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PubMed2005

Functional interaction between p75NTR and TrkA: the endocytic trafficking of p75NTR is driven by TrkA and regulates TrkA-mediated signalling.

The topology and trafficking of receptors play a key role in their signalling capability. Indeed, receptor function is related to the microenvironment inside the cell, where specific signalling molecules are compartmentalized. The response to NGF (nerve growth factor) is strongly dependent on the trafficking of its receptor, TrkA. However, information is still scarce about the role of the cellular localization of the TrkA co-receptor, p75NTR (where NTR is neurotrophin receptor), following stimulation by NGF. It has been shown that these two receptors play a key role in epithelial tissue and in epithelial-derived tumours, where the microenvironment at the plasma membrane is defined by the presence of tight junctions. Indeed, in thyroid carcinomas, rearrangements of TrkA are frequently found, which produce TrkA mutants that are localized exclusively in the cytoplasm. We used a thyroid cellular model in which it was possible to dissect the trafficking of the two NGF receptors upon neurotrophin stimulation. In FRT (Fischer rat thyroid) cells, endogenous TrkA is localized exclusively on the basolateral surface, while transfected p75NTR is selectively distributed on the apical membrane. This cellular system enabled us to selectively stimulate either p75NTR or TrkA and to analyse the role of receptor trafficking in their signalling capability. We found that, after binding to NGF, p75NTR was co-immunoprecipitated with TrkA and was transcytosed at the basolateral membrane. We showed that the TrkA-p75NTR interaction is necessary for this relocation of p75NTR to the basolateral side. Interestingly, TrkA-specific stimulation by basolateral NGF loading also induced the TrkA-p75NTR interaction and subsequent p75NTR transcytosis at the basolateral surface. Moreover, specific stimulation of p75NTR by NGF activated TrkA and the MAPK (mitogen-activated protein kinase) pathway. Our data indicate that TrkA regulates the subcellular localization of p75NTR upon stimulation with neurotrophins, thus affecting the topology of the signal transduction molecules, driving the activation of a specific signal transduction pathway.

Cell Line↗

PubMed1998

Thymic-shared antigen-1 (TSA-1). A lymphostromal cell membrane Ly-6 superfamily molecule with a putative role in cellular adhesion.

The seeding and colonization of the thymus by bone marrow stem cells and the maturation of these cells into mature T lymphocytes are dependent on cell-surface recognition events between different cell lineages within the thymic microenvironment. Positive and negative selection processes within the thymus produce a peripheral T-cell repertoire capable of recognizing peptides derived from foreign antigen bound to self MHCmolecules. In addition to the TCR/MHC-peptide interaction, many other cell-surface molecules act in concert to regulate the kinetics of cellular interactions and intracellular signaling events during thymopoiesis. We have investigated the complexity of the thymic stroma by using monoclonal antibodies to clone cell-membrane molecules of thymic stromal cells. Thymic-shared antigen-1 (TSA-1) is a molecule of interest because it is expressed by both immature thymocytes and stromal cells. We report herein the structural and evolutionary relationships between TSA-1 and molecules of the Ly-6 superfamily (Ly-6SF), and present evidence that TSA-1 functions as a cell-surface receptor by binding a cognate cell target molecule on the surface of a subset of thymocytes.

Amino Acid Sequence↗

PubMed2005

[Establishment of cellular hypoxia model and its effects on biological behavior of gastric cancer cell line SGC-7901].

