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PubMed1982

The origin of the hematopoietic microenvironment in continuous bone marrow culture.

Marrow-derived adherent cells (MDAC) have been shown to provide a microenvironment which supports the proliferation of hematopoietic stem cells in continuous bone marrow culture. A study was undertaken to investigate the origin of MDAC. Normal CBA mice were transplanted with marrow cells from CBA donors bearing two T6 chromosomes. Five weeks after transplantation, the mice were sacrificed, their marrow cells explanted in liquid culture and the numbers of T6 positive and T6 negative mitoses were monitored during cultivation of MDAC. After 6 weeks, established MDAC monolayers were recharged with second explants of marrow cells and their capacity to support HSC proliferation in continuous marrow culture was assessed. The number of T6 positive mitoses declined steadily during the period of MDAC cultivation and none were detected after 4 weeks. The MDAC monolayers were able to support in vitro proliferation of CFUs for periods of at least 5 weeks. These results suggest that the in vitro hematopoietic microenvironment was of recipient origin and therefore stromal.

Animals↗
PubMed1982

Formation of symbiotic complex by microenvironment-dependent mouse leukemias and thymic epithelial reticular cells.

Developing thymic leukemias of the mouse have been assumed to form symbiotic complexes with thymic microenvironments. This symbiosis is morphologically based on pseudoemperipolesis (PEMP). The mechanism of the association of microenvironment-dependent leukemia cells with thymic epithelial reticular cells (TER) was analyzed in vitro by scanning electron microscopy, microcinematography, and a quantitative assessment of PEMP. PEMP was a consequence of active locomotion of the leukemia cells, with TER passively accepting the leukemia cells "crawling" under their cytoplasm. The integrity of the cytoskeletal system of both cells was essentially required for PEMP, since cytochalasins and colchicine were highly inhibitory to PEMP. The mechanism of action of these compounds was probably dual: inhibition of the locomotive movements of the leukemia cells. A similar inhibition of PEMP was also observed with the tumor promoter 12-O-tetradecanoylphorbol 13-acetate.

Animals↗
PubMed1978

[Bone marrow microenvironment transfer by clones of stromal mechanocytes].

Clones of bone marrow stromal fibroblasts harvesed from monolayer cultures of mice and guinea pig bone marrow cells are transferring the hemopoietic microenvironment when transplanted in vivo. Individual fibroblast clones form bone tissue and create the microenvironment for erytroid, myeloid and megakariocyte differentiation of hematopoietic cells simultaneously.

Animals↗
PubMed1994

Analysis of steel factor (stem cell factor) isoforms in the hematopoietic microenvironment.

Hematopoietic cell proliferation and differentiation is dependent in part on the interaction of hematopoietic stem and progenitor cells with cells making up the hematopoietic microenvironment (HM). Direct cell-cell interactions appear to be important in the hematopoietic microenvironment. One mechanism to accomplish such interactions is the expression of membrane-associated growth factors. Stem cell factor (SCF), the product of the steel gene in mice (also termed mast cell growth factor, c-kit ligand, or Steel factor), is a hematopoietic growth factor demonstrating substantial synergistic activity with a number of other cytokines on primitive hematopoietic stem and progenitor cells. Cloned SCF cDNA encode both a membrane-associated and a secreted growth factor. The physiologic relevance of these isoforms is unknown at present. In order to better understand the physiologic role of these SCF isoforms in normal hematopoiesis, we have established multiple stromal cell lines expressing each isoform. We have used these cell lines to study protein sequences that are required for appropriate post-translational processing of SCF protein in HM-derived stromal cell lines. These lines have also been used to study the interaction of membrane-associated and secreted SCF with murine and human hematopoietic cells. In addition, we have generated transgenic mice expressing each isoform of murine and human SCF. These transgenic mice will be used to study the function of each isoform in hematopoiesis in vivo.

Amino Acid Sequence↗
PubMed1994

Perikaryal projections of spinal ganglion neurons: quantitative differences between membrane domains in contact with different microenvironments.

