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PubMedDate not supplied

Development of the definitive hematopoietic hierarchy in the mouse.

Recent research on the ontogeny of the hematopoietic system in mammals has shown that a simple textbook steady-state hematopoietic hierarchy can not be strictly applied to the hematopoietic cells found within the embryo. During embryonic development, hematopoietic cells originate, migrate and differentiate in a number of distinct anatomical sites such as the yolk sac AGM region and liver and thus represent various classes of cells within diverse microenvironments. In this manuscript we review both cellular and molecular aspects of developmental hematopoiesis and present our current views on the numerous complex mechanisms underlying the establishment of definitive hematopoiesis.

Animals↗

PubMed2003

Thymic generation and regeneration.

The thymus is a complex epithelial organ in which thymocyte development is dependent upon the sequential contribution of morphologically and phenotypically distinct stromal cell compartments. It is these microenvironments that provide the unique combination of cellular interactions, cytokines, and chemokines to induce thymocyte precursors to undergo a differentiation program that leads to the generation of functional T cells. Despite the indispensable role of thymic epithelium in the generation of T cells, the mediators of this process and the differentiation pathway undertaken by the primordial thymic epithelial cells are not well defined. There is a lack of lineage-specific cell-surface-associated markers, which are needed to characterize putative thymic epithelial stem cell populations. This review explores the role of thymic stromal cells in T-cell development and thymic organogenesis, as well as the molecular signals that contribute to the growth and expansion of primordial thymic epithelial cells. It highlights recent advances in these areas, which have allowed for a lineage relationship amongst thymic epithelial cell subsets to be proposed. While many fundamental questions remain to be addressed, collectively these works have broadened our understanding of how the thymic epithelium becomes specialized in the ability to support thymocyte differentiation. They should also facilitate the development of novel, rationally based therapeutic strategies for the regeneration and manipulation of thymic function in the treatment of many clinical conditions in which defective T cells have an important etiological role.

Animals↗

PubMed2000

In situ oxidative catalysis by neurofibrillary tangles and senile plaques in Alzheimer's disease: a central role for bound transition metals.

There is a great deal of evidence to support a pathogenic role of oxidative stress in Alzheimer's disease (AD), but the sources of reactive oxygen species have not been directly demonstrated. In this study, using a novel in situ detection system, we show that neurofibrillary tangles and senile plaques are major sites for catalytic redox reactivity. Pretreatment with deferoxamine or diethylenetriaminepentaacetic acid abolishes the ability of the lesions to catalyze the H2O2-dependent oxidation of 3,3'-diaminobenzidine (DAB), strongly suggesting the involvement of associated transition metal ions. Indeed, following chelated removal of metals, incubation with iron or copper salts reestablished lesion-dependent catalytic redox reactivity. Although DAB oxidation can also detect peroxidase activity, this was inactivated by H2O2 pretreatment before use of DAB, as shown by a specific peroxidase detection method. Model studies confirmed the ability of certain copper and iron coordination complexes to catalyze the H2O2-dependent oxidation of DAB. Also, the microtubule-associated protein tau, as an in vitro model for proteins relevant to AD pathology, was found capable of adventitious binding of copper and iron in a redox-competent manner. Our findings suggest that neurofibrillary tangles and senile plaques contain redox-active transition metals and may thereby exert prooxidant or possibly antioxidant activities, depending on the balance among cellular reductants and oxidants in the local microenvironment.

3,3'-Diaminobenzidine↗

PubMed2000

Effects of very high antibiotic concentrations on human intervertebral disc cell proliferation, viability, and metabolism in vitro.