BACKGROUND & OBJECTIVE: Hypoxia is an elementary characteristic of tumor microenvironment. Establishing hypoxia microenvironment in vitro will be of help in studying the effects of hypoxia on tumor cells. Previous methods of establishing hypoxic cell culture model are fussy, and researches on the effects of hypoxia on gastric cancer cells are rare. This study was to establish hypoxia microenvironment with GasPaK method in vitro, and observe the effects of hypoxia on biological features of gastric cancer cell line SGC-7901. METHODS: The hypoxia microenvironment was established by GasPaK method; the changes of PO2, PCO2, and pH in RPMI-1640 were monitored by blood gas analysis. The effect of hypoxia on cell cycle of SGC-7901 cells was analyzed by flow cytometry (FCM). The morphology of SGC-7901 cells was observed under light microscope and transmission electron microscope. Live cells were counted with trypan blue staining. The adhesiveness of SGC-7901 cells was detected by MTT assay; migration ability of SGC-7901 cells was assessed by movement experiment. RESULTS: GasPaK formed hypoxia microenvironment in 0.5-48 h with stable PO2, PCO2, and pH. When cultured in hypoxia for 16 h, no significant change in cell cycle of SGC-7901 cells was observed; morphology of some SGC-7901 cells was changed; the number of live cells didn't significantly decreased; the adhesiveness and migration ability of SGC-7901 cells were significantly enhanced. CONCLUSIONS: GasPaK method can stably establish hypoxia microenvironment with good repetition. Hypoxia has slight effect on SGC-7901 cells, and may induce morphologic change of SGC-7901 cells.

Animals↗

PubMed2006

Parallel chemical dosing of subcellular targets.

To characterize the role of spatially heterogeneous signaling in cellular function, methods are required for differentially exposing distinct regions of individual cells to externally applied reagents. Although a range of standard approaches exists for generating localized chemical gradients in culture, including puffer pipet spritzing and photolytic release of caged effectors, each is limited in key respects. Here, we report development of a cell-dosing strategy that addresses these limitations, providing the means to create steep gradients of any aqueous-miscible compound at essentially unlimited numbers of sites in parallel. In this approach, cells are cultured on a micrometer-thick polymer membrane that serves as a barrier between two stacked laminar-flow channels: one containing the cell culture and the other serving as a reagent flow cell. By focusing a pulsed laser beam onto one or more selected membrane positions, micrometer-diameter pores can be ablated upstream of desired cellular targets. Nascent pores thus serve as ports of entry into the culture environment for reagent streams capable of modifying subcellular features at positions potentially hundreds of micrometers from ablation sites. Importantly, individual reagent streams also can be rapidly eliminated by photo-cross-linking a protein plug over a selected pore. This versatile strategy for dynamically reshaping the chemical microenvironments in which cells reside should be useful in a variety of cell biology applications, ranging from neurotrophic modulation of neurite pathfinding to stimulation of cellular networks.

Cell Differentiation↗

PubMed1997

Regulation of hematopoiesis by microvascular endothelium.

The bone marrow microenvironment is a complex three dimensional structure where hematopoietic stem cells proliferate, mature, migrate into the sinusoidal space, and enter the circulation in an exquisitely regulated fashion. Stromal cells within the BM microenvironment provide a suitable environment for self-renewal, proliferation and differentiation of hematopoietic stem cells. Within the hematopoietic microenvironment, whether it is embryonic yolk sac, fetal liver, or adult bone marrow, microvascular endothelium not only acts as a gatekeeper controlling the trafficking and homing of hematopoietic progenitors, but also provides cellular contact and secretes cytokines that allows for the preservation of the steady state hematopoiesis. Recently, homogenous monolayers of bone marrow endothelial cells (BMEC) have been isolated and cultivated in tissue culture. Long-term coculture studies have shown that BMEC monolayers are unique type of endothelium and can support long-term proliferation of hematopoietic progenitor cells particularly megakaryocytic and myeloid progenitor cells by constitutive elaboration of lineage-specific cytokines such as G-CSF, GM-CSF, M-CSF, Kit-ligand, IL6, FLK-2 ligand, and leukemia inhibitory factor. Direct cellular contact between hematopoietic progenitor cells and BMEC monolayers through specific adhesion molecules including beta1, beta2 integrins and selectins play a critical role in trafficking and possibly proliferation of hematopoietic stem cells. Dysfunction of microvascular endothelial cells within the hematopoietic microenvironment may result in stem cell disorders and progression to aplastic anemias, and contribute to graft failure during bone marrow transplantation. Further studies on the role of microvascular endothelium in the regulation of hematopoietic stem cell homing and proliferation may enhance our understanding of the pathophysiology of stem cell and leukemic disorders.

