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PubMed1991

Neural repair and glial proliferation: parallels with gliogenesis in insects.

There is a growing recognition, stemming from work with both vertebrates and invertebrates, that the capacity for neuronal regeneration is critically dependent on the local microenvironment. That environment is largely created by the non-neuronal elements of the nervous system, the neuroglia. Therefore an understanding of how glial cells respond to injury is crucial to understanding neuronal regeneration. Here we examine the process of repair in a relatively simple nervous system, that of the insect, in which it is possible to define precisely the cellular events of the repair process. This repair is rapid and well organised; it involves the recruitment of blood cells, the division of endogenous glial elements and, possibly, migration from pre-existing glial pools in adjacent ganglia. There are clear parallels between the events of repair and those of normal glial development. It seems likely that the ability of the insect central nervous system to repair resides in the retention of developmental capacities throughout its life and that damage results in the activation of this potential.

Animals↗
PubMed1997

Practical and theoretical issues in 1993 concerning radiation effects on the growth of normal and neoplastic hematopoietic cells.

Radiation has multiple effects on eukaryotic cells, ranging from altered gene expression and cell-cell signaling to induction of programmed cell death (i.e., apoptosis). These changes may lead to neoplastic transformation of the cell and diverse effects on differentiation and growth. The Belarusians were exposed to greater levels of radiation from the Chernobyl nuclear reactor melt-down than any other population. Medical consequences of this exposure are reviewed, focusing on the appearance of thyroid cancer and the possible increased risk of future hematologic malignancies. Since circulating hematopoietic cells must be relaced continually at high rates, the effects of ionizing radiation are reviewed at the cellular level, utilizing the hematopoietic system as a model tissue. An overview of normal hematopoiesis (as understood in 1993) is provided, and the effects of ionizing radiation on hematopoietic stem cell compartments are reviewed. Hematopoietic growth factors (i.e., cytokines) that are associated with the plasma membrane (i.e., membrane-bound cytokines), or that are released as "soluble" molecules into the microenvironment and circulation, may "protect" organisms from radiation injury and may accelerate hematopoietic recovery following radiation exposure. Cloned hematopoietic cytokines, individually or in combination, may be useful in the treatment of radiation accident victims in the future.

Animals↗
PubMed2026

Imaging-Guided Omics Technologies for Resolving Rare Cancer States and Advancing Nanomedicine.

The ability to resolve rare and transient cellular states is critical for understanding metastasis, immune evasion, and therapy resistance in cancer, yet these dynamic processes often escape detection by conventional sequencing and imaging approaches. Recent advances at the interface of nanotechnology, high-resolution live-cell imaging, and single-cell/spatial multiomics methods have enabled functional profiling of cells with unprecedented precision within their native microenvironment. In this Mini-Review, we highlight emerging nanoscale platforms that couple real-time phenotypic imaging with molecular readouts, such as FUNseq and CIN-seq, to directly link functional heterogeneity to transcriptomic, proteomic, and epigenomic information. By integrating nanoscale optical imaging, microengineered perturbation tools, and AI-driven computational analysis, these technologies open up new avenues for dissecting rare metastatic, therapy-resistant, or immune-evasive subpopulations. We further discuss how these next-generation imaging-guided single-cell and spatial omics platforms not only advance fundamental cancer biology but also create opportunities to accelerate the development of nanomedicine applications.

Humans↗
PubMed2006

Lysyl oxidase is essential for hypoxia-induced metastasis.

Metastasis is a multistep process responsible for most cancer deaths, and it can be influenced by both the immediate microenvironment (cell-cell or cell-matrix interactions) and the extended tumour microenvironment (for example vascularization). Hypoxia (low oxygen) is clinically associated with metastasis and poor patient outcome, although the underlying processes remain unclear. Microarray studies have shown the expression of lysyl oxidase (LOX) to be elevated in hypoxic human tumour cells. Paradoxically, LOX expression is associated with both tumour suppression and tumour progression, and its role in tumorigenesis seems dependent on cellular location, cell type and transformation status. Here we show that LOX expression is regulated by hypoxia-inducible factor (HIF) and is associated with hypoxia in human breast and head and neck tumours. Patients with high LOX-expressing tumours have poor distant metastasis-free and overall survivals. Inhibition of LOX eliminates metastasis in mice with orthotopically grown breast cancer tumours. Mechanistically, secreted LOX is responsible for the invasive properties of hypoxic human cancer cells through focal adhesion kinase activity and cell to matrix adhesion. Furthermore, LOX may be required to create a niche permissive for metastatic growth. Our findings indicate that LOX is essential for hypoxia-induced metastasis and is a good therapeutic target for preventing and treating metastases.

Animals↗
PubMed2003

Michael Mason prize essay 2003. Why do leucocytes accumulate within chronically inflamed joints?

