic Agents↗
PubMed1998

Interleukin 2 expression by tumor cells alters both the immune response and the tumor microenvironment.

Microenvironmental conditions within solid tumors can have marked effects on the growth of the tumors and their response to therapies. The disorganized growth of tumors and their attendant vascular systems tends to result in areas of the tumors that are deficient in oxygen (hypoxic). Cells within these hypoxic areas are more resistant to conventional therapies such as radiation and chemotherapy. Here, we examine the hypoxic state of EMT6 mouse mammary tumors and the location of host cells within the different areas of the tumors to determine whether such microenvironmental conditions might also affect their ability to be recognized by the immune system. Hypoxia within tumors was quantified by flow cytometry and visualized by immunohistochemistry using a monoclonal antibody (ELK3-51) against cellular adducts of 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)acetam ide (EF5), a nitroimidazole compound that binds selectively to hypoxic cells. Thy-1+ cells, quantified using a monoclonal antibody, were found only in the well-oxygenated areas. The location of these Thy-1+ cells was also examined in EMT6 tumors that had been transfected with the gene for interleukin-2 (IL-2) because these tumors contain greatly increased numbers of host cells. Surprisingly, we found that IL-2-transfected tumors had significantly decreased hypoxia compared to parental tumors. Furthermore, using the fluorescent dye Hoechst 33342, an in vivo marker of perfused vessels, combined with immunochemical staining of PECAM-1 (CD31) as a marker of tumor vasculature, we found increased vascularization in the IL-2-transfected tumors. Thus, expression of IL-2 at the site of tumor growth may enhance tumor immunity not only by inducing the generation of tumor-reactive CTLs but also by allowing increased infiltration of activated T cells into the tumors.

Animals↗
PubMed2001

Abnormalities of bone marrow mesenchymal cells in multiple myeloma patients.

BACKGROUND: The importance of the bone marrow microenvironment in multiple myeloma is receiving increasing attention. Recent studies have suggested the importance of cytokine production and cell-cell contact by bone marrow stromal cells in the survival of myeloma cells. METHODS: In the current study, the authors examined bone marrow mesenchymal progenitor cell (MPC) cultures derived from eight multiple myeloma patients (mean age, 58 years) and nine normal donors (mean age, 61 years), with emphasis on cell surface antigens, cytokine, and growth factor expression. RESULTS: The authors have found, based on analysis of cellular receptors, growth factors, and cytokine expression, that myeloma MPCs are phenotypically and functionally distinguishable from normal donor MPCs. Immunofluorescence analysis of MPC monolayers shows that myeloma MPC cultures expressed reduced cell surface vascular cell adhesion molecule-1 and fibronectin, in contrast with the strong expression found on normal donor MPCs. Furthermore, a subset of myeloma MPCs strongly express intracellular receptor for hyaluronan-mediated motility, whereas normal MPCs do not. Cytokine expression in bone marrow MPC cultures was examined by reverse transcription-polymerase chain reaction and enzyme linked immunosorbent assay. Bone marrow MPCs constitutively express interleukin (IL)-1beta, IL-6, granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage (GM)-CSF, stem cell factor (SCF), and tumor necrosis factor (TNF)-alpha. In comparison to normal MPCs, multiple myeloma MPCs express increased basal levels of IL-1beta and TNF-alpha. In vitro exposure of MPC cultures to dexamethasone resulted in the down-regulation of IL-6, G-CSF, and GM-CSF in both normal and myeloma MPC cultures. However, dexamethasone treatment significantly increased expression of SCF-1 in myeloma MPCs. CONCLUSIONS: In myeloma, bone marrow stromal cells provide paracrine factors, through cytokine production and cell-cell contact, which play a role in plasma cell growth and survival. The authors' data indicate differences in bone marrow MPCs, which may be biologically relevant to the growth and survival of myeloma plasma cells.

Adult↗
PubMed1988

[Development of the immune system].

Immune protection in vertebrates is provided by a dual system: the cellular immune response, mediated by T lymphocytes and the humoral immune response, mediated by B lymphocytes. These lymphocytes develop immunocompetence in the primary lymphoid organs: thymus, for the T lymphocytes and bursa of Fabricius (in birds), on its equivalent (in mammals), for B lymphocytes. The crucial period during which thymus and bursa influence the immunological development is the embryonic and early postnatal life. Hemopoietic stem cells home to these primary lymphoid organs during well-defined periods of colonization. Under the influence of thymic and bursal microenvironments, they become oriented respectively toward the T or B cell differentiation pathway. They acquire various membrane antigens and an antigen receptor. T lymphocytes also learn to recognize self-antigens (antigens encoded by the Major Histocompatibility Complex). T and B lymphocytes then colonize respectively T-dependent and B-dependent areas of secondary lymphoid organs where they become functional. Some immune deficiencies result from a defect in development which can affect selectively T or B lymphocytes or both systems in case of severe combined immunodeficiency disorders.

