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PubMed2026

Spatial Proteomics of the Human Atherosclerotic Microenvironment Reveals Heterogeneity in Intraplaque Proteomes and Extracellular Matrix Remodeling.

Plaque heterogeneity underlies the propensity of atherosclerotic lesions to rupture and trigger cardiovascular events. Most proteomic studies examine bulk changes, obscuring key spatial differences in protein abundance. We report a high-resolution spatial proteomics workflow exploring the molecular landscape of human plaques and a murine myocardium. By combining laser capture microdissection with high-sensitivity ion-mobility mass spectrometry, spatial profiling of cellular and extracellular matrix (ECM) proteomes was achieved. Over 2700 proteins were detected from 50,000 μm2 areas, revealing substantial intraplaque heterogeneity across distinct regions (lipid-rich, media, shoulder, necrotic core, intima) and distance from the artery lumen. Inverse correlations between proteases (cathepsin B) and core structural ECM proteins (perlecan, HSPG2) indicated active ECM remodeling. Analysis of media layers indicated distinct protein signatures associated with smooth muscle contraction and cell-cell communication. Blood coagulation signatures, including platelet degranulation and fibrin formation, were enriched at the intima. Inflammatory (clusters of differentiation 4/68, CD4/CD68; vascular cell adhesion molecule 1, VCAM1) and vascular damage markers (tenascin-C, TNC) were enriched in shoulder regions. The necrotic core was dominated by blood proteins, consistent with intraplaque hemorrhage. This workflow resolves proteomic changes over ∼200 μm distances, providing unprecedented insights into plaque morphology and offers a powerful tool for elucidating plaque biology.

Humans↗
PubMed2005

Oral tolerance and regulation of mucosal immunity.

Regulated mechanisms sustain the ability of the gut immune system to discriminate harmless food antigens (Ag) and commensal bacteria from pathogenic microorganisms, resulting in tolerance versus protective immunity, respectively. Antigens of the gut commensals are not simply ignored, but rather trigger an active immunosuppressive process, more commonly known as oral tolerance, which prevents the outcome of immunopathology. Both intrinsic properties of the gut microenvironment and cellular actors, as well as peripheral events induced by systemic dissemination of oral Ag, promote the induction of regulatory mechanisms that ensure maintenance of gut homeostasis. The aim of this review is to provide a synthetic update on the mechanisms of oral tolerance, with particular emphasis on the complex interplay between regulatory CD4+ T cells, dendritic cells and the gut microenvironment.

Animals↗
PubMed1999

[Protection from oxidant injury on airway epithelial cells and the local microenvironment modulation].

An cellular injury model of primary cultured rabbit bronchial epithelial cells (BEC) exposed to ozone was established in this study and cytoprotective effects of factors in local microenvironment of airway such as vasoactive intestinal peptide (VIP), epidermal growth factor (EGF) and heat stress were observed. These factors could lighten damage in cell and elevate the level of glutashione(GSH), which depended upon phosphorylation modulation by protein kinases and gene transcription. A low level of bcl-2 gene expression could be detected in BEC at basic state, and either VIP or EGF stimulated the transcription of bcl-2, which improved the capability of BEC to resist oxidant injury. Otherwise, EGF and heat stress increased VIP autocrine from BEC and upregulated the expression of VIP receptor on BEC, so that the protective effect of VIP can be amplified in local sites. This study confirmed that there is an anti-injury protection on airway epithelium and the protection can be adaptively modulated by the regulatory peptides in local microenvironment and exogenous stimulus.

Animals↗
PubMed2026

Mapping subcellular microenvironments using oligonucleotide-directed proximity labeling.

Understanding how cells compartmentalize their biomolecules into discrete structures remains one of the fundamental goals of cell biology. The proliferation of proximity labeling (PL) technologies has been invaluable toward this goal, enabling biochemical "dissection" of compartments that would be intractable to classical biochemical methods. While robust PL approaches have long been established for targeting proteins of interest, targeting nucleic acids-RNAs and genomic loci-has remained significantly more challenging. Here, we review recent advancements in the field that overcome this longstanding roadblock by using programmable DNA oligonucleotides to direct PL enzyme localization. These tools are already revealing new insights into the molecular architecture of cellular compartments that lie at the heart of gene expression. They also provide a foundation for developing a new generation of PL tools that exploit the modularity and programmability of oligonucleotide-based devices to enable precise spatiotemporal control at previously inaccessible targets and in challenging specimen types.

Oligonucleotides↗
PubMed2004

Molecular and cellular mechanisms of T cell development.

The thymus is central to the establishment of a functioning immune system. Here is the place where T cells mature from hematopoietic progenitors, driven by mutual interactions of stromal cells and the developing thymocytes. As a result, different types of T cells are generated, all of which have been carefully selected for the ability to act in host defense towards non-self and against the potential to mount pathogenic self-reactive autoimmune responses. In this review we summarize our present knowledge on the lineage decisions taking place during this development, the selection processes responsible for shaping the T cell antigen-receptor repertoire, the interactions with the stromal components and the signal transduction pathways which transform the interactions with the thymic microenvironment into cellular responses of survival, proliferation, differentiation and, importantly, also of cell death.

Adaptor Proteins, Signal Transducing↗
PubMed1986

A new approach to the evolution of the blastic crisis from chronic myelocytic leukemia: dynamic interplay of cellular alterations and a changing microenvironment.

The mechanisms responsible for the massive hyperplasia and for the blastic crisis in chronic myelocytic leukemia are poorly understood. The most generally accepted hypothesis proposes that this progression is due to the development of genetic instability in the leukemic cells. In particular, the two phases of the disease are believed to reflect different, discrete genetic events. Such events remain undefined as yet, and the causal significance of observed genetic aberrations is not clear. An alternative hypothesis is presented here. It is assumed that the feedback interactions adjust the relative probabilities of maturation and replication of the 'committed' as well as the pluripotent cells, and further that mitotic cells at all stages possess considerable phenotypic adaptability; in particular their self-renewal capacity can vary in response to changes in the cellular composition of the tissue even within a conventionally defined compartment. On this basis, it is shown that chronic leukemia can arise and evolve into the blastic crisis from a progressive decline in a single clonal characteristic--inducibility to maturation. It is shown, with the help of mathematical considerations, how an initial hereditable event in an early hemopoietic cell can cause a disturbance of the tissue which feeds back onto the individual members of the clone, resulting in a cascade of dynamic changes which can lead to blast cell dominance.

Cell Cycle↗
PubMed2025

Discovery of a Linked Constellation of Gene Expression Revealed by Local Editing of Fibroblasts in Tumors.

Fibroblasts play critical roles in regulating cellular relationships during tissue homeostasis, immunity, and tumor biology at multiple sites. However, tools to perturb fibroblasts at just one site in vivo are limited, restricting our understanding of how these cellular relationships develop on a local level. We optimized local gene editing of fibroblasts in multiple mouse tumor models to investigate how locally restricted fibroblast perturbations affect the cellular tumor microenvironment (TME). By knocking out surface receptors Osmr, Tgfbr2, or Il1r1 on cancer-associated fibroblasts (CAFs), we uncover that TGFBR2 signaling loss uniquely induces the emergence of a Col18a1 hi CAF cell state that is distinct from previously described fibroblast states and is associated with worse survival in human PDAC patients. Further application of a local as well as combinatorial gene knockout technology in CAFs reveals a circuit in which these Col18a1 hi CAFs reshape the TME by recruiting Siglec-Fhi neutrophils via Cxcl5 expression; and that the Col18a1 hi CAF cell state is further dependent on TNFR1 and canonical Wnt signaling. Together, a fast, affordable, and modular engineering method is demonstrated, allowing discovery of a modified fibroblast identify, as well as the network details of a local inter-cellular circuitry in a tumor.

Journal Article↗
PubMed1990

Blood flow, oxygen consumption and tissue oxygenation of human tumors.

The objective of this article was to summarize current knowledge of blood flow and oxygen supply to human tumors, parameters which go hand in hand, and in turn critically determine the cellular metabolic microenvironment of human malignancies. A compilation of available data on blood flow, oxygen supply, and tissue oxygen distribution in human tumors is presented. Though 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. Comparable to rodent tumors, O2-depleted areas develop in human malignancies which coincide with nutrient and energy deprivation, and with a hostile metabolic microenvironment. Significant variations in these relevant parameters have to 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.

Erythrocytes↗
PubMed2006

Microfabricated discontinuous-edge surface topographies influence osteoblast adhesion, migration, cytoskeletal organization, and proliferation and enhance matrix and mineral deposition in vitro.

The fabrication of surfaces that stimulate increased adhesion, migration, and differentiated function of osteoblasts has been viewed as being desirable for many orthopedic applications. Previous studies have shown that microfabricated pits and grooves alter adhesion, spreading, matrix secretion, and production of mineral by rat calvarial osteoblasts (RCOs). The mechanisms underlying these effects are unknown, although microenvironment and cell alignment are considered to play a role. The aim of this work was to investigate the behavior of RCOs on microfabricated discontinuous-edge surfaces (DESs), which could provide an alternative means to control both the microenvironment and cellular alignment. Two types of discontinuous-type structures were employed, gap-cornered boxes and micron scale pillars. DES gap-cornered boxes and the pillars influenced the arrangement of F-actin, microtubules, and vinculin. Osteoblasts were guided in their direction of migration on both types of substrata. Both box DESs and pillars altered the staining intensity and localization pattern of phosphotyrosine and src-activated FAK localization. Cell multilayering, matrix deposition, and mineralization were enhanced on both discontinuous topographies when compared with smooth controls. This study shows that DESs alter adhesion, migration, and proliferative responses from osteoblasts at early time points (<1 week) and promote multilayering, matrix deposition, and mineral deposition at later times (2-6 weeks). Such topographical patterns could potentially be employed as effective surface features on bone-contacting implants or in membrane-based periodontal applications.

Actins↗
PubMed1991

Arachidonic acid and diacylglycerol act synergistically to activate protein kinase C in vitro and in vivo.

Using a well-defined model membrane bilayer system, incorporation of both lipid second messengers, 1,2-diacylglycerol and arachidonic acid, at submaximal activating concentrations, resulted in a synergistic activation of protein kinase C in a Ca2+/phosphatidylserine-dependent manner as measured by monitoring phosphorylation of phosphoprotein substrates. The arachidonic acid appears to modulate membrane properties both at the hydrocarbon core and the membrane surface increasing the availability of the diacylglycerol which can bind to and subsequently activate the enzyme. Co-application of these two lipid activators to the Hermissenda photoreceptor reduced K+ channel conductance in a synergistic manner via a PKC-dependent pathway. Thus, these in vivo and in vitro studies suggest that the membrane bilayer properties of these PKC lipid activators interact to specifically regulate the cellular lipid microenvironment resulting in PKC activation.

Animals↗
PubMed2006

Disassembly of layer-by-layer films of plasmid DNA and reducible TAT polypeptide.

This paper reports the disassembly of layer-by-layer (LbL) films of plasmid DNA and a reducible cationic polypeptide. To utilize a reducing microenvironment of cellular plasma membrane as a potential trigger, LbL films are assembled to contain both DNA and the TAT-based polypeptide (PTAT) with reducible disulfide bonds in the backbone. The assembly and disassembly processes are monitored by goniometry, ellipsometry, and atomic force microscopy (AFM). The structure of the PTAT films is compared with that of non-reducible poly(L-lysine) (PLL) films. Both PTAT and PLL films exhibit exponential growth but with the contact angle alternating between characteristic values. Ellipsometry and AFM show a gradual and complete disassembly of the PTAT but not the PLL films in a 24h period in the reducing environment in vitro. This study suggests a potential of using reducible LbL films for controlled DNA delivery.

DNA↗
PubMedDate not supplied

Prediction of drug sensitivity and drug resistance in cancer by transcriptional and proteomic profiling.

The oncologist's challenges, particularly with advanced cancers, are (a) how to predict tumor response to a given drug or regimen; (b) how to predict which tumors of identical histology will remain indolent and which will be likely to progress; and (c) how to determine the appropriate timing of the emergence of drug-resistant cancer cells and hence switch to appropriate therapy. These issues are still unresolved; current clinical practice is hampered by the complexity and heterogeneity of anti-tumor drug resistance where multiple cellular, tumor microenvironment and host factors operate simultaneously. The rapid accumulation of genomic and proteomic databases for complex biological systems, such as cancer, together with advances in technology platforms, have paved the way to an increased molecular understanding and prediction of antitumor drug response. The complex phenotype of drug resistance can now be dissected and specific, clinically relevant markers pinpointed. Several microarray studies of genetic patterns from untreated and pre-treated cancers have provided "fingerprints" that can predict response to therapeutics. Nevertheless, such approaches require further validation in experimental models and in large clinical trials before their routine clinical use. Moreover, comparative transcriptional profiling alone is unlikely to predict drug sensitivity/resistance, a dynamic process where protein phosphorylation, protein trafficking, and protein-protein interactions with secondary effectors play key roles in the fate of cancer cells following therapeutic stress. Functional proteomics is potentially more predictive, but still faces technical challenges with regards to sampling, tumor heterogeneity, and lack of standardized methodologies. These obstacles are surmountable with current concerted research efforts and availability of powerful high-throughput genomic and proteomic instrumentations, and thus approaches to predict and overcome drug resistance could be rationalized.

Animals↗
PubMed2000

Basal lamina of avian ovarian follicle: influence on morphology of granulosa cells in-vitro.

Experiments were conducted to determine the influence of basal lamina on the morphology of ovarian granulosa cells in vitro. Pure and intact basal lamina was isolated from the large preovulatory follicles of the chicken ovary and designated basal lamina of avian ovarian follicle (BLAOF). Examination of the isolated basal lamina with electron microscope revealed an ultrastructure that is similar to that of basal lamina in the intact ovarian follicle. Pieces of the intact basal lamina were attached to the bottom of 32 mm culture dishes (BLAOF-coated dishes) in which differentiated granulosa cells isolated from the largest preovulatory follicle or undifferentiated granulosa cells isolated from immature small yellow chicken ovarian follicles were cultured; uncoated dishes served as controls. Granulosa cells incubated on intact basal lamina assumed spherical shape, whereas granulosa cells incubated directly on plastic in control dishes became highly flattened. Interestingly, granulosa cells that attached to plastic close to BLAOF (in BLAOF-containing dishes) became rounded. The storage of BLAOF-coated culture dishes at 4 degrees C for 2 years had no apparent effect on its ability of the matrix material to induce changes in granulosa cell shape. Some components of the basal lamina could be solubilized with guanidine-HCl alone (fraction 1; 90-95% of total protein in BLAOF) with the remaining components solubilized with beta-mercaptoethanol containing guanidine-HCl (fraction 2; 5-10% of total protein in BLAOF). Differentiated and undifferentiated chicken granulosa cells became rounded when incubated in fraction 1-pre-coated wells; whereas those incubated directly on plastic in control wells were flattened. Similarly, when fraction 1 of solubilized basal lamina was added as liquid to incubation mixture, it caused both differentiated and undifferentiated granulosa cells to assume spherical shapes. The storage of fraction 1-coated culture dishes at 4 degrees C for 12 or more months had no apparent effect on its ability to influence granulosa cell shape. Fraction 1-induced changes in granulosa cell shape were similar to those observed for complete and intact basal lamina (BLAOF). These findings demonstrate that intact homologous basal lamina (BLAOF) or its solubilized (fluidized) form can induce normal (in vivo) morphology in granulosa cells. It is suggested that BLAOF or its solubilized form can be used to culture cells in experiments designed to examine the influence of the natural basal lamina microenvironment on cellular behavior and function.

Animals↗
PubMed2001

Identification of extracellular matrix components and their integrin receptors in the human fetal adrenal gland.

The development of the human fetal adrenal gland is characterized by a gradient of mitotic activity, cell migration, and cell apoptosis, all of which dictate its particular function. Such plasticity may possibly be under the control of the extracellular environment. The goal of this study was to identify components of the extracellular matrix in second-trimester fetal adrenal glands. Whereas collagen IV was expressed evenly throughout the gland, both fibronectin and laminin demonstrated a mirror-imaged distribution, with higher expression of fibronectin in the central portion and laminin at the periphery of the gland. The integrin subunit alpha1 was found mainly in the definitive zone and the alpha2-subunit mainly in the transitional zone, whereas integrin alpha3 (which binds both fibronectin and laminin) was detected only in the fetal zone. The beta2-subunit was observed solely in chromaffin cells. Such specific gradients of integrin and MEC component expression suggest that the extracellular environment does play a definite role during adrenal gland development. Indeed, compared with that in untreated plastic dishes, ACTH stimulation of dehydroepiandrosterone sulfate and cortisol was enhanced by collagen IV. In addition, fibronectin enhanced dehydroepiandrosterone sulfate but decreased cortisol secretion, compared with collagen IV substrates. These results provide fundamental insight into the contribution of the microenvironment in cellular processes leading to fetal adrenal gland development.

Adrenal Glands↗
PubMed1999

Drug resistance mediated by cellular stress response to the microenvironment of solid tumors.

Most solid tumors show resistance to current chemotherapy. This drug resistance can be associated with the unique physiology of solid tumors. Solid tumors generally have regions of low oxygen (hypoxia), low pH and low levels of glucose, which are not observed in normal tissues. These tumor-specific conditions commonly cause the glucose-regulated stress response of cancer cells. Accumulating evidence shows that the stress response leads to induction of resistance to multiple drugs, such as etoposide, doxorubicin, camptothecin and vincristine. This type of drug resistance is reversible and decays rapidly when stress conditions are removed. The induction of drug resistance can be partly explained by cell cycle arrest at the G1 phase in stressed cells because most anticancer drugs are primarily effective against rapidly dividing cells. Specific mechanisms, such as the decreased expression of DNA topoisomerase (topo) II alpha for the resistance to topo II poisons, are also involved in the drug resistance. Stressed cells, however, become hypersensitive to cisplatin, one of the most effective drugs against solid tumors, suggesting that preferential cytotoxicity to stressed cells may be important for the clinical efficacy against solid tumors. Further characterization of stressed cells will provide a unique target to circumvent the drug resistance of solid tumors.

Animals↗
PubMed1990

Oxygenation of human tumors.

The objective of this article is to summarize current knowledge of oxygen supply to human tumors and of tumor tissue oxygenation, parameters which go hand in hand, and in turn critically determine the cellular metabolic microenvironment of human malignancies. A compilation of available data on these factors is presented. Though data on human tumors in situ are scarce and there may be significant errors associated with the technique used for measurements, experimental evidence is provided for the existence of a compromised and anisotropic oxygen supply to many tumor cells. Comparable to experimental rodent tumors, O2-depleted areas develop in many human malignancies which coincide with nutrient and energy deprivation, and with a hostile metabolic microenvironment. Significant variations in these relevant parameters have to 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. Therefore, evaluation of the oxygenation status in individual tumors before therapy might be most beneficial for designing specifically tailored treatment protocols for individual subjects in order to improve tumor response to treatment.

Blood Flow Velocity↗
PubMed1997

Neutrophil apoptosis is modulated by endothelial transmigration and adhesion molecule engagement.

Termination of a neutrophil-mediated inflammatory response occurs through the activation of the endogenous cell death program, apoptosis. Neutrophil apoptosis is a constitutive process that can be accelerated or delayed by signals from the microenvironment. Since cellular localization at the site of an inflammatory challenge is the critical first step in a neutrophil response, we investigated the effects of neutrophil transendothelial transmigration on the kinetic expression of apoptosis. Neutrophils isolated from rat lung following challenge with LPS demonstrated a significant delay in spontaneous apoptosis. This delay was a consequence of transmigration, since a comparable delay was seen when TNF-alpha, a potent inducer of apoptosis in vitro, was used as the inflammatory stimulus. Human neutrophils demonstrated comparable delays in apoptosis in vitro following migration across an endothelial monolayer in response to FMLP. Delayed apoptosis only occurred in cells that had first been primed by LPS, a stimulus shown to up-regulate beta2 integrins and down-regulate L-selectin. Finally, crosslinking of CD11a or CD11b, but not of CD18, with mAbs and F(ab')2 fragments produced a delay in spontaneous apoptosis, whereas crosslinking of L-selectin with mAb or its natural ligand, sulfatides, accelerated the apoptotic process. Cells in which apoptosis was inhibited demonstrated persistent functional respiratory burst activity. These observations establish a role for endothelial transmigration in the regulation of neutrophil apoptosis, and suggest that adhesion molecules serve a modulatory role in the expression of neutrophil programmed cell death.

Animals↗