The perikarya of spinal ganglion neurons display numerous slender projections. In the present investigation we have studied whether the extent of these projections is uniform over the entire perikaryal surface or whether there is a difference between the regions of the perikaryon in contact with different microenvironments. In spinal ganglia of the rat and the lizard we have analysed about 200 neuronal cell bodies arranged in pairs and have compared the extent of the projections quantitatively in the areas of interneuronal contact with that in the areas of neuron-to-satellite cell contact. In both species we have found that the projections are present over the entire perikaryal surface and that the overall development of the perikaryal projections is significantly greater in those portions of the surface in contact with satellite cells than in the portions in contact with another neuron. On the basis of these observations we conclude that the outgrowth of perikaryal projections is an intrinsic property of the nerve cell body which is manifested over the entire perikaryal surface; there is, however, an extrinsic influence from the microenvironment of the neuron, which may account for the quantitative differences in different domains of the perikaryal surface.

Animals↗
PubMed1995

Collagen type VI in the human bone marrow microenvironment: a strong cytoadhesive component.

Collagen type VI, which forms characteristic microfibrillar structures, is assembled from three individual alpha(VI) chains that form a short triple helix and two adjacent globular domains. Expression of all three alpha (VI) collagen chains in the human bone marrow (BM) microenvironment could be detected by chain-specific antibodies in tissue sections and in the adherent stromal layer of long-term BM cultures. In functional studies, collagen type VI was shown to be a strong adhesive substrate for various hematopoietic cell lines and light-density BM mononuclear cells. The adhesive site within the molecule seems to be restricted to the triple helical domain of all three alpha (VI) chains, because individual alpha (VI) chains were not active in the attachment assays. Adhesion of the hematopoietic cell lines to collagen VI was dose-dependent and could be inhibited by heparin. Although the triple helix contains several RGD sequences, adhesion of the hematopoietic cell types to collagen VI could be blocked neither by RGD-containing peptides nor by a neutralizing antibody to the beta 1 integrin subunit. In combination with an antiadhesive substrate, the binding properties of collagen VI could be downregulated. These data suggest that this collagen type may play an important role in the adhesion of hematopoietic cells within the BM microenvironment.

Bone Marrow↗
PubMed1995

On the influence of the perineuronal microenvironment on the outgrowth of perikaryal projections of spinal ganglion neurons.

While the outgrowth of the slender projections from the perikaryon of spinal ganglion neurons is an intrinsic property of these neurons, it is also influenced by the surrounding microenvironment. To obtain evidence concerning whether the outgrowth of these projections is influenced by one or both components of the perineuronal microenvironment (satellite cells plus extracellular matrix) we have taken advantage of a rare arrangement of these neurons. In the spinal ganglia of adult animals nerve cell bodies are occasionally arranged in pairs, the two nerve cell bodies of the pair being separated by a satellite cell sheet lacking a basal lamina, while along the remaining portions of their surfaces they are enveloped by a satellite cell sheath, in turn surrounded by a basal lamina and connective tissue. By studying these paired nerve cells we have been able to compare, in the same nerve cell body, the extent of the perikaryal projections in surface domains associated only with satellite cells and in surface domains associated with both satellite cells and extracellular matrix. In spinal ganglia of the rat and lizard we have found that the overall development of the perikaryal projections does not differ significantly in either of these surface domains. This finding suggests that neuron-satellite cell interactions rather than factors in the extracellular matrix play a role in promoting the outgrowth of perikaryal projections from spinal ganglion neurons.

Animals↗
PubMed1993

Analysis of corneal and conjunctival microenvironments using monoclonal antibodies.

PURPOSE: The authors phenotypically compared epithelial and nonepithelial components of human corneal and conjunctival microenvironments using a panel of monoclonal antibody reagents that included markers of epithelial cell maturation, markers of mesodermal-derived fibrous tissue and vessels, markers of specific keratins, and markers of major histocompatibility complex Class I and II antigens. METHODS: Corneoscleral rims obtained after trephination of the donor button for use in penetrating keratoplasty procedures were studied. RESULTS: A comparison of cornea and conjunctiva with anti-epithelial and antikeratin antibodies demonstrated that corneal and conjunctival keratinocytes undergo similar antigenically defined pathways of maturation. However, the reactivity of antibody 12/1-2 (antibody against low molecular weight keratins) with conjunctival but not corneal basal cells suggested differences in keratin expression between the two epithelial types. Using antibodies against major histocompatibility complex Class I and II antigens, it was demonstrated the two tissues were similar with Class I determinants found on all epithelial, stromal, and endothelial cells, and Class II determinants found on Langerhans' cells, vessels, and a subset of stromal cells. CONCLUSIONS: The availability of tissue-specific markers of epithelial and nonepithelial components of the cornea and conjunctiva should be of use in the study of the roles the ocular microenvironment might play in the pathogenesis of ocular inflammatory diseases.