Animals↗
PubMed2006

Age dependent and cellular origin (stem versus progenitor) of a selected group of spontaneous brain tumors in humans.

The origin of spontaneous human brain tumors has been recently debated as originating from a stem rather than a progenitor cell. Based on the statistical distribution of a selected group of primary brain tumors, and on the clonality and field theory for cancer growth, we propose as plausible the contribution of progenitor cells in the origin of the most common brain tumors such as, pediatric, mixed (glial and neuronal), and the aggressive glioblastoma multiforme in adults. Operationally, stem cell is defined as having a renewal probability of p=1, a progenitor 0<p<1, and a terminally differentiated cell as p=0. The space-time field location (microenvironment, cell-cell interactions...) and mitotic potential of a cell limits the distinguishability between stem and progenitors, due to the interconvertibility of these states via the process of retrodifferentiation (dedifferentiation). If excessively iterated retrodifferentiation of a mitotically competent cell prompts such a cell to organize programs that are atypical vis-à-vis the standard ones. Regarding specifically malignant cells, aperiodic cycles of dedifferentiation favour emergence of subclonal populations whose anachronistic evolution might become idiosyncratically resistant to therapies previously efficient against the initial tumoral mass. Unfortunately the "ab initio" identification of such subclonal "drifters" is impaired by systematic uncertainties as quali-quantified in appendix.

Aging↗
PubMedDate not supplied

Stem cell biology and the cellular pathways of carcinogenesis.

Tissues in the body are maintained by somatic stem cells. This has been demonstrated both in organs with high cell turnover rate, such as the bone marrow, colon and skin, and in organs with low cell turnover rate, such as the brain. To maintain homeostasis in the body it is important to keep tight control over stem cell fate. Stem cells are under strict control from both intrinsic and extrinsic factors and loss of this control has been postulated to be a key step in the carcinogenic process. There is increasing evidence that cancer initiation results from accumulative oncogenic mutations (intrinsic loss of control) in long-lived stem cells or their immediate progenitor, followed by modification of the surrounding microenvironment (loss of extrinsic control). Decades ago, studies on teratocarcinoma led to the hypothesis that a small subset of self-renewing cancer stem cells with differentiation potential exists within tumors. These studies showed that teratocarcinomas contain undifferentiated embryonic carcinoma cells that are able to give rise to differentiated cells which belong to all three germ layers. More recent studies have confirmed cancer stem cells in such diverse cancers as leukemia, brain and breast cancer. It is, however, unclear whether cancer stem cells originate from resident stem cells or whether they arise as a result of an acquired gain of self-renewal capacity in tissue progenitor cells or even more differentiated cells. The characterization of a cancer stem cell profile within diverse cancer types may open up new avenues for cancer treatment. In this review we discuss the concept of cancer stem cells and focus on examples where these cells have been identified.

Animals↗
PubMed2003

Host microenvironment in breast cancer development: inflammatory and immune cells in tumour angiogenesis and arteriogenesis.

Breast cancer progression is associated with and dependent upon robust neovascularization. It is becoming clear that tumour-associated 'normal' cells, such as immune/inflammatory cells, endothelial cells and stromal cells, conspire with cancer cells in promoting this process. In particular, infiltrating immune/inflammatory cells secrete a diverse repertoire of growth factors and proteases that enable them to enhance tumour growth by stimulating angiogenesis and, as we suggest here, by promoting 'tumour arteriogenesis' - enlargement of feeding vessels supplying the expanding tumour capillary bed. Macrophages and their chemoattractants (e.g. macrophage chemoattractant protein-1) are critical for the arteriogenic process in ischaemia, and probably also in breast neoplasia. A better understanding of these various cellular and molecular constituents of breast cancer neovascularization may be useful in designing more effective therapies.

Animals↗
PubMed2006

A review on pro- and anti-angiogenic factors as targets of clinical intervention.

Angiogenesis plays an important role in physiology and pathology. It is a tightly regulated process, influenced by the microenvironment and modulated by a multitude of pro- and anti-angiogenic factors. A thorough understanding of the angiogenic process may lead to novel therapies to target ischemic vascular diseases as well as diseases characterised by excessive angiogenesis such as rheumatoid arthritis, psoriasis or tumours. This review gives an overview of the (groups of) factors involved in different steps of the angiogenic process, divided into factors affecting endothelial proliferation and migration and factors affecting blood coagulation, fibrinolysis and the degradation of basement membranes and the extra-cellular matrix, with a specific emphasis on angiopoietins and their related growth factors. The therapeutic implications of these factors are discussed.

Angiogenesis Inducing Agents↗