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PubMed1991

Ultrastructure of bone marrow tissue in so-called primary (idiopathic) myelofibrosis-osteomyelosclerosis (agnogenic myeloid metaplasia). II. The myeloid stroma (hematopoietic microenvironment).

An ultrastructural study was performed on bone marrow tissue in 8 patients revealing early and late stages of so-called primary (idiopathic) myelofibrosis - osteomyelosclerosis (agnogenic myeloid metaplasia) to evaluate the constituents of the hematopoietic microenvironment (myeloid stroma). A survey of the stroma cells disclosed an overall increase, particularly in so-called undifferentiated (primitive - pluripotent), but also in transitional (fibroblastic) reticular cells and myofibroblasts. The most primitive reticular cells were characterized by their stellate aspect with elongated slender cytoplasmic processes traversing the interstitial space, and by the scarcity of organelles. The transition into a fibroblast was preceded by the appearance of branching cisternal structures of the rough endoplasmic reticulum, extensively developed Golgi fields and an abundance in mitochondria. Frequently, so-called myofibroblasts were encountered displaying bundles of filaments along the subplasmalemmal region. Extracellularly fibrillar material with an irregular cross-banding as well as microfibrils could be observed. The many vascular structures (sinusoids and capillaries) exhibited a multilayered basement membrane-like material including many fibrils and adventitial cells (pericytes, smooth muscle and transitional reticular cells) with numerous cytoplasmic processes. Undifferentiated and transitional reticular cells as well as myofibroblasts seem to form an integral part of the hematopoietic microenvironment in OMF and are assumed to play an important role for the evolution of the disease-specific myelofibrosis in this disorder.

Bone Marrow↗
PubMed1985

The human thymic microenvironment. Phenotypic characterization of Hassall's bodies with the use of monoclonal antibodies.

The human thymic microenvironment is important in promotion of T cell maturation, particularly during early stages of thymic ontogeny. Hassall's bodies (HB) are epithelial swirls in the human thymic medulla that are thought to be derived from endocrine medullary thymic epithelium. To study the ontogeny and function of various components of the human thymic microenvironment, we have produced four monoclonal antibodies (TE-8, TE-15, TE-16, and TE-19) that selectively reacted in thymus with HB. Antibodies TE-8 and TE-16 reacted with the cells forming the outer rim of the HB swirl. Antibody TE-19 reacted with the entire cellular portion of HB and with epithelial cells immediately surrounding HB. Granular foci in the cellular swirls of greater than 90% of HB reacted with antibody TE-15. During thymic ontogeny, the antigens defined by antibodies TE-8, TE-15, TE-16, and TE-19 were first detected in fetal thymus on HB beginning at 16 wk gestation, the age when HB morphologically appear in the thymus. Aberrant expression of the antigens corresponding to antibodies TE-8, TE-15, TE-16, and TE-19 was observed on thymic tissue from individuals with severe cellular immunodeficiency disease. In human skin, antibodies TE-8, TE-16, and TE-19 reacted with the stratum granulosum; antibody TE-15 reacted with the stratum corneum. Thus, with the use of antibodies TE-8, TE-15, TE-16, and TE-19, we have identified HB as antigenically distinct regions of endocrine thymic epithelium. Furthermore, we have shown that these anti-HB reagents also selectively react with epidermal keratinocytes in the terminal stages of keratinocyte maturation.

Animals↗
PubMed1989

Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review.