Chronic inflammation is characterized by the accumulation of leucocytes within tissues. In rheumatoid arthritis the inflammatory infiltrate shares many architectural features with lymphoid tissue. For example, CD4 T cells and B cells accumulate in perivascular lymphoid structures within synovial tissue. CD8 T cells and neutrophils are found predominantly within synovial fluid. What drives these distinctive lymphoid microstructures and the relative contribution of lymphocytes and stromal cells such as fibroblasts to this process is the subject of this review. Cellular interactions between leucocytes and stromal cells such as macrophages and fibroblasts are important in generating tumour necrosis factor-alpha within the inflamed synovium. Therefore understanding how leucocytes accumulate within the inflamed synovium is likely to provide new therapeutic approaches to modify the inflammatory process. We have found that fibroblasts play a dominant role in defining the disordered synovial microenvironment in rheumatoid arthritis. Through their production of a variety of cytokines (interferon-beta, transforming growth factor-beta) and constitutive chemokines (stromal cell-derived factor-1, CXCL12) they directly alter the behaviour of lymphocytes that accumulate within chronically inflamed joints leading to their inappropriate survival and retention. We have extended these observations to another chronic persistent rheumatic disease, Sjögren's syndrome, and found that ectopic production of the constitutive B cell-attracting chemokine BCA-1 (CXCL13) is associated with lymphocyte accumulation and lymphoid tissue formation. These findings suggest that stromal cells such as fibroblasts play an important role in the switch from acute resolving to chronic persistent arthritis by allowing lymphocytes to accumulate in the wrong place at the wrong time.

Arthritis, Rheumatoid↗
PubMed1983

Fibronectin-mediated attachment of hematopoietic cells to stromal elements in continuous bone marrow culture.

Hematopoiesis in continuous bone marrow culture is dependent upon close-range interaction between hematopoietic cells and marrow-derived adherent cells. The latter have been shown to include a significant proportion of fibroblastic elements, synthesizing the attachment protein fibronectin. The role of fibronectin in continuous bone marrow culture was therefore investigated. Continuous marrow cultures were stained by the peroxidase-anti-peroxidase technique, using an affinity-purified anti-fibronectin antibody. The stained cultures were then examined by transmission electron microscopy for the presence of fibronectin at sites of cellular attachment. Fibronectin was detected on the substratum attachment surfaces of marrow-derived adherent cells and at sites of interaction between stromal elements in the adherent layer. Fibronectin was also detected at many attachment sites between marrow-derived adherent cells and developing granulocytes and monocytes. The possible significance of these observations is discussed in relation to the hematopoietic microenvironment.

Animals↗
PubMed1983

Splenic accumulation of stromal progenitor cells in response to bacterial lipopolysaccharides.

An analysis was made of fibroblastoid colony-forming units (CFUF) in spleens of mice treated with bacterial lipopolysaccharide (LPS). Increased CFUF numbers were observed on days 2, 3 and 4 after treatment with 10, 30 and 100 micrograms of LPS. The splenic CFUF accumulation occurred at the same time as spleen hemopoiesis increased, however, the CFUF returned to normal and subnormal numbers on day 5, while the spleen cellularity was still elevated on day 21 after LPS treatment. The mechanism of splenic CFUF accumulation appeared to involve CFUF migration via the blood from other sites of hemopoiesis rather than increased CFUF plating efficiency in vitro or enhanced CFUF proliferation. The results suggest a relationship between the LPS-induced fibroblastoid progenitor cell increase and a requirement for splenic microenvironments to support LPS-induced hemopoiesis.

Animals↗
PubMed2006

Calcification and cellularity in human aortic heart valve tissue determine the differentiation of bone-marrow-derived cells.

Human bone-marrow-derived mesenchymal stem cells (MSC) are responsible the remodeling of human tissue. However, damaged aortic valves are lack the ability to regenerate which is an active cell-mediated process. Diseased aortic valve remodeling has similarities even to bone formation. In this study, the prerequisites for cultured MSCs to undergo osteoblastic differentiation on aortic valves were explored. An ex vivo model using a human aortic valve microenvironment was developed. The expression of type I procollagen, alkaline phosphatase activity, osteocalcin secretion and osteocalcin immunostaining were studied to evaluate the induction of osteogenesis of the MSCs on noncalcified and calcified human aortic valves. Aortic valves were exposed to freeze-thaw injury to devitalize valves in order to separately study the role of valve matrix vs. endothelial cells in the explants. Thus, valves were assigned to 1 of 4 treatment groups: noncalcified uninjured valves, calcified uninjured valves, noncalcified injured and calcified injured. Finally, valves were decalcified to separately explore the effect of a calcified matrix on the osteogenesis. In this co-culture system, the noncalcified uninjured valves inhibited osteogenesis of MSCs, whereas the calcified valves promoted differentiation towards osteoblastic lineage. Devitalization of the valve matrix inflicted a significant increase in the osteogenesis of co-cultured MSCs. Calcified matrix in the valves seemed to have a role in the spontaneous osteogenesis of the MSCs. This spontaneous matrix induced differentiation of MSCs into osteoblast lineage could not be inhibited by pravastatin, indomethacin or tetracycline. In conclusion, these results suggest that interactions between MSCs and aortic valve matrix components and cells modulate MSC phenotype in this environment. Further studies are required to characterize this interesting phenomenon in greater detail.