Antigens, CD34↗

PubMed2005

CXCL12 overexpression and secretion by aging fibroblasts enhance human prostate epithelial proliferation in vitro.

The direct relationship between the aging process and the incidence and prevalence of both benign prostatic hyperplasia (BPH) and prostate cancer (PCa) implies that certain risk factors associated with the development of both diseases increase with the aging process. In particular, both diseases share an overly proliferative phenotype, suggesting that mechanisms that normally act to suppress cellular proliferation are disrupted or rendered dysfunctional as a consequence of the aging process. We propose that one such mechanism involves changes in the prostate microenvironment, which 'evolves' during the aging process and disrupts paracrine interactions between epithelial and associated stromal fibroblasts. We show that stromal fibroblasts isolated from the prostates of men 63-81 years of age at the time of surgery express and secrete higher levels of the CXCL12 chemokine compared with those isolated from younger men, and stimulate CXCR4-mediated signaling pathways that induce cellular proliferation. These studies represent an important first step towards a mechanistic elucidation of the role of aging in the etiology of benign and malignant prostatic diseases.

Aged↗

PubMed2001

Controlling culture dynamics for the expansion of hematopoietic stem cells.

The ex vivo expansion of hematopoietic stem cells (HSCs) is the subject of intense commercial and academic interest due to the potential of HSCs to be a renewable source of material for cellular therapeutics. Unfortunately, because methodologies have not yet been developed to grow clinically relevant numbers of HSCs (or their derivatives) consistently, the potential of this technology is limited. Manipulation of the in vitro culture microenvironment, primarily through cytokine supplementation, has been the predominant approach in studies attempting to expand primary human HSC numbers in vitro. While promising results have been obtained, it is becoming clear that novel methods must be developed before cellular therapies using these stem cells can become routine. Ideally, bioprocesses must be designed to target specifically the growth of stem cell populations while incorporating positive and negative feedback from potentially dynamic mature and maturing cell populations. The product of these culture systems should consist of not only HSCs, but also of cells that allow the engraftment of HSCs and, ideally, cells responsible for the immediate or accelerated functional support of patients. Development of such "designer transplants" will require combining optimal culture conditions capable of amplifying HSC numbers with novel approaches for finely controlling the number, functional capabilities, and characteristics of potentially therapeutic cells in these very complex cell culture systems.

Animals↗

PubMed2000

Mechanochemical manipulation of hepatocyte aggregation can selectively induce or repress liver-specific function.

Controlled activation of hepatocyte aggregation is critical to three-dimensional (3D) multicellular morphogenesis during native regeneration of liver as well as tissue reconstruction therapies. In this work, we quantify the stimulatory effects of two model hepatotrophic activators, epidermal growth factor (EGF) and hepatocyte growth factor (HGF), on the aggregation kinetics and liver-specific function of hepatocytes cultured on organotypic substrates with differing mechanical resistivity. Substrate-specific morphogenesis of cultured hepatocytes is induced on a tissue basement membrane extract, Matrigel, formulated at two distinct levels of mechanical compliance (storage modulus G', at oscillatory shear rate 1 rad/s, was 34 Pa for basal Matrigel and 118 Pa for crosslinked Matrigel). Overall, we report that growth factor stimulation selectively promotes the kinetics of aggregation in the form of two-dimensional corded aggregates on basal Matrigel and three-dimensional spheroidal aggregates on crosslinked Matrigel. Our analysis also indicates that costimulation with EGF and HGF (20 ng/mL each) cooperatively maximizes the kinetics of aggregation in a substrate-specific manner. In addition, we show that the role of growth factor stimulation on hepatocyte function is sensitively governed by the mechanical compliance of the substrate. In particular, on matrices with high compliance, costimulatory aggregation is shown to elicit a marked increase in albumin secretion rate, whereas on matrices with low compliance aggregation results in effective functional repression to basal, unstimulated levels. Thus, our studies highlight a novel interplay of physicochemical parameters of the culture microenvironment, leading to selective enhancement or repression of differentiated functions of hepatocytes, in concert with the activation of cellular morphogenesis.