Animals↗
PubMed1994

Age-dependent regulation of the tumorigenic potential of neoplastically transformed rat liver epithelial cells by the liver microenvironment.

Neoplastically transformed rat liver epithelial cell lines (GN6TF and GP7TB), which form tumors with short latency at s.c. or i.p. transplantation sites of syngeneic rats, did not form tumors or were weakly tumorigenic following transplantation into the livers of young adult rats and expressed increasing tumorigenicity in livers of increasingly aged rats. These results suggest that progressive alterations in the hepatic parenchyma with increasing age enabled tumor formation by providing a less suppressive microenvironment for expression of the tumorigenic phenotype. Age is widely recognized as a significant risk factor in the development of neoplasia; this study describes a model for investigation of the influence of age-dependent changes in the hepatic microenvironment on the development of hepatic cancer.

Age Factors↗
PubMedDate not supplied

Neglected factors in cancer treatment: cellular interactions and dynamic microenvironment in solid tumors.

Solid tumors are "organoids" consisting of highly heterogeneous populations of malignant, stromal and inflammatory cells and dynamic extracellular matrix. In particular, distinct cellular microenvironments are observed. The survival strategies of malignant cells might therefore be highly differentiated, causing the high genotypic and phenotypic instability characteristic of malignant cells in vivo. A constant interplay between the tumor compartments and the host immune and hemostatic systems determines the behavior of the tumor. A description of typical microenvironments and of cellular and matrix interactions is provided. Based on these, it is here postulated that: (a) any cancer treatment, by influencing differently the various tumor compartments, will alter previously established equilibria; (b) the behavior (growth, invasiveness, metastatic potential, resistance to further treatment) of a malignancy after treatment might be altered with respect to what is assumed in terms of effect of the treatment on the malignant cells alone.

Cell Communication↗
PubMed1993

The influence of tissue microenvironment (stroma and extracellular matrix) on the development and function of mammary epithelium.

The morphogenesis and functional differentiation of mammary epithelium depends on signalling from systemic hormones and on cues from the local tissue microenvironment. With regard to the latter, regulatory cues are mainly provided by two subcompartments of the mesenchyme/stroma [fibroblastic and adipocyte] and the subjacent basement membrane. During embryogenesis, fibroblastic mesenchyme determines the sexual phenotype of the gland while adipocyte mesenchyme controls mammary-specific ductal morphogenesis. In the juvenile animal, adipocyte stroma continues to support ductal expansion while fibroblasts negatively regulate ductal outgrowth via interactions with the epithelium possibly involving TGF-beta mediated deposition of collagen I and chondroitin sulphate. In the adult, evidence from culture studies show that the signals required for the induction of tissue-specific differentiation during pregnancy and maintenance of function during lactation arise primarily from basement membrane. Beta-casein synthesis is induced in single mammary epithelial cells embedded within a basement membrane matrix via an integrin-dependent pathway. Further support for a critical role for basement membrane in the functional differentiation of the gland comes from studies in involution where degradative loss of basement membranes correlates with loss of functional activity in the epithelium. Thus the extracellular matrix in conjunction with certain cytokines plays a central role in coordinating mammary epithelial development. The findings discussed give further credence to a modal where mammary epithelium, together with certain elements of the subjacent microenvironment, form a dynamic and reciprocally interactive functional unit that regulates tissue specific gene expression in the mammary gland.

Animals↗
PubMed1993

Hematopoiesis on cellulose ester membranes. XIII. A combination of cloned stromal cells is needed to establish a hematopoietic microenvironment supportive of trilineal hematopoiesis.