The objective of this review article is to summarize current knowledge of blood flow and perfusion-related parameters, which usually go hand in hand and in turn define the cellular metabolic microenvironment of human malignancies. A compilation of available data from the literature on blood flow, oxygen and nutrient supply, and tissue oxygen and pH distribution in human tumors is presented. Whenever possible, data obtained for human tumors are compared with the respective parameters in normal tissues, isotransplanted or spontaneous rodent tumors, and xenografted human tumors. Although data on human tumors in situ are scarce and there may be significant errors associated with the techniques used for measurements, experimental evidence is provided for the existence of a compromised and anisotropic blood supply to many tumors. As a result, O2-depleted areas develop in human malignancies which coincide with nutrient and energy deprivation and with a hostile metabolic microenvironment (e.g., existence of severe tissue acidosis). Significant variations in these relevant parameters must be expected between different locations within the same tumor, at the same location at different times, and between individual tumors of the same grading and staging. Furthermore, this synopsis will attempt to identify relevant pathophysiological parameters and other related areas future research of which might be most beneficial for designing individually tailored treatment protocols with the goal of predicting the acute and/or long-term response of tumors to therapy.

Adenosine Triphosphate↗
PubMed1989

Role of the microenvironment on hematopoiesis. I. Stem cell differentiation into granulocytic and megakaryocytic cell lineage.

Lineage commitment and differentiation of stem cells derived from bone marrow was investigated by using specific histochemistry for identification of spleen colonies. The number of colonies formed by injection of 1 x 10(5) bone marrow cells into irradiated murine syngeneic recipients was similar to the previously reported results with 1 x 10(6) spleen cells. The results of this study with bone marrow-derived cells have been compared with those from studies done with spleen-derived cells. A significant increase (p less than 0.01) was observed in the number of granulocytic colonies formed by bone marrow cells versus spleen-derived cells. This suggests that bone marrow-derived cells promote granulopoiesis in the recipient spleen. A 50% increase of megakaryocyte colonies was observed within the splenic pulp in the midzone region when compared with that on the surface (p less than 0.01). This indicates that the splenic microenvironment in this area was conducive for megakaryocytopoiesis. These results provide further evidence of the influence of the microenvironment on hematopoiesis.

Animals↗
PubMed1989

Role of the microenvironment on hematopoiesis. II. Regulation of cell kinetics in vitro during granulopoiesis and megakaryocytopoiesis.

A long-term liquid culture system derived from adult Syrian hamster spleen that supports hematopoiesis from a single inoculum without supplemental coritcosteroids was used. Clonal assays from progenitor cells in the supernatant and adherent phases of liquid cultures revealed an increased concentration of myeloid and megakaryocytic progenitor cells in the adherent layer. Cell kinetic studies with these stable unstimulated cultures indicate that the initially labelling cohort of cells were present in the adherent cell layer. However, incorporation of tritiated thymidine into DNA occurred in less than 5% of the total cells present in the adherent cell layer. The data indicate that regulation of hematopoiesis by the stromal microenvironment was achieved by maintaining hematopoietic cells in a quiescent G0 or prolonged G1 phase and was associated with the initially labeling cells. The assays demonstrate the phenomenon that megakaryocyte precursors were present almost exclusively on the adherent stromal cell layer, which also contained a storage pool of mature megakaryocytes. The mature cells did not undergo further DNA synthesis and did not show morphologic changes of senescence. Cell kinetic studies revealed that megakaryocytes were released into the supernatant phase from the adherent stromal layer after endomitosis had occurred and cytoplasmic maturation ensued, indicating a role of stromal cells in megakaryocyte differentiation, maintenance, and maturation. The results of these investigations provide additional data on the regulation of megakaryocytopoiesis by the microenvironment.

Animals↗
PubMed1987

Morphological evidence of an altered bone marrow microenvironment in patients with acute nonlymphoblastic leukemia and myelodysplastic disorders.