STUDY DESIGN: Four antibiotics commonly used during spinal surgery (cefazolin, gentamycin, cefamandole, and vancomycin) were tested for their effects on cultured human disc cells from the anulus. OBJECTIVE: To determine the viability, proliferation, and metabolism of cells cultured from the human anulus after they were exposed to four antibiotics. SUMMARY OF BACKGROUND DATA: Previous studies concerning the effect of antibiotics on the disc have used animal models or explanted discs, but little is understood about the effect of antibiotics on the proliferation, viability, and metabolism of cells from the anulus. METHODS: In this study, 3H-thymidine incorporation, trypan blue exclusion, and cell metabolism were determined using cells from the human anulus grown in monolayer culture. The latter measurement used a cytosensor microphysiometer to monitor the rate at which cells acidified their microenvironment, an event that is proportional to cellular metabolism because it reflects the excretion over time of acidic products such as lactic acid from glycolysis and CO2 from cellular respiration. RESULTS: After 48 hours of antibiotic exposure, cell viability was significantly lower as a result of all four antibiotics at the highest concentration tested. Cell proliferation was lower after exposure to cefazolin and cefamandole. During a 6-hour antibiotic exposure, anulus cells in the highest concentration of cefamandole or vancomycin displayed a significantly decreased rate of cell metabolism. CONCLUSIONS: These findings show that high doses of antibiotics can have direct, deleterious effects on cultured disc cell survival, cell proliferation, and metabolic rates. Discitis is a serious primary or postoperative complication that often requires prolonged antibiotic treatment. Studies such as the current investigation with cultured cells from the anulus show the importance of a greater understanding concerning antibiotic effects on disc cell proliferation and metabolism.

Adult↗

PubMed1988

A possible role for taurine in osmoregulation within the brain.

Intracranial microdialysis was used to measure changes in extracellular amino acids within the rat brain during local osmotic alteration of the extracellular microenvironment or during systemic water intoxication. Increased cellular hydration produced by either of these methods was accompanied by a marked increase in extracellular taurine levels without affecting the other amino acids measured. With local osmotic alteration, this increase was osmolarity dependent and reversible. The specificity, sensitivity, and reversibility of the increase in extracellular taurine strongly suggest a functional role in osmoregulation in the brain under normal as well as pathological conditions.

Animals↗

PubMed1992

Epidermal growth factor receptor in odontogenic cysts and tumors.

The expression of epidermal growth factor receptor (EGFR) was investigated in 67 cases of odontogenic cysts and 35 cases of odontogenic tumors using monoclonal antibody to EGFR (Biomarker, Israel) to determine the presence and significance of this transmembrane growth factor receptor. The cystic epithelial cells of odontogenic cystic lesions (keratocyst 60%; primordial cyst 75%; radicular cyst 35%; and follicular cyst 47.4%) were positive to EGFR staining. Cytochemical characterization of EGFR in those cystic epithelium was cell membrane positive type as in the normal epithelium. No expression of EGFR was found in the odontogenic tumors. This diversity of EGFR represents no binding activity of EGF, or loss of EGFR in the tumor cell upon EGFR mediated growth in odontogenic tumors was suggested a different tumor cell growth factor status or microenvironment in cell proliferation mechanism at the cellular level in cysts and tumors of odontogenic origin.

Ameloblastoma↗

PubMed2005

Molecular evaluation of BK polyomavirus nephropathy.

Understanding at a molecular level, the immunologic response of polyomavirus nephropathy (PVN), a critical cause of kidney graft loss, could lead to new targets for treatment and diagnosis. We undertook a transcriptional evaluation of kidney allograft biopsies from recipients with PVN or acute rejection (AR), as well as from recipients with stable allograft function (SF). In both the PVN and AR groups, Banff histologic scores and immunohistochemical analysis of inflammatory infiltrates were similar. Despite their different etiologies, the transcriptional profiles of PVN and AR were remarkably similar. However, transcription of genes previously linked to AR including CD8 (65.9 +/- 18.8) and related molecules IFN-gamma(55.1 +/- 17.0), CXCR3 (49.9 +/- 12.8) and perforin (153.8 +/- 50.4) were significantly higher in PVN compared to AR (30.9 +/- 2.0, 14.0 +/- 7.3, 12.1 +/- 7.3 and 15.6 +/- 3.8-fold, respectively; p < 0.01). Importantly, transcription of molecules associated with graft fibrosis including matrix collagens, TGFbeta, MMP2 and 9, as well as markers of epithelial-mesenchymal transformation (EMT) were significantly higher in PVN than AR. Thus, renal allografts with PVN transcribe proinflammatory genes equal in character and larger in magnitude to that seen during acute cellular rejection. BK infection creates a transcriptional microenvironment that promotes graft fibrosis. These findings provide new insights into the intrarenal inflammation of BK infection that promotes graft loss.

Adult↗

PubMed1997

Expression and function of adhesion receptors in acute myelogenous leukemia: parallels with normal erythroid and myeloid progenitors.