A mixture of stromal cells from murine bone marrow placed upon cellulose ester membranes (CEM) and then implanted intraperitoneally (i.p.) in mice results in a regenerated hematopoietic microenvironment which supports trilineal hematopoiesis. We used this model to study the capacity of 5 cloned murine stromal cell lines of marrow origin to support hematopoiesis in vivo: MBA-1 (fibroblast); MBA-2 (endothelial); MBA-13 (fibroendothelial); 14F1.1 (endothelial-adipose); and 14M1.4 (macrophage).10(7) stromal cells of a single cell line were applied to 1.5 cm2 CEM, which were folded into tubes and implanted i.p. into mice. Similarly, combinations of 4, 3 and 2 stromal cell lines were applied to CEM and implanted i.p. Single lines were implanted into syngeneic hosts of the same murine strain from which the clone was derived and into nude mice. Combinations of stromal cells were implanted only in nude mice to avoid allogeneic incompatibility. CEM implants were removed after intervals of 5 to 36 weeks and examined histologically. 1) Stromal cells of a single phenotype did not develop hematopoiesis. 2) A combination of 4 stromal phenotypes (MBA-1, MBA-2, MBA-13 and 14F1.1) formed a hematopoietic microenvironment supportive of trilineal hematopoiesis and bone. 3) The combination of 14F1.1 (endothelial adipose) + a second stromal phenotype--MBA-1 (fibroblast) or MBA-2 (endothelial) or MBA-13 (fibroendothelial) also supported trilineal hematopoiesis and bone. 4) CEM coated with MBA-13 or MBA-1 developed bone but no hematopoiesis. The endothelial-adipose phenotype appears to be essential to support hematopoiesis but requires other types of stromal cells--fibroblast, fibroendothelial or endothelial phenotype.

Animals↗
PubMed1993

Optimal erythroid cell production during erythropoietin treatment of mice occurs by exploiting the splenic microenvironment.

In this study, quantitative effects on erythroid cell production by a prolonged recombinant human erythropoietin (rhEpo) treatment of mice are presented. Epo treatments, given subcutaneously (s.c.) twice per day in doses of 0.5 to 500 U per day, were performed under steady-state production conditions. We found striking differences between the behavior of the different erythroid cell compartments (burst-forming unit erythroid [BFU-E], colony-forming unit erythroid [CFU-E] and erythroid precursors), as well as between the microenvironments of bone marrow and spleen. Whereas the total-body BFU-E was not changed by Epo, a redistribution of BFU-E from marrow to spleen occurred, resulting in decreasing marrow and increasing splenic BFU-E numbers. Splenic BFU-E produced CFU-E as much as 8 times more efficiently than marrow BFU-E at 50 U of Epo. At low Epo doses (to 1 U/day) no difference was found. The CFU-E in the spleen produced erythroblasts at a higher efficiency at all Epo doses (1.5 to 5 times). It seems as if this efficiency was higher at low Epo doses. Because of the migration phenomenon and the excellent microenvironment in the spleen, at the highest Epo concentrations nearly 70% of all erythroid cells reside in the spleen. Even at the highest Epo doses, granuloid cell production was not affected. Similar to the BFU-E, total-body granuloid cells remained constant (despite a shift of granulocyte-macrophage progenitors [CFU-GM]) from marrow to spleen; however, these cells did not flourish in the spleen. Under these conditions, 90% of the granuloid precursors were still localized in the marrow. Erythropoietin did not change the transit time of erythroid cells at high Epo doses.

Animals↗
PubMed1993

Regulation of the differentiation of diploid and some aneuploid rat liver epithelial (stemlike) cells by the hepatic microenvironment.

Following intrahepatic transplantation in adult syngeneic Fischer 344 rats, diploid cultured rat liver epithelial cells (WB-F344), modified to carry the Escherichia coli beta-galactosidase reporter gene and/or the fluorescent membrane dye PKH26-GL, integrate into hepatic plates and acquire the size and nuclear structure of mature hepatocytes. Additionally, of two aneuploid, neoplastically transformed derivatives of WB-F344 cells, both of which produce aggressively growing tumors when transplanted subcutaneously, cells of one line (GN6TF) do not produce tumors in the liver but integrate into hepatic plates and morphologically differentiate. The other transformed line (GP7TB) retains tumorigenicity in the liver, but cells in the intrahepatic tumors are more differentiated morphologically than are tumors at subcutaneous sites. These results suggest that WB-F344 cells are stemlike cells for hepatocytes and that the hepatic microenvironment induces them to incorporate into hepatic plates and differentiate. Our results also suggest that the hepatic microenvironment regulates the differentiation of some neoplastically transformed hepatic stemlike cells, thereby eliminating or reducing their tumorigenic potential.

Aneuploidy↗
PubMedDate not supplied

[Regulating effect of the hematopoiesis-inducing microenvironment on hematopoietic processes as affected by cytostatic drugs].