Type IV nuclear bodies are classified as true intranuclear inclusions that ultrastructurally contain numerous densely packed 20- to 30-nm osmiophilic granules surrounded by a microfibrillar cortex. In the present study, we have found statistically significant ultrastructural differences in the frequency and size of type IV nuclear bodies in the in vitro bone marrow fibroblastic cells (FC) derived from eight nonleukemic subjects and 13 patients with acute nonlymphoblastic leukemia (ANLL) and myelodysplastic disorders (MDD). Patients with ANLL, MDD, and myelofibrosis, as a group, had four times as many type IV nuclear bodies as nonleukemic subjects. The mean frequency of type IV nuclear bodies for patients with ANLL and MDD was 2.68% +/- 3.27% as compared with 0.63% +/- 1.06% for the nonleukemic subjects (p less than 0.05). The mean maximum type IV nuclear body area of the ANLL and chronic myelomonocytic leukemia (CMML) patients as a group was 2.08 +/- 1.10 micron2, compared with a mean maximum area of 0.93 +/- 0.10 micron2 from nonleukemic subjects (p less than 0.05). The FC were otherwise morphologically indistinguishable and displayed the typical ultrastructural features of fibroblasts. These findings have provided the first morphologic evidence that supports the concept of an altered bone marrow microenvironment in patients with ANLL and MDD. Since type IV nuclear bodies are found in high frequency in virally infected tissues, our quantitative ultrastructural findings raise the possibility of a local viral infection that affects the bone marrow microenvironment of patients with ANLL and some MDD disorders.

Acute Disease↗
PubMed1978

Hematopoiesis on cellulose ester membranes (CEM). II. Enrichment of the hematopoietic microenvironment by the addition of selected cellular elements.

Cellulose ester membranes (CEM) were folded into a trilaminar open-ended tube which was implanted into the peritoneal cavity of mice. CEM rapidly acquired a stromal core with many features of marrow such as fat, fibroblasts, an abundant sinusoidal microcirculation and monocyte-macrophage-like cells. CEM took up 59iron, 99technetium sulfur colloid and produced CSF in in vitro culture but their microenvironment supported only granulopoiesis. CEM were coated on their interior surfaces with bone marrow or regenerating medullary cavity mesenchyme or bone but the stromal cores supported only granulopoiesis after 3 weeks to 3 months of implantation. CEM coated with spleen and implanted into mice developed trilineal hematopoiesis within 6 weeks with abundant erythropoiesis and megakaryocytopoiesis in addition to granulopoiesis. These CEM differed from splenic tissue in that only scattered lymphoid tissue was present. CEM coated with bone marrow and bone developed trilineal hematopoiesis but only after3--6 months of peritoneal implantation. CEM coated with regenerating medullary cavity mesenchyme failed to develop trilineal hematopoiesis. Cyclophosphamide injection did not enhance hematopoiesis. These experiments indicate that splenic, marrow and bone tissue contain stromal elements capable of being transferred onto CEM which then develop a microenvironment capable of supporting trilineal hematopoiesis.

Animals↗
PubMed1987

Reorganization of thymic microenvironments during development and lymphomagenesis.

Modulation of thymic microenvironments during ontogeny and lymphomagenesis in mice was studied with two rat monoclonal antibodies (moAb) which recognized distinct subpopulations of thymic epithelial reticular cells (TER). In adult thymus, the TER subpopulation stained by moAb B6TS-1 was localized in the subcapsular zone, cortico-medullary junction, and medulla. In fetal thymus, it was initially distributed throughout the rudiment, but after day 16 of gestation, it was rapidly redistributed to the locations seen in adult thymus. From an early stage of thymic lymphomagenesis, the TER bearing mB6TS-1 (epitope defined by moAb B6TS-1) in the cortico-medullary junction, in particular those associating with small blood vessels, proliferated and formed a characteristic network throughout the thymus, in which numerous growing lymphoma cells were entrapped. On the other hand, moAb AKTS-1 stained another TER subpopulation that was localized in the cortex in both fetal and adult thymus. Unlike mB6TS-1+ TER, mAKTS-1+ TER became increasingly sparser during lymphomagenesis. Selective proliferation of the mB6TS-1+ TER subpopulation in the cortico-medullary junction was seen in spontaneous, radiation-induced, and chemical-induced mouse thymic lymphomas. The possible biological significance of such modulation of thymic microenvironments in the natural history of lymphomagenesis is discussed.

Animals↗
PubMed1988

[Hematopoietic microenvironment: cellular and extracellular matrix elements].