A variety of adhesion receptors are expressed on the blast cells in patients with acute myelogenous leukemia. The panel of receptors expressed demonstrates heterogeneity just as there is morphologic, histochemical, cytogenetic, and molecular genetic variation between various cases of acute myelogenous leukemia. The adhesion receptors expressed contain representatives of all the main classes of adhesion receptors, but often there is no correlation of the adhesion receptor phenotype with the morphologic or clinical features of acute myelogenous leukemia. These receptors function in interactions of myelogenous leukemia blasts with the cellular and matrix components of the marrow microenvironment, and there is evidence that they are involved in blast release from marrow and in homing of blasts to extramedullary sites. Evidence is starting to accumulate suggesting that adhesive interactions may influence the proliferation and survival of leukemic cells, but the precise role that these molecules play in the generation and sustenance of the leukemic state remains undetermined.

Acute Disease↗

PubMed2006

Splenic endothelial cell lines support development of dendritic cells from bone marrow.

Although growth factors are commonly used to generate dendritic cells (DCs) in vitro, the role of the microenvironment necessary for DC development is still poorly understood. The mixed splenic stromal cell population STX3 defines an in vitro microenvironment supportive of DC development. Dissection of cellular components of the STX3 stroma should provide information about a niche for DC development. STX3 was therefore cloned by single-cell sorting, and a panel of 102 splenic stromal cell lines was established. Four representative splenic stromal cell lines that support hematopoiesis from bone marrow are described here in terms of stromal cell type and DC production. All four stromal lines express the endothelial genes Acvrl1, Cd34, Col18a1, Eng, Flt1, Mcam, and Vcam1 but not Cd31 or Vwf. Three of the four lines form tube-like structures when cultured on Matrigel. Their endothelial maturity correlates with the ability to support myeloid DC development from bone marrow. A fourth cell line, unable to form tube-like structures in Matrigel, produced large granulocytic cells expressing CD11b and CD86 but not CD11c and CD80. Conditioned media from splenic stromal cell lines also support DC production, indicating that soluble growth factors and cytokines produced by stromal lines drive DC development. This article reports characterization of immature endothelial cell lines derived from spleen that are supportive of DC development and predicts the existence of such a cell type in vivo which regulates DC development within spleen.

Animals↗

PubMedDate not supplied

Corticosteroid-induced osteoporosis: pathogenesis and prevention.

In spite of their adverse side effects, natural and synthetic glucocorticoids (GCs) occupy a unique role in several fields of medicine. They are potent regulators of bone cell growth and differentiation and the actions on the skeleton and related tissues depend on several factors including the dose, duration of the exposure, the steroid type and the species. In humans some of the effects are indirect, such as the regulation of intestinal calcium absorption and PTH secretion. Other effects are due to the cellular response that occurs within the bone microenvironment. It has been well established in in vitro studies that GCs can promote osteoblast differentiation from mesenchymal osteoprogenitors both in rat calvarial culture and in adherent marrow stromal cells. Moreover, GCs are able to enhance expression of the mature osteoblast phenotype, increasing mineralized nodules, osteocalcin secretion, and the bone morphogenetic protein-6 message level. However, the mechanisms by which GCs affect bone metabolism are still unclear. Recent studies with GCs on bone cells suggested that the production of cytokines and growth factors and the expression of their receptors may also be influenced by GCs. In fact, GCs are able to inhibit the synthesis of cytokines, such as interleukin-1 which stimulates bone remodeling by monocytes and macrophages. Moreover, osteoprotegerin, a recently cloned member of the tumor necrosis factor receptor family, is down-regulated by GCs, offering a possible interpretation for the induction of bone resorption by GCs. GC-induced inhibition of bone resorbing cytokines may contribute to explain the therapeutic actions of GCs in several diseases such as rheumatoid arthritis and myeloma. Furthermore, GCs modulate osteoclast recruitment, even if there is no clear explanation for a direct effect of GCs on osteoclastic precursors. Sustained stimulation of matrix degradation by isolated avian osteoclasts incubated with GCs has been reported, as well as cytotoxic effects on osteoclastic cells from neonatal rat long bones.

Glucocorticoids↗

PubMed1991

A catecholaminergic sensory neuron phenotype in cranial derivatives of the neural crest: regulation by cell aggregation and nerve growth factor.