Animals↗

PubMed1985

The relationship between tumour geometry and the response of tumour cells to cytotoxic drugs--an in vitro study using EMT6 multicellular spheroids.

Multicellular spheroids of the EMT6/Ca/VJAC mouse mammary tumour cell line have been used in an investigation of the effect of tumour geometry on the response of tumour cells to 3 cytotoxic drugs, adriamycin (ADM), nitrogen mustard (HN2) and CCNU. In addition to the inherent cellular drug response, factors related to spheroid structure, namely cell-cycle distribution, intercellular contact, drug penetration and microenvironment (pH, oxygen, glucose, etc.) are believed to influence the response of cells within spheroids to cytotoxic drugs. Selective enzymatic dissociation (with bacterial neutral protease) has been used to separate the cells within large (approximately 800 micron in diameter) spheroids into 4 distinct subpopulations. The cells within the subpopulations have been characterized by their DNA content, RNA content, tritiated thymidine labelling index, cell size and clonogenic capacity. It was found that cells at the surface of spheroids are relatively larger and more proliferative than cells towards the centre while their clonogenic capacity is similar. Studies on the responses of EMT6/Ca/VJAC log and plateau-phase monolayer cells have been carried out in parallel and have shown that cycling cells are more sensitive to ADM and HN2 than are non-cycling cells but somewhat less sensitive for the response to CCNU. Since the response patterns of cells from different regions of spheroids to HN2, treated either before disaggregation (intact spheroid) or after disaggregation (isolated spheroid cells), are similar and the surviving fraction increases from the surface towards the centre of the spheroid, cell cycle distribution is thought to be the only factor involved in the cytotoxicity of HN2 towards cells within the spheroids. Although the patterns of response to ADM of cells within intact spheroids and isolated spheroid cells are similar to those for HN2, the initial slope of the curve for intact spheroids is much steeper than that of the isolated spheroid cells. Therefore, in addition to the factor of cell-cycle distribution, drug penetration also appears to be involved in the action of ADM on spheroids, while the factors of intercellular contact and microenvironment appear to be relatively less important. The reverse pattern was found for the response of cells within different regions of spheroids to CCNU, treated as intact spheroids or as isolated spheroid cells (i.e., greater killing of inner compared with outer cells).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2003

Apoptotic signaling in multiple myeloma: therapeutic implications.

Fifteen thousand new cases of multiple myeloma (MM) will occur in the United States in 2003, and the disease remains incurable. Diverse classes of chemotherapeutic agents induce cell death or apoptosis in MM cells; however, prolonged drug exposures ultimately induce chemoresistance. The mechanisms whereby MM cells resist drugs include alterations in intracellular signaling as well as adherence and cytokines in the bone marrow (BM) microenvironment. Novel agents that target the MM cell in its BM microenvironment are needed to both enhance anti-MM activity and prevent development of drug resistance. Delineation of cellular growth and apoptotic signaling pathways in MM cells may identify molecules that serve as novel therapeutic targets on the basis of interruption of MM cell growth or triggering of MM cell death.

Antineoplastic Agents↗

PubMed2026

Mechanisms of Hematopoietic Stem Cell Aging and Emerging Rejuvenation Strategies.

Hematopoietic stem cell (HSCs) aging is a complex biological process driven by both cell-intrinsic alterations and extrinsic cues from the bone marrow niche. Understanding these mechanisms is critical for developing therapies against aging-related hematopoietic disorders. This review synthesizes recent advances in the molecular mechanisms underlying HSCs aging, including microenvironmental aging, genomic instability, epigenetic dysregulation, mitochondrial dysfunction, and aberrant nuclear mechanotransduction. We summarize that the functional decline of HSCs during aging drives a compensatory expansion of the phenotypically defined stem cell pool, leading to an aberrant increase in cell number. We also highlight aging-associated HSCs heterogeneity, including CD150high and P-selectin-positive subsets that enrich for myeloid-biased or functionally compromised HSCs states while emphasizing that surface phenotype alone may not fully indicate functional rejuvenation. Finally, we discuss emerging rejuvenation strategies-including targeting myeloid-biased HSCs, modulating inflammatory pathways, and implementing epigenetic or metabolic interventions-supported by cutting-edge technologies such as single-cell multi-omics, gene editing, and computational modeling. These approaches hold promise for counteracting age-related hematopoietic decline and restoring immune competence.

Humans↗

PubMed1993

Assessment of fluorochromes for cellular structure and function studies by flow cytometry.

Because flow cytometry permits the analysis of individual whole cells, one of the key requirements in selecting a probe is its ability to target the site of interest into cells. In addition, dyes must possess ideal properties (ie extinction coefficient, Stoke's shift) rendering them appropriate for this methodology. Other characteristics, such as fluorescence quenching and energy transfer, inherent to the staining, provide numerous applications in flow cytometry. The available fluorophores used in flow cytometry are classified according to their cellular incorporation and binding. Thus, probes are presented and discussed as follows: 1) dyes of cellular components (DNA, RNA, proteins, lipids); 2) probes of membrane potential; 3) fluorophores that are sensitive to their microenvironment (pH, calcium, etc); and 4) those used for measurement of enzymatic activities into cells.

Animals↗

PubMed2026

Th2 bias and T-cell exhaustion characterize the immunopathology of non-tuberculous mycobacterial pulmonary disease.

Non-tuberculous mycobacterial pulmonary disease (NTM-PD) is an escalating global health concern with poorly defined immunological mechanisms, necessitating comprehensive profiling to guide therapeutic advances. We analyzed peripheral blood from 28 treatment-naïve NTM-PD patients (19 Mycobacterium avium complex, 9 Mycobacterium abscessus) and 27 matched controls using 42-marker mass cytometry (CyTOF) and Luminex multiplex assays. A random forest model identified predictive markers, while an in vitro murine macrophage model evaluated chemokine production. NTM-PD patients displayed significant immune shifts, including increased classical monocytes (CD14+ CD16-), reduced NKT-like cells (CD3+ CD56+), and elevated T-cell exhaustion markers (PD-1, TOX). This coincided with a Th1/Th2 balance shift characterized by heightened IL-13. Elevated IFN-γ-inducible chemokines CXCL9 and CXCL10 coexisted with this Th2-biased signature, indicating a complex, dysregulated inflammatory state. A model integrating immune-cell frequencies and cytokine profiles achieved robust diagnostic accuracy (AUC = 0.922) with prognostic potential. In vitro, NTM-infected macrophages produced substantial CXCL9 and CXCL10 levels relative to the LPS maximal activation benchmark, identifying them as a major cellular source. These findings propose an immunological framework wherein T-cell exhaustion and a Th2-biased microenvironment strongly correlate with NTM-PD pathogenesis. CXCL9, CXCL10, and IL-13 emerge as candidate therapeutic targets, while our predictive model offers a foundational approach for risk stratification.

Humans↗

PubMedDate not supplied

The general case for redox control of wound repair.