The study of bone marrow hemopoiesis, the count of hemopoietic precursor cells, bone marrow structural and functional organization, the level of humoral stimulators and secretion by hemopoiesis-inducing microenvironment (HIM) cells following a single injection of 5-fluorouracil, cyclophosphamide or adriamycin has found out that cytostatic-related changes in hemopoiesis recovery depend primarily on relationships between proliferation and differentiation of hemopoietic cells. These relationships are dictated by the state of HIM cells. Enhanced functional activity of HIM elements in response to hemopoietic tissue damage caused by adriamycin or cyclophosphamide promotes rapid hemopoiesis regeneration. At the same time, 5-fluorouracil gave rise to prolonged bone marrow hypoplasia, severe disorder of microenvironment cell function.

Animals↗
PubMed1996

Functional heterogeneity of the hematopoietic microenvironment: rare stromal elements maintain long-term repopulating stem cells.

It has been hypothesized that distinct stromal cells from niches within the microenvironment that selectively regulate stem cell functions. To test this hypothesis, we derived a panel of matched stromal cell lines from murine fetal liver. The lines were immortalized with a retroviral vector encoding a temperature sensitive SV40 T antigen, to provide a snapshot of potential heterogeneity of the in vivo stroma compartment. All the stromal cell lines tested, supported the proliferation and differentiation of myeloid cells in Dexter type bone marrow cultures. Furthermore, RT-PCR analysis indicates that these lines are similar with respect to the production of an array of cytokines. However, the stromal cell lines differed markedly in their ability to maintain in vitro stem cells with in vivo repopulating capacity. Stem cell levels were measured in the competitive repopulation assay, following 3 weeks of coculture on individual stromal cell lines. Three classes of stromal cell lines were identified: (1) lines that did not support stem cells, (2) lines that sustained low levels of stem cells that often showed limited persistence in vivo, and (3) an infrequent line (1 out of 16 lines tested) that maintained high levels of primitive, long-term repopulating stem cells. This suggests that stromal cells that can support primitive stem cells are rare in the hematopoietic microenvironment. Taken together, these data substantiate the hypothesis that distinct stromal cells interact selectively with stem cells.

Animals↗
PubMed1996

Quantitation and physiological characterization of angiogenic vessels in mice: effect of basic fibroblast growth factor, vascular endothelial growth factor/vascular permeability factor, and host microenvironment.

A prerequisite for the development of novel angiogenic and anti-angiogenic agents is the availability of routine in vivo assays that permit 1) repeated, long-term quantitation of angiogenesis and 2) physiological characterization of angiogenic vessels. We report here the development of such an assay in mice. Using this assay, we tested the hypothesis that the physiological properties of angiogenic vessels governed by the microenvironment and vessel origin rather than the initial angiogenic stimulus. Gels containing basic fibroblast growth factor (bFGF) or vascular endothelial growth (VEGF) were implanted in transparent windows in the dorsal skin or cranium of mice. Vessels could be continuously and non-invasively monitored and easily quantified for more than 5 weeks after gel implantation. Newly formed vessels were first visible on day 4 in the cranial window and day 10 in the dorsal skinfold chamber, respectively. The number of vessels was dependent on the dose of bFGF and VEGF. At 3000 ng/ml, bFGF- and VEGF-induced blood vessels had similar diameters, red blood cell velocities, and microvascular permeability to albumin. However, red blood cell velocities and microvascular permeability to albumin were higher in the cranial window than in the dorsal skinfold chamber. Leukocyte-endothelial interaction was nearly zero in both sites. Thus, newly grown microvessels resembled vessels of granulation and neoplastic tissue in many aspects. Their physiological properties were mainly determined by the microenvironment, whereas the initial angiogenic response was stimulated by growth factors.

Animals↗
PubMedDate not supplied

An in vivo model for evaluating wound repair and regeneration microenvironments.

BACKGROUND: Factors differentially regulating regeneration and repair as contrasting resolutions to injury are unknown. We adapted a common wound healing model to further characterize mammalian wound repair and regeneration microenvironments. METHODS: Polyvinyl alcohol sponges, sponges containing minced muscle, or blocks of minced muscle were implanted onto the backs of Fischer rats. Vascularization was assessed by infusion with india ink and progress of regeneration was evaluated histologically. RESULTS: Regeneration occurring within sponges was histologically similar to that of free muscle blocks; but, was initiated more slowly. Vascularization of minced muscle implanted in sponges was delayed slightly compared to implanted free muscle blocks. CONCLUSIONS: Regeneration of minced muscle in sponges parallels normal regeneration of free minced muscle. Incorporation into a wound repair model provides access to interstitial fluids conditioned by regenerating muscle and will lead to more detailed comparisons of the content and properties of repair and regeneration microenvironments.

Animals↗