Anti-Bacterial Agents↗
PubMed2002

Solution structure of the Alzheimer amyloid beta-peptide (1-42) in an apolar microenvironment. Similarity with a virus fusion domain.

The major components of neuritic plaques found in Alzheimer disease (AD) are peptides known as amyloid beta-peptides (Abeta), which derive from the proteolitic cleavage of the amyloid precursor proteins. In vitro Abeta may undergo a conformational transition from a soluble form to aggregated, fibrillary beta-sheet structures, which seem to be neurotoxic. Alternatively, it has been suggested that an alpha-helical form can be involved in a process of membrane poration, which would then trigger cellular death. Conformational studies on these peptides in aqueous solution are complicated by their tendency to aggregate, and only recently NMR structures of Abeta-(1-40) and Abeta-(1-42) have been determined in aqueous trifluoroethanol or in SDS micelles. All these studies hint to the presence of two helical regions, connected through a flexible kink, but it proved difficult to determine the length and position of the helical stretches with accuracy and, most of all, to ascertain whether the kink region has a preferred conformation. In the search for a medium which could allow a more accurate structure determination, we performed an exhaustive solvent scan that showed a high propensity of Abeta-(1-42) to adopt helical conformations in aqueous solutions of fluorinated alcohols. The 3D NMR structure of Abeta-(1-42) shows two helical regions encompassing residues 8-25 and 28-38, connected by a regular type I beta-turn. The surprising similarity of this structure, as well as the sequence of the C-terminal moiety, with those of the fusion domain of influenza hemagglutinin suggests a direct mechanism of neurotoxicity.

Alzheimer Disease↗
PubMed2025

Progressive T cell exhaustion and predominance of aging tissue associated macrophages with advancing disease stage in penile squamous cell carcinoma.

Penile squamous cell carcinoma (PSCC) is a rare malignancy with limited understanding of the tumor immune microenvironment (TIME). The interplay between PSCC and the immune system across disease progression and HPV infection status remains poorly characterized. This study aims to assess the TIME changes from localized to advanced disease and between HPV-positive versus negative tumors to identify potential immune evasion mechanisms in advanced PSCC. scRNA-seq was performed on ten PSCC tissue samples from penile, lymph node and distant metastatic sites with four matched penile and lymph node samples to understand the cellular heterogeneity within PSCC tumors. Analysis of immune cell populations and transcriptional hallmarks were performed stratified by localized (pT1-3, N0) versus advanced (N1-3, M0 or any N, M1) disease states and HPV infection status. We observed significant differences in immune cell infiltration between localized and advanced PSCC disease states and by HPV status. Advanced disease states demonstrated an exhausted immune phenotype, characterized by terminally exhausted CD8+ T cells, M2-like macrophages and hypoxic signature, while localized disease states demonstrated an active innate immune system characterized by increased DCs. HPV-negative tumors displayed low immune cell infiltration while HPV-positive tumors demonstrated an immune exhausted phenotype. These findings offer valuable insights into the evolving PSCC immune landscape, paving the way for the development of potential therapeutic approaches for advanced PSCC.

Humans↗
PubMed2002

Enhanced viability and neuronal differentiation of neural progenitors by chromaffin cell co-culture.

The transplantation of neural stem cells and progenitors has potential in restoring lost cellular populations following central nervous system (CNS) injury or disease, but survival and neuronal differentiation in the adult CNS may be insufficient in the absence of exogenous trophic support. Adrenal medullary chromaffin cells produce a trophic cocktail including basic fibroblast growth factor (FGF-2) and neurotrophins. The aim of this study was to evaluate whether chromaffin cells can provide a supportive microenvironment for neural progenitor cells. In order to assess this, the growth and differentiation of neural progenitor cell cultures from embryonic rat cortex were compared in standard FGF-2-supplemented neural progenitor growth media, in standard media but lacking FGF-2, or in media lacking FGF-2 but co-cultured with bovine chromaffin cells. Using bromodeoxyuridine (BrdU)-prelabeling, findings indicated poor survival of progenitor cultures in the absence of FGF-2. In contrast, the addition of chromaffin cells in co-culture appeared to 'rescue' the progenitor cultures and resulted in robust neurospheres containing numerous BrdU-labeled cells interspersed with and closely apposed to chromaffin cells. As indicated by H3 labeling, cells in co-cultures continued to proliferate, but at a substantially reduced rate compared with standard FGF-2 supplemented growth media. The co-cultures contained more beta-tubulin III-positive processes than parallel cultures maintained in FGF-2-supplemented media and these cells displayed a more mature phenotype with numerous varicosities and complex processes. These findings indicate that chromaffin cells can provide a supportive environment for the survival and neuronal differentiation of neural progenitor cells and suggest that their addition may be useful as a sustained source of trophic support to improve outcomes of neