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PubMed1979

Prolonged hematopoiesis in a primate bone marrow culture system: characteristics of stem cell production and the hematopoietic microenvironment.

Maintenance of myelopoiesis and pluripotential stem cell production for prolonged periods in vitro hitherto has been limited to mouse bone marrow culture. In an effort to adapt the system for use in higher species, particularly in human and non-human primates, studies were undertaken using the prosimian species, Tupaia glis (tree shrew). In a number of experiments the duration of sustained normal hematopoiesis observed in cultures of this species, following a single inoculum of 5 X 10(6)--10(7) bone marrow cells, with or without addition of fresh allogeneic bone marrow exceeded 1 yr. Analysis of suspension cells obtained by weekly demidepopulation of such cultures revealed production of CFU-C, differentiating neutrophils, and basophils at high levels. Direct comparison with murine cultures indicated that in both species a complex series of cellular interactions takes place within an adherent environment of marrow-derived endothelial cells, macrophages, and fat-containing cells. Certain functional and ultrastructural features served to distinguish murine from Tupaia marrow cultures, and the prolonged duration of in vitro hematopoiesis in the latter species could be attributed to a regenerative capacity possessed by its adherent hematopoietic microenvironment. The availability of this primate marrow culture system should facilitate studies of hematopoiesis, viral leukemogenesis, and transplantation biology, which have more direct relevance to man than that provided by the existing murine system.

Animals↗

PubMed2001

Astrogliosis in the adult and developing CNS: is there a role for proinflammatory cytokines?

Astrogliosis, characterized by the enhanced expression of GFAP, represents a remarkably homotypic response of astrocytes to all types of injuries of the CNS, including injuries of the developing CNS. As such, astrocytes serve as microsensors of the injured microenvironment regardless of their location in the CNS. The diversity of insults that engender astrogliosis and the brain-wide nature of the astrocytic response suggest that common injury factors serve as the trigger of this cellular reaction. One prominent theme that has emerged in recent years is that proinflammatory cytokines and chemokines serve as a stimulus for induction of astrogliosis. Here we present a brief critique of this hypothesis based on a review of literature and some of our own recentfindings. Studies of astrocytes, in vitro, clearly indicate that these cell types are responsive to a variety of growth factors, including cytokines and chemokines. A somewhat different picture, however, can be seen from data obtained in vivo. It is true that trauma and diseases of the nervous system, as well as some exposures to neurotoxic chemicals, can be associated with the expression in brain of large varieties of cytokines and chemokines. That these same conditions result in astrogliosis has fostered the circumstantial link between cytokine/chemokine expression and the induction of astrogliosis. Several lines of evidence argue against this view, including (a) suppression of cytokine expression does not suppress gliosis, (b) gliosis can occur in the absence of enhanced expression of cytokines, (c) elevations in brain cytokines can occur in the absence of gliosis and (d) the patterns of cytokine expression in the adult and developing CNS are more consistent with a trophic role for these chemical messengers rather than a role in the induction of inflammation. Enhanced expression of cytokines and chemokines after brain injury appear to be signal transduction events unrelated to the induction of astrogliosis.

Animals↗

PubMed2006

Bone-marrow haematopoietic-stem-cell niches.

Adult stem cells hold many promises for future clinical applications and regenerative medicine. The haematopoietic stem cell (HSC) is the best-characterized somatic stem cell so far, but in vitro expansion has been unsuccessful, limiting the future therapeutic potential of these cells. Here we review recent progress in characterizing the composition of the HSC bone-marrow microenvironment, known as the HSC niche. During homeostasis, HSCs, and therefore putative bone-marrow HSC niches, are located near bone surfaces or are associated with the sinusoidal endothelium. The molecular crosstalk between HSCs and the cellular constituents of these niches is thought to control the balance between HSC self-renewal and differentiation, indicating that future successful expansion of HSCs for therapeutic use will require three-dimensional reconstruction of a stem-cell-niche unit.

Animals↗

PubMed2004

B-cell homeostasis: digital survival or analog growth?

Maintenance of B-lymphocyte homeostasis requires balanced cell production, death, and proliferation. To coordinate these processes, B cells are dependent on cell extrinsic signals. In lymphocyte development, precursor cells are dependent on Fms-like tyrosine kinase ligand 3 (Flt3L), and pre-B cells are dependent on the cytokine interleukin-7. Transitional B cells require B-lymphocyte stimulator (BLyS) for survival. Mature B cells require B-cell receptor (BCR) signals and also remain sensitive to their microenvironment. An emerging model suggests that extrinsic signals do not regulate B-cell survival through a digital mechanism where cells are simply instructed to survive or die. Instead, availability and competition for extrinsic signals regulates cellular physiology and metabolism in an analog fashion that then influences cell commitment to apoptosis or proliferation. Decreases in cellular metabolism may sensitize cells to activation and action of the pro-apoptotic Bcl-2 family members, Bak and Bax, and promote apoptosis. In contrast, increases in metabolism may predispose cells to proliferate. Analog control of cell physiology can, thus, be integrated with other inputs by individual cells to produce a fate decision for survival, proliferation, or apoptosis and prevent diseases of cell death, such as immunodeficiency, and cell activation and proliferation, such as autoimmunity or cancer.

Animals↗

PubMed2002

Ex vivo expansion of bone marrow and cord blood cells to produce stem and progenitor cells for hematopoietic reconstitution.

Ex vivo expansion of a small volume of bone marrow offers an alternate approach to cellular support for repair of a hematopoietic system damaged by radiation exposure. Unpurified bone marrow cells cultured using frequent exchange of medium (perfusion) results in (1) the growth of an adherent layer that provides a supportive microenvironment for hematopoiesis and (2) the growth of hematopoietic stem and progenitor cells. Similar increases in stem and progenitor cells were also observed in cord blood cultures using frequent medium exchange methods. An automated clinical scale system, the AastromReplicell Cell Production System, has been developed to implement the biology of this ex vivo expansion process. Clinical use of ex vivo expanded bone marrow alone or in augmenting a low dose of mobilized peripheral blood stem cells has successfully reconstituted hematopoiesis. Ex vivo expanded cord blood cells combined with unmanipulated cord blood cells have also shown significant benefits in overall survival and engraftment in pediatric and adult patients, respectively. These results suggest that ex vivo expansion of hematopoietic cells provides a mechanism for generating cells capable of hematopoietic reconstitution.

Adult↗

PubMed1990

[Morphometric research on the germ and Sertoli cells in prespermatogenesis].

The author investigated the changes in the morphology of germinative and Sertoli's cells during prespermatogenesis of the rat. This problems were studied by morphometric investigations in 20 rats of Wistar strain, divided into age groups: newborns, 5, 10 and 15 postnatal days. The morphofunctional characteristic of these two types of cellular populations in immature rats showed existence of parallelism in the proliferation of these cells, the level of organization and interrelationships between them, which was of substantial significance for creation and further maintenance of an optimal microenvironment, needed for differentiation of sex cells.

Aging↗

PubMed1983

Long term bone marrow cultures: an ultrastructural review.

Long-term liquid cultures of bone marrow support the growth and proliferation of self renewing haemopoietic stem cells and the majority of myeloid lineages. The maturation of granulocyte elements occurs in normal cultures, but this may be shifted to erythropoiesis by the addition of a stimulus such as serum from anaemic mice. The continued production of stem cells and differentiating populations of either granulocytes or erythroid cells is dependent upon the establishment and maintenance of an adherent layer in the cultures which arise from the stromal cells in the original marrow inoculum. To date, the presence of adipocytes, fibroblasts, reticulum cells, and endothelial cells has been established amongst the stromal cells; and neutrophil and basophil granulocytes, megakaryocytes, full erythroid differentiation, and monocytes and macrophages have been identified in the haemopoietic lineages. Interactions at the cellular level appear to occur between the lipid synthesising adipocytes and developing granulocytes, and a central macrophage and erythroblasts, forming an 'in vitro' erythroblastic islet. These associations may form aspects of an 'in vitro' haemopoietically inductive microenvironment.