Tyrosine hydroxylase (TH) is transiently detectable in cells distributed throughout cranial sensory ganglia during early stages of gangliogenesis [embryonic day (E) 10.5-15.5]. Although TH cells appear in embryonic ganglia of both neural crest and placode origin, mature cranial sensory neurons that express catecholaminergic properties are restricted to placode derivatives. The mechanism(s) underlying the loss of TH expression in crest-derived sensory ganglia is unknown, and the present study was undertaken to define the temporal regulation of this phenotype. Our data indicate that transient TH cells belong to a large subset of primary sensory neurons that exhibit the capability to express TH throughout development. The lack of TH expression after E15.5 appears to be due to modulation of this catecholaminergic potential. The phenotype reappears, however, when E16.5 and older ganglia are dissociated in culture into single cells, suggesting that factors associated with cell aggregation modulate TH expression. In support of this hypothesis, sensory neurons grown at high cell density exhibit lower levels of TH expression than low-density cultures. The decrease in TH levels seen at high density was associated with changes in sensory neuron morphology that are characteristic of ganglion cell maturation in vivo; therefore, modulation of TH expression may be only one facet of a more general program of sensory neuron differentiation associated with cell aggregation in developing ganglia. In contrast to the effects of cell aggregation, treatment with NGF increased the proportion of TH cells in dissociate cultures of E14.5 and E16.5 cranial sensory ganglia. Our findings indicate that sensory transmitter phenotype may be modulated by multiple factors during gangliogenesis, including cellular interactions intrinsic to the developing ganglionic microenvironment.

Animals↗

PubMed1991

Human B-lymphopoiesis is supported by bone marrow-derived stromal cells.

We have recently reported an in vitro culture system that allows the clonal growth and differentiation of normal human bone marrow B-lineage cells. In the report presented here, we have used this B-cell colony assay to study the influence of cellular components of the human bone marrow microenvironment on B-lymphopoiesis. It is demonstrated that bone marrow stromal cells were able to provide all the necessary requirements for the growth and differentiation of B-lineage cells under the conditions of the B-cell colony assay. These stromal cells were obtained from long-term bone marrow cultures (LTBMC) that had been established from the spicules in human bone marrow. When these stromal cells were plated as an adherent underlayer in the double-agar B-cell colony assay, both immature and mature B-lineage cells were induced to differentiate into colonies containing cells that secreted immunoglobulin. The stromal cells from these spicule-derived LTBMCs maintained the capacity to support B-cell colony formation for up to 9 months.

Antigens, CD↗

PubMed1977

In vivo bioelectrochemical changes associated with exposure to extremely low frequency electric fields.

One hundred seventy-four 21- to 24-day-old Sprague-Dawley rats were continuously exposed to a 60 Hz electric field of 150 V/cm for one month in ten separate experiments. Biological effects observed included depressed body weights, serum corticoids, and water consumption. The findings are tentatively in terpreted as indicating that a power frequency electric field is a biological stressor. The observed effects cannot be a consequence of Joule heating and therefore indicate that electric fields can influence biological systems either at the systemic level, or at the cellular level via electrochemical alteration of the microenvironment.

Adaptation, Physiological↗

PubMed1982

A note on dysenzymia in the liver of rats fed on zinc, an essential metal.

Although zinc in traces is essential for the growth and well being of the animal, however a long-term treatment has been found equally toxic to the liver and kidney. Present report describes its effects on few key enzymes viz. alkaline phosphatase, acid phosphatase, 5-nucleotidase, lipase, glucose-6-phosphatase, and cholinesterase in the liver of rat, Rattus rattus albino. Histochemical observations have provided visual evidences on Zn-induced dysenzymia. The results have further been interpreted in terms of its effects on cellular organelle, levels of enzyme protein and microenvironment of the hepatic parenchyma.

Acetates↗

PubMed1995

[Experience with the use of reaferon (alfa 2-interferon) for treating patients with chronic myeloleukemia].

The effectiveness of domestic alpha 2-interferon preparation reaferon was studied in vivo and in vitro for eradication of pathological hemopoietic clone in chronic myeloid leukemia. Reaferon administration for 1-30 months produced cytogenetic remission in 7%, hematological remission in 21%, partial hematological remission in 36% of the patients. Reaferon is indicated in chronic myeloid leukemia without splenomegaly. In the disease progression reaferon is uneffective. Mechanism of reaferon therapeutic action comprises three components: a direct antiproliferative effect on hemopoietic precursor cells, activation of cellular immunity, an effect on stem cell microenvironment.

Adult↗

PubMed1997

Arterial microvascularization and breast cancer colonization in bone.

Bone is one of the most preferential target organs of cancer metastases. Breast, prostate and lung cancers have a special predilection for colonization in bone. In an animal model in which inoculation of cancer cells into the left cardiac ventricle selectively develops osteolytic bone metastases but rarely forms metastases in non-bone organs, the pattern of breast cancer colonization in bone was studied radiologically and histologically. Colonization of cancer cells in bone was found to initiate and develop along with or at the terminal end of the major arteries running into bone. It should, therefore, be re-recognized that the anatomical vasculature still remains as a critical factor which influences cancer colonization in bone in addition to cellular and molecular properties of the bone microenvironment and metastatic cancer cells.

Animals↗

PubMedDate not supplied

Intrathymic non-lymphatic hematopoiesis during mammalian ontogenesis.

Histogenetically, the thymus is the primary lymphopoietic organ and provides an optimal microenvironment for the differentiation of T lymphocytes, independently of the influence of foreign antigens. Lymphocytes with diverse potential are produced in a protective microenvironment optimal for their maturation, whose dual cellular network is provided by endodermally derived RE cells and numerous ectomesenchymal cells derived from the neural crest. The full development of intrathymic hematopoiesis depends upon the successful completion of a series of well coordinated cellular interactions between widely divergent (in terms of origin) cells [epithelium (primitive pharynx); ectomesenchyrne (neural crest); and PHSCs (yolk sac, fetal liver)]. The cells of the thymic epithelial primordium do not proliferate in the absence of "inductive" interactions with the ectomesenchyme. Moreover, the nature of the mesenchyme determines the behavior of the thymic epithelial anlagen. The ectomesenchymal origin of chemotactic stem cell factor secretion, responsible for hemopoietic stem cell immigration, is a distinct possibility. The human thymus is a generalized hematopoietic tissue with between 7 to 9 weeks of ontogenesis. In human and dog fetuses various elements of mammalian hematopoiesis were identified intrathymically: B lymphocytes, plasma cells, erythropoietic and granulocytopoietic (neutrophils and eosinophils) cells, antigen presenting dendritic cells, and mast cells. Our light and ultrastructural (transmission and scanning), as well as immunocytochemical observations have established that during the embryonal and fetal period, the thymus is seeded by pluripotent, yolk sac derived PHSCs characterized by the following immunophenotype CD34+CD43+CD38-Lin-HLA-DR+CD69+. Stem cell c-kit tyrosine kinase (also referred to as mast cell growth factor, stem cell factor, or steel factor) in combination with autocrine and paracrine growth factors and cytokines (IL-3, IL-4, IL-5, IL-6, IL-7, G-CSF, etc.) stimulates myelopoiesis, including erythropoiesis, as well as lymphopoiesis. These hematopoietic growth factors are produced by activated lymphoblastic cells and stromal RE cells under the influence of immunoneuroendocrine regulation, supported by the finding that experimental or spontaneous, in vivo neural crest ablation during early mammalian ontogenesis always results in an abnormal development of the thymus, as well as the heart and great vessels, thyroid, and parathyroid glands.

Adolescent↗

PubMed2000

Diminished DNA repair and elevated mutagenesis in mammalian cells exposed to hypoxia and low pH.

The tumor microenvironment is characterized by regions of fluctuating and chronic hypoxia, low pH, and nutrient deprivation. It has been proposed that this unique tissue environment itself may constitute a major cause of the genetic instability seen in cancer. To investigate possible mechanisms by which the tumor microenvironment might contribute to genetic instability, we asked whether the conditions found in solid tumors could influence cellular repair of DNA damage. Using an assay for repair based on host cell reactivation of UV-damaged plasmid DNA, cells exposed to hypoxia and low pH were found to have a diminished capacity for DNA repair compared with control cells grown under standard culture conditions. In addition, cells cultured under hypoxia at pH 6.5 immediately after UV irradiation had elevated levels of induced mutagenesis compared with those maintained in standard growth conditions. Taken together, the results suggest that cellular repair functions may be impaired under the conditions of the tumor microenvironment, causing hypermutability to DNA damage. This alteration in repair capacity may constitute an important mechanism underlying the genetic instability of cancer cells in vivo.

Animals↗