The orthodox view has been that reactive oxygen species are primarily damaging to cells. There is general agreement that while high (3%) doses of H(2)O(2) may serve as a clinical disinfectant, its overall effect on healing is not positive. Current work shows that at very low concentrations, reactive oxygen species may regulate cellular signaling pathways by redox-dependent mechanisms. Recent discoveries show that almost all cells of the wound microenvironment contain specialized enzymes that utilize O(2) to generate reactive oxygen species. Numerous aspects of wound healing are subject to redox control. An understanding of how endogenous reactive oxygen species are generated in wound-related cells may influence the healing process and could result in new redox-based therapeutic strategies. Current results with growth factor therapy of wounds have not met clinical expectations. Many of these growth factors, such as platelet-derived growth factor, rely on reactive oxygen species for functioning. Redox-based strategies may serve as effective adjuncts to jump-start healing of chronic wounds. The understanding of wound-site redox biology is also likely to provide novel insights into the fundamental mechanisms that would help to optimize conditions for oxygen therapy. While a window of therapeutic opportunity seems to exist under conditions of low concentrations of reactive oxygen species, high levels may complicate regeneration and remodeling of nascent tissue.

Animals↗

PubMed2003

Upregulation of MHC class II, interferon-alpha and interferon-gamma receptor protein expression in HIV-associated nephropathy.

BACKGROUND: Renal cellular HIV infection has been linked to the pathogenesis of HIV-associated nephropathy (HIVAN), but mediators of its development are unknown. HIV infection is associated with disordered cytokine metabolism, and chemokine receptors are coreceptors for HIV immune cellular infection. Chemokines such as interleukin (IL)-8, monocyte chemoattractant protein-1 (MCP-1) and RANTES, and interferons (IFNs) have been implicated in the progression of nephropathy. Renal major histocompatibility complex (MHC) protein expression is involved in antigen presentation and modulating tissue cellular immune responses. Their relative importance in HIVAN pathogenesis is unknown. METHODS: We measured levels of chemokines, IFN-alpha, IFN-gamma receptor and non-polymorphic MHC Class II protein by high performance capillary electrophoresis, and incubation with antibodies for quantification by chemiluminesce in renal tissue of patients with HIVAN, compared with tissue without HIV infection, in the presence and absence of nephropathy. Renal biopsy tissue protein levels were correlated with the number and type of infiltrating tissue immune cells. RESULTS: Mean renal interstitial and glomerular MCP-1, RANTES and IL-8 tissue levels were higher in patients with HIV infection compared with tissue without HIV infection, regardless of the presence of renal disease. In contrast, mean renal interstitial and glomerular non-polymorphic MHC Class II, IFN-alpha and IFN-gamma receptor protein were higher in patients with HIVAN compared with all other groups. Tissue MHC Class II and IFN-gamma receptor protein levels did not correlate with immune cellular infiltration in patients with HIV infection and renal disease. CONCLUSIONS: The data suggest an upregulated renal immune microenvironment, capable of antigen presentation, exists in HIVAN. MHC Class II proteins and IFNs, and the capacity to present antigen may be crucial in HIVAN pathogenesis.

AIDS-Associated Nephropathy↗

PubMed1997

The role of adhesion molecules in multiple myeloma.

The neoplastic plasma cells of multiple myeloma differ from normal plasma cells and other B-cell malignancies by an almost exclusive homing to the bone marrow microenvironment which clearly provides the appropriate support, both physical and cytokine, to mediate clonal proliferation and terminal differentiation. Cellular adhesion molecules are involved in the homing of malignant plasma cells to the bone marrow, the production of growth factors and the recirculation of these tumour cells in the advanced stages of disease. Neoplastic plasma cells express H-CAM (CD44), VLA-4 (CD49d/CD29), ICAM-1 (CD54), N-CAM (CD56) and LFA-3 (CD58). In addition VLA-5 (CD49e/CD29) expression seems to be related to cells with less proliferative potential and more potential for paraprotein production. In addition there are fundamental changes in the bone marrow stroma of patients with multiple myeloma including altered composition of the extracellular matrix, increased growth capability of the cellular elements and increased synthesis of interleukin-6 and interleukin-3, which are features postulated to localise and promote growth of the circulating neoplastic progenitors in the bone marrow. However, the evidence to date does not fully explain the inter-relationship of the clonal B cells and the bone marrow stroma in patients with myeloma, including factors which trigger and facilitate the extravasation and recirculation of neoplastic plasma cells as seen in advanced disease.