Animals↗

PubMed1998

Cellular and functional aspects of the renal kallikrein system in health and disease.

The kallikrein kinin system is a tissue-derived system with potent renal and cardiovascular effects. Within the kidney, the components of the kallikrein kinin system (kallikrein, kininogen, kinins, kininases, kinin receptors and mediators/modulators) originate from or are located in discrete segments of the nephron in highly specialized cells which determine its physiological effects. The kallikrein system acts on the kidney in a paracrine fashion in two anatomical microenvironments where the system regulates glomerular function, renal hemodynamics, and salt and water excretion. Impairment of the renal kallikrein system contributes to the development of hypertension, in particular to the salt-sensitive hypertension, and other pathologies like diabetes. There are several links between the vasodepressor kallikrein system and the vasopressor renin system which are relevant to normal renal function and to the pathophysiology of hypertension and renal diseases. Local induction of kininase II or angiotensin converting enzyme in the kidney could be a novel mechanism contributing to the renal damage in hypertension and other renal diseases. This review evaluates cellular and functional aspects of the renal kallikrein system with emphasis placed on the cellular localization of its components along the nephron, the links to other vasoactive systems, and the contribution of the system to the pathogenesis of hypertension.

Animals↗

PubMed2004

Low density lipoprotein receptor-related protein: regulation of the plasma membrane proteome.

Proteins in the plasma membrane anchor the cell within its microenvironment and sense changes occurring outside the cell. The anchoring interactions are cell type-specific and may involve adjacent cells or extracellular matrix proteins (ECMPs). In development, wound healing, and in various forms of pathology, including thrombosis and atherosclerosis, the microenvironment of the cell may change rapidly and dramatically. How the cell responds is strongly dependent on the protein composition of its plasma membrane, which we refer to as the plasma membrane proteome. Processes that regulate the plasma membrane proteome may alter cellular response. Low density lipoprotein receptor-related protein-1 (LRP-1) is a member of the LDL receptor family; however, LRP-1 and other less well studied members of this gene family demonstrate multiple activities unrelated to lipid homeostasis. LRP-1 binds and internalizes numerous, structurally diverse ligands, delivering most but not all these ligands to lysosomes for degradation. The intracellular tail of LRP-1 binds signaling adaptor proteins and thus may function in cell signaling. Biological activities of LRP-1 include antigen presentation, phagocytosis, removal of apoptotic cells, and regulation of vascular permeability. This review focuses on an emerging view of LRP-1 activity, in which LRP-1 regulates the protein composition of the plasma membrane and thereby "models" or "landscapes" the cell surface. In some cases, plasma membrane modeling results from the binding to bifunctional ligands or intracellular adaptor proteins, so that LRP-1 is bridged to another plasma membrane protein and the entire complex undergoes endocytosis. Membrane proteins already known to be subject to this form of regulation include urokinase-type plasminogen activator receptor, amyloid precursor protein, tissue factor, and alpha(V)-containing integrins. LRP-1 also controls the plasma membrane proteome by regulating maturation and transport of proteins in the secretory pathway. At the same time, LRP-1 serves as a receptor for specific ECMPs, including fibronectin and thrombospondin. Although ECMP-binding to LRP-1 results in endocytosis and catabolism, these receptor-ligation events also may be coupled, directly or indirectly, to cell-signaling. Based on these novel activities, LRP-1 emerges as a protein capable of modeling the interface of the cell with its microenvironment.

Animals↗

PubMed1999

Cellular mechanisms of calcium phosphate ceramic degradation.

Calcium phosphate (CaP) ceramics are widely used for bone substitution in orthopedic, maxillofacial and dental surgery. Many environmental factors are involved in the gradual degradation of calcium phosphate ceramic after implantation, including physiocochemical processes (dissolution-precipitation) and the effects of various cell types. Several of these cell types degrade ceramics by phagocytotic mechanisms (fibroblasts, osteoblasts, monocytes/macrophages) or by an acidic mechanism with a proton pump to reduce the pH of the microenvironment and resorb these synthetic substrates (osteoclasts). Various mesenchymal cells located at the implantation sites can induce the solubilization of CaP ceramics. Crystal-cell contacts were required to induce such crystal dissolution. Mesenchymal cells such as fibroblastic cells are also actively involved in the ceramic degradation process. In this context, CaP crystals underwent dissolution into the phagosome. If osteoclasts resorb CaP ceramics similarly to the natural bone, they possess a phagocytic capability. This phagocytosis mechanism consisted of three steps: crystal phagocytosis, disappearance of the endophagosome envelope membrane and fragmentation of phagocytosed crystals within the cytoplasm. Similar phenomenons have been observed during the phagocytic mechanism induced by monocytes/macrophages. The cellular mechanisms of CaP ceramic degradation are modulated by various parameters, such as the properties of the ceramic itself, the implantation sites and the presence of various proteins (cytokines, hormones, vitamins, ions, etc.). The cells involved in these mechanisms could intervene directly or indirectly through their cytokine/growth factor secretions and their sensitivity to the same molecules. This article reviews recent knowledge on the cellular mechanisms of calcium phosphate ceramic degradation.

Animals↗

PubMed1998

Macrophages induce cellular immunity by activating Th1 cell responses and suppressing Th2 cell responses.

Differentiation of naive CD4+ T cells (Th0) into Th1 or Th2 cells determines whether antigen will raise a cellular or a humoral immune response. The maturation pathway chosen by the Th0 cell is often decisive for the outcome of disease and depends among others on the (co-)stimulatory attributes of the APC and the nature and abundance of cytokines provided by the APC and the microenvironment. In this study, we used macrophages, loaded ex vivo with antigen, for inciting Th0 activation and differentiation in vivo. The macrophages were derived from a clonal, immortalized population that both functionally and phenotypically expressed features characteristic of mature macrophages. Injection into syngeneic mice of IFN-gamma-treated, Ag-loaded macrophages induced a primary T cell response, indicated by the occurrence of a proliferative response in vitro after restimulation of splenocytes with Ag. Analysis of the accompanying cytokine secretion revealed high numbers of IFN-gamma-producing Th1 cells and only a few IL-4-secreting Th2 cells. This dominance of Th1 cells had functional implications, reflected in the high titer of Th1 cell-dependent IgG2 Abs and the absence of IgG1, characteristic of humoral immunity. Moreover, administration of Ag-loaded macrophages to mice with an ongoing Th1/Th2 response resulted in a complete suppression of IgG1 production, whereas IgG2 levels remained unaffected. These results demonstrate that macrophages exert APC activity in the organism, strongly skew primary responses to cellular immunity, and in addition suppress an already generated Th2-dependent humoral response, thus characterizing these cells as Th1-oriented APC.

Animals↗

PubMed1996

Interferon-gamma induced cell death in a cultured human salivary gland cell line.

Increased levels of several cytokines, including interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha), have been demonstrated in the salivary gland microenvironment of patients with Sjögren's syndrome (SS). How these cytokines may be contributing to the pathogenesis of the disease is not well understood. This study examined the role of IFN-gamma +/- TNF-alpha on cellular death in a cultured human salivary gland cell line (HSG). Cells treated long-term with IFN-gamma +/- TNF-alpha demonstrate a profound antiproliferative effect with a decrease in cell number to below that initially plated. Treatment of HSG cells with TNF-alpha alone did not have any significant effects on growth but did increase the expression of the IFN-gamma receptor. Cells labelled with propidium iodide and anti-digoxigenin dUTP/dATP were examined by flow cytometry to determine the percentage of cells exhibiting low DNA content and DNA strand breaks. The percentage of cells exhibiting subdiploid DNA and DNA strand breaks increased with increased time of exposure to the cytokines. The maximum percentage of cells exhibiting DNA degradation at 12 days was 58% for cells treated with IFN-gamma + TNF-alpha, 31% for IFN-gamma treated cells, and < 5% for TNF-alpha-treated and untreated cells. The cells with subdiploid ( < 2n) DNA were subsequently demonstrated to represent two populations, both with evidence of increased DNA strand breaks but with differing light scatter characteristics. One population had features of cells undergoing necrosis, whereas the second population exhibited features of apoptosis. These findings were confirmed by transmission electron microscopy. Cells not exposed to cytokines did not exhibit significant evidence of either death process. We conclude that long-term exposure of a human salivary gland epithelial cell line to IFN-gamma +/- TNF-alpha leads to increased DNA degradation and subsequent cell death. This suggests a potential SS disease mechanism and implicates the role of the epithelial cell in this disease as an important area for future study.