In bone marrow, cellular stroma together with extracellular matrix (EM) provide an adequate microenvironment for the proliferation and differentiation of hemopoietic progenitor cells. In this article we describe studies on the cell characteristics of a main stromal phenotype, a fibroblast-like cell and its ability to produce in vitro EM components. Comparative studies were performed in fibroblast cultures derived from normal and acute lymphoblastic leukemic (ALL) bone marrow. The grow characteristics of fibroblasts from ALL marrow as well as its capacity to synthetize collagen, fibronectin and GAGs are impaired when compared to fibroblast from normal marrow. Thus, in ALL the impaired production of EM biomolecules by a transient damaged population of stromal cells, may contribute to the development of a defective microenvironment for hemopoiesis.

Bone Marrow Cells↗
PubMed1988

Lymphoid microenvironments in the thymus and lymph node.

The three-dimensional architecture of the thymus and mesenteric lymph node reveals several different stromal cell types important in the development and function of T cells. In the thymic cortex, T cells proliferate and differentiate in a meshwork of epithelial-reticular cells. They then migrate towards the medulla where they may interact with interdigitating cells. T cells migrate from the thymus through perivascular spaces, surrounding large vessels at the cortico-medullary boundary. In this area also large thymic cystic cavities are found, their function remains at present unclear. Mature "selected" T cells leave the thymus most probably by the venous bloodstream, to enter peripheral lymph nodes. Upon entering the lymph node they cross the wall of high endothelial venules. On the other hand, lymph enters the node by afferent lymphatics draining into various types of sinuses. Here, macrophages are strategically located to phagocytose and process antigen. These cells then expose antigen to T cells and B cells within the lymph node parenchyma, thus creating a microenvironment for the onset of an immune response. The various microenvironments important in T cell development and T cell function are shown in this paper using scanning electron microscopy as a dissecting tool. We discuss our morphological findings in the light of recent data on the physiology of T cell differentiation and function.

Animals↗
PubMed1987

Differential elaboration of prostaglandin E2 by cells of the hemopoietic microenvironment in response to endotoxin.

Eight daily intraperitoneal injections of endotoxin (LPS) induced hematologic abnormalities in mice like those previously observed with chronic inflammation, sterile abscess, and tumor bearing. By the ninth day, anemia, leukocytosis, hypocellularity of the bone marrow, and compensatory hemopoietic hyperplasia of the spleen had occurred. The suppressed hemopoietic recovery and impaired survival of mice with these abnormalities, after receiving an ordinarily sublethal dose of total body irradiation (600 cGy T.B.), confirmed their importance to the intact mouse and suggested that splenic hyperplasia was insufficient to compensate for a total body deficit of functional hemopoietic stem cells. Atrophy of hemopoietic tissue in the marrow with hyperplasia in the spleen implicated changes in the hemopoietic microenvironment to account for the different responses to endotoxin. Prostaglandin E2 (PGE2) serves as an important mediator of the inflammatory response and profoundly affects hemopoiesis. Previous studies had shown that low concentrations of PGE2 enhanced, and high concentrations suppressed erythropoiesis in vitro; therefore, we wondered whether stromal cells from the marrow's microenvironment produced more PGE2 in response to LPS than splenic stromal cells to explain the suppression of hemopoiesis in the marrow and its enhancement in the spleen. Indeed, synthesis of PGE2 in primary short-term cultures of adherent marrow stromal cells in response to LPS proved much greater than that observed in cultures of splenic stromal cells. Extending adherence times from 3 to 24 to 48 hours did not change the relationship. We believe that the results of our studies point to a role of PGE2 in the microenvironmental modulation of hemopoiesis in mice with activation of the inflammatory response.

Animals↗
PubMed1987

[The microenvironment and hematopoiesis].

Successive steps in hematopoietic differentiation occur in the bone marrow in close contact with non hematopoietic components of the microenvironment. The crucial importance of these interactions in the regulation of early hematopoietic events has been convincingly demonstrated in vivo in the mutated steel mouse, and confirmed more recently in vitro in long-term cultures. Parts of the signal mediating these interactions are represented by locally secreted CSF-like growth factors or more recently characterized inhibitors of proliferation. more importantly however appears to be direct cell-cell communication, especially in the regulation of erythropoiesis and recent data suggest that specific adhesion processes might be required initially. As neoplastic clonal dominance is usually not maintained in vitro, experimental evidence for the involvement of the microenvironment in the regulation of leukemic hemopoiesis is still pending. However, it has been shown recently that in some conditions stromal cells may be manipulated in vitro and alter growth properties of leukemic cells. Understanding mechanisms regulating the interactions between hematopoietic and stromal cells may be of considerable importance since it should be possible to delineate and subsequently modulate in vitro the factors affecting stem cell properties. This might lead to alternative therapeutic strategy.

Animals↗
PubMed1983

Hemopoietic stromal precursors in long-term culture of bone marrow: II. Significance of initial packing for creating a hemopoietic microenvironment and maintaining stromal precursors in the culture.

Conversion of bone marrow cells to a single cell suspension prevents them from creating a hemopoiesis maintaining adherent cell layer (ACL) in culture. The ACL of such cultures is devoid of hemopoietic stromal precursors capable of transferring the hemopoietic microenvironment on implantation under the renal capsule of syngeneic mice. The regeneration of ACL after injury is possible in 1-wk-old, but not older, Dexter-type bone marrow cultures. The results prove the significance of the initial packing of the bone marrow cells in the differentiation of the hemopoietic stromal precursors. These data contradict previous reports which concluded that the structural orderliness of stromal tissue need not be preserved for the hemopoietic microenvironment to be transferred.

Animals↗
PubMed1982

Modulation of the immune response by anaphylatoxin in the microenvironment of the interacting cells.

It was shown that the anaphylatoxins C3a and C5a can modulate in vitro immunological reactivities. C3a suppresses both the in vitro polyclonal antibody response and the specific antibody response to sheep red blood cells (SRBC) of both mouse spleen cells and human peripheral blood cells. The target cell in the mouse for C3a appears to be an Lyt-1+2- suppressor-inducer cell and macrophages appear not to be required. In contrast to C3a, C5a enhances in vitro responses of mice. Both the response to SRBC and the mixed lymphocyte reaction are enhanced by C5a. This enhancement appears to be through an Ia- macrophage that contains receptors for C5a. It appears that enhancement may be brought about by interleukin 1, which is released when Ia- macrophages are pulsed with C5a. It is suggested that these anaphylatoxins, when present in high concentrations in the microenvironment of the interacting cells of the immune system, play a dynamic role in the regulation of the immune response. Peptide fragments cleaved from the Fc portion of antibody, complexed with antigen in this microenvironment, may have a similar regulating role.

Animals↗
PubMed1983

Diffusion in the slice microenvironment and implications for physiological studies.

The brain cell microenvironment includes the extracellular space surrounding the cell together with the cellular elements that define the space. The dense packing of cells in the mammalian nervous system ensures that the extracellular space is narrow but highly complex in geometry. Recent studies with ion-selective micropipettes have revealed that the cerebellar slice can support changes in [K+]o that resemble those seen in the intact preparation. In the slice, [K+]o responses of individual cells can even be resolved. Studies with iontophoretic techniques and quantitative analysis in the slice have shown that the extracellular space has diffusion properties, characterized by a volume fraction and a tortuosity, that are very similar to those seen in the intact animal. These data confirm that the microenvironment in the slice is comparable to that in the intact animal. The diffusion parameters can be used to make predictions about the time necessary for substances to diffuse into slices under various conditions. Such estimates, together with other studies, indicate that it is probably inadvisable to use slices with thicknesses in excess of 300--400 micrometers, and that the bathing conditions can be critical in maintaining slice viability.

Animals↗
PubMed1983

Cell microenvironment and carcinogenesis in vivo and in vitro.