B-Lymphocytes↗

PubMedDate not supplied

Effects of human recombinant erythropoietin on differentiation and distribution of erythroid progenitor cells on murine medullary and splenic erythropoiesis during hypoxia and post-hypoxia.

Hemopoietic cells, the extracellular matrix, growth factors and the microenvironment are involved in the regulation of hemopoiesis. Although the regulation of erythropoiesis is well understood at the cellular level in vivo and in vitro, the role of hemopoietic sites of erythroid progenitors production has not been well defined in both steady state conditions and in stress erythropoiesis. In this study we examined the qualitative erythroid differentiation and quantitative changes of the erythroid progenitors in different erythropoietic organs during erythropoiesis of stress in a hypoxia-induced polycythemia and post-hypoxic changes in a mice model. Chronic intermittent exposure to hypobaric hypoxia induced polycythemia in mice and the post-hypoxic period was characterized by total suppression of erythropoiesis. The number and distribution in hemopoietic sites of Immature Erythroid Burst (BFU-EI), Mature Erythroid Burst (BFU-EM) and Erythroid Colony Forming Units (CFU-E) was evaluated in bone marrow and spleen of hypoxic and post-hypoxic mice after removal from the chamber. The number of BFU-EI and CFU-E, was evaluated in both femoral bone marrow and spleen of ex-hypoxic polycythemic mice, at two times intervals after the end of hypoxia. We found that in both bone marrow and spleen, the kinetics of the CFU-E pool was characterized by a sharp fall from above normal to lower than normal levels. BFU-EM increased from normal to higher than normal levels. These results have been correlated with both erythropoietin (EPO) and the erythropoietic activity. The results show that EPO levels largely control both the differentiation and the amplification of the CFU-E pool and they suggest that EPO may acts as a "survival factor" at the CFU-E level and/or increase the flow of cells from BFU-E to CFU-E. After the termination of the period of hypoxia and during post-hypoxia there was a reduction in EPO production which subsequently caused a depletion of the CFU-E population, indicating that the size of the CFU-E pool is EPO-dependent. After the injection of 1U of recombinant human erythropoietin (rHuEPO) the size of that pool was increased and the pool of BFU-EI was decreased. It is noteworthy that our studies show that the spleen functions as a large reservoir of erythroid precursors for hypoxia-induced stress erythropoiesis.

Animals↗

PubMed1992

Malondialdehyde modification of lipoprotein(a) produces avid uptake by human monocyte-macrophages.

Increased plasma levels of the apoB-100-containing lipoprotein(a) (Lp(a)) are associated with an increased risk for atherosclerosis and myocardial infarction, but the mechanisms by which lipoprotein(a) may accelerate these processes remain obscure. In this study we have investigated the impact of the association of apoprotein(a) with the low density lipoprotein (LDL)-like Lp(a) particle upon specificity of receptor recognition after lipoprotein modification by malondialdehyde or transition metal-induced oxidation. We have determined that radioiodination labels both apoprotein components of Lp(a), that malondialdehyde modification produces an anionic lipoprotein comparable to native Lp(a) in Stokes' radius, and that N,N'-disubstituted 1-amino-3-iminopropene derivatives preferentially cross-link apoprotein(a) to apoB-100 protein. Like LDL, native Lp(a) is recognized in human monocyte-macrophages by the LDL receptor. Like LDL, progressive modification of Lp(a) by malondialdehyde abolishes lipoprotein recognition by the LDL receptor and produces uptake and hydrolysis by the scavenger receptor of human monocyte-macrophages. We propose that intimal retention of Lp(a) by extracellular components of the atherosclerotic reaction places the lipoprotein in a microenvironment favoring subsequent peroxidative modification. The chronic production of lipid peroxide-modified Lp(a) together with unmitigated cellular clearance by scavenger receptors may contribute to the accumulation of lipoprotein-derived lipid in macrophage-derived foam cells of the atherosclerotic reaction.

Cells, Cultured↗