Cell Count↗

PubMed2025

Comprehensive proteomic and pathological profiling identifies PRAS40 as a novel biomarker and mediator of primary immune checkpoint blockade resistance in non-small cell lung cancer.

BACKGROUND: Immune checkpoint blockade (ICB) has revolutionized the treatment landscape of non-small cell lung cancer (NSCLC), yet primary resistance remains a significant clinical challenge. Recent evidence implicates PRAS40 (AKT1S1) in regulating cellular survival and immune responses, but its role in immunotherapy resistance is not fully understood. METHODS: Transcriptomic data from TCGA and GTEx cohorts were analyzed to assess PRAS40 expression. Prognostic value was evaluated using Cox regression. Immune microenvironment features were characterized with CIBERSORT and TIMER. Predictive efficacy for ICB response was examined using TIDE and IPS. Plasma PRAS40 levels in 66 NSCLC patients receiving ICB were quantified by proximity extension assay (PEA), and multiplex immunohistochemistry assessed associations among PRAS40, PD-L1, and CD8+ T cells in tumor tissues. RESULTS: High PRAS40 expression was associated with poor prognosis, reduced CD8+ T cell infiltration, and downregulation of immune checkpoint genes. Elevated circulating PRAS40 predicted primary ICB resistance and shorter progression-free survival, independent of PD-L1 or CD8+ T cell status. CONCLUSION: PRAS40 is strongly associated with primary ICB resistance in NSCLC and may serve as a novel predictive biomarker. These findings support its potential to guide personalized immunotherapy in lung cancer.

Humans↗

PubMed1998

Structural cues from the tissue microenvironment are essential determinants of the human mammary epithelial cell phenotype.

Historically, the study of normal human breast function and breast disorders has been significantly impaired by limitations inherent to available model systems. Recent improvements in human breast epithelial cell lines and three-dimensional (3-D)3 culture systems have contributed to the development of in vitro model systems that recapitulate differentiated epithelial cell phenotypes with remarkable fidelity. Molecular characterization of these human breast cell models has demonstrated that normal breast epithelial cell behavior is determined in part by the precise interplay that exists between a cell and its surrounding microenvironment. Recent functional studies of integrins in a human model system provide evidence to support the idea that the structural stability afforded by integrin-mediated cell-extracellular matrix interactions is an important determinant of normal cellular behavior, and that alterations in tissue structure can give rise to tumorigenic progression.

Breast↗

PubMed2026

Methylation profiling of normal tissue adjacent to breast tumors reveals two distinct groups with divergent tumor microenvironment features.

We previously identified diverse genetic evolutionary patterns in whole-genome sequencing of paired normal tissue adjacent to tumor (NAT) and tumor tissues from Hong Kong breast cancer (HKBC) patients. Here, we investigated whether DNA methylation (DNAm) contributes to NAT heterogeneity and shapes the tumor microenvironment (TME). Genome-wide DNAm profiling was performed on paired NAT and tumor tissues from 188 HKBC patients using the Infinium 850 K array. RNA-seq data were available for 76 NATs and 177 tumors. Cellular composition was inferred using MethylCIBERSORT, CIBERSORTx, and EpiDISH, and histopathologic features were assessed on 115 H&E-stained sections. Unsupervised clustering identified two distinct NAT subtypes with divergent TME characteristics. Cluster 1 (N = 139) showed higher epithelial and fibroblast content and enrichment of estrogen response pathways. Cluster 2 (N = 49) exhibited an immune-metabolic phenotype characterized by increased fat and immune cells, stromal disruption, inflammatory pathway activation, and greater macrophage infiltration. Cluster 2 patients also demonstrated significantly younger epigenetic age estimated using multiple epigenetic clocks. These DNAm-defined NAT subtypes and associated TME features were validated in 97 NAT samples from TCGA breast cancer patients. Overall, our findings identify DNAm-driven NAT heterogeneity with distinct TME landscapes, providing new insights into field cancerization and tumor evolution in breast cancer.

Journal Article↗

PubMed1998

Adhesion molecules in clinical medicine.

Cellular adhesion molecules (CAMs) are critical components in the processes of embryogenesis, tissue repair and organization, lymphocyte function, lymphocyte homing and tumor metastasis, as well as being central to the interactions between hemopoietic progenitors and bone marrow microenvironment, and between leukocytes and platelets with vascular endothelium. Expression of CAMs regulates normal hemopoiesis and migration and function of mature hemopoietic cells. CAMs are an important part of the inflammatory response and may regulate cytokine synthesis. In addition, CAM expression may be critical for tumorigenesis. Monoclonal antibodies to CAMs have been developed for clinical use; initial results suggest that these agents have great potential in the prevention and treatment of inflammation, thrombosis, reperfusion injury, and graft rejection.

Antibodies, Monoclonal↗

PubMed2006

Sustained thymopoiesis and improvement in functional immunity induced by exogenous KGF administration in murine models of aging.

Age-related thymopoietic insufficiency has been proposed to be related to either defects in lymphohematopoietic progenitors or the thymic microenvironment. In this study, we examined whether keratinocyte growth factor (KGF), an epithelial cell-specific growth factor, could increase thymopoietic capacity in aged mice by restoration of the function of thymic epithelial cells (TECs). The thymic cellularity in KGF-treated aged mice increased about 4-fold compared to placebo-treated mice, resulting in an equivalent thymic cellularity to young mice. Enhanced thymopoiesis was maintained for about 2 months after a single course of KGF, and sustained improvement was achieved by administration of monthly courses of KGF. With the enhanced thymopoiesis after KGF treatment, the number of naive CD4 T cells in the periphery and T-cell-dependent antibody production improved in aged mice. KGF induced increased numbers of TECs and intrathymic interleukin-7 (IL-7) production and reorganization of cortical and medullary architecture. Furthermore, KGF enhanced thymopoiesis and normalized TEC organization in klotho (kl/kl) mice, a model of premature degeneration and aging, which displays thymopoietic defects. The result suggests that TEC damage is pathophysiologically important in thymic aging, and KGF therapy may be clinically useful in improving thymopoiesis and immune function in the elderly.

Aging↗

PubMed1993

Low molecular weight IgM in the sera of patients with chronic lymphocytic leukemia.

With the use of 2 independent techniques, circulating monomeric and oligomeric IgM were detected in the majority of 29 patients with chronic lymphocytic leukemia (CLL). In contrast it was detected only in trace quantities in a minority of healthy subjects. In the CLL group no significant correlation was observed between monomeric IgM and the total serum IgM level or the absolute lymphocyte count. Mitogen stimulated peripheral blood mononuclear cells from CLL patients were observed to secrete monomeric and oligomeric IgM in-vitro. Experiments manipulating the microenvironment of an IgM secreting cell line revealed that the addition of low concentrations of the reducing reagent 2-mercaptoethanol to the culture medium would enhance the proportions of monomeric IgM in the culture supernatant and the cellular cytoplasmic lysate. However the same concentrations would not directly reduce the secreted IgM. We conclude that the secretion of incompletely assembled IgM is commonly found in CLL and suggests an intrinsic defect(s) in the mechanisms involved in the polymerization of the monomeric units into the pentameric molecule.

Aged↗