Normal cells of many types are located in vivo and in vitro at the boundary between the two compartments of their microenvironment: between the noncellular surface (artificial substrates and cell-made matrices) and the humoral medium. Altered reactions to both these parts of microenvironment and to neighbouring cells are characteristic of neoplastic cells. Due to deficient spreading on the substrate and to decreased anchorage-dependence of growth, neoplastic cells become less demanding in their requirements for the noncellular substrate. These data obtained in vitro suggest that neoplastic cells in vivo may be less specific in their territorial requirements than are normal cells. Formation of promoting territories, that is, of boundaries between the humoral medium and abnormal non-cellular matrix, may play an important role in many types of carcinogenesis. In particular, capsules around implanted plastic films can be regarded as promoting territories for proliferation of neoplastic cells at the early stages of foreign body carcinogenesis. The role of local changes in tissue environment in carcinogenesis and, in particular, the importance of stromal factors, were advocated many years ago by such investigators as Ribbert, Fischer-Wasels, Bogomolez, Orr and others. The study of this problem is now gaining new momentum, due mainly to recent advances in the understanding of interactions of normal and neoplastic cells with their environment in cultures. In the first part of this communication I summarize briefly some conclusions obtained in studies in vitro. In the second part, I discuss the possible role of environmental changes in certain types of carcinogenesis in vivo, and especially in foreign body carcinogenesis.

Animals↗
PubMed1981

Haemopoietic microenvironments in vitro: ultrastructural aspects.

Haemopoietically active long-term bone marrow cultures from several species have been investigated ultrastructurally. Human, tree shrew and mouse cultures generally support granulopoiesis, although recently it has been possible to convert a granulopoietic mouse culture to extensive erythropoiesis. The haemopoietic products of the cultures include granulocytes (neutrophil and basophil), mast cells, monocytes, megakaryocytes and all stages of the erythrocytic series. Plasmacytes and occasional lymphocytes have been observed in small numbers in human cultures (possible indicating retention rather than formation). The stromal elements of the adherent layer of these cultures include endothelial cells, reticulum cells, fat cells and fibroblasts. The adherent layers are responsible for the inductive microenvironment within the cultures, and show features specific for the line of differentiation. In the granulocytic cultures there is close association between developing fat cells (reticulum cells) and granulocyte precursors. Endothelial cell monolayers cover large regions of these cultures, and the areas beneath this monolayer are rich in early granulocytes. Mature granulocytes and monocytes migrate through the endothelial layer, demonstrating in vitro "transmural passage". Cultures stimulated for erythropoiesis show a considerable reduction in fat cells, in endothelial cell cover and in the numbers of classical monocytes. Erythropoiesis appears to be promoted by a close association of the entire erythrocytic series with monocytic cells, forming "erythroblastic islets" in vitro. A possible pathway of intracellular communication between differentiating haemopoietic cells and the stromal cells in their microenvironment is suggested.

Adipose Tissue↗
PubMed1982

Dissecting the hematopoietic microenvironment. V: limitations of repair following damage to the hematopoietic support stroma.

Damage and repair of the hematopoietic microenvironment of the spleen was studied using X-irradiation, anoxic necrosis induced by splenic ligation, or a combination of the two, as the destructive agents. Spleen colony number, size and type, 59Fe uptake, and microscopic study of splenic structure were used as means of assessment. The most severe or least repaired damage was induced by high dose irradiation (4000 r), by 1000 r followed immediately by splenic ligation, and by two successive splenic ligations separated by a 30 day recovery period. It was seen that reduction of CFUs lodgment, as measured by f factor, played a very major role in the lesser number of spleen colonies formed after either kind of damage. Following the several treatments, the numbers of spleen colonies formed, their size and their typing as erythrocytic or granulocytic varied independently of each other, suggesting that these functions of the microenvironment, and the cell types responsible for them, are independent of each other. The exhaustion of regenerative capacity displayed by repeatedly ligated spleens suggested a maximal limit for stromal cell replications commensurate with Hayflick's hypothesis.

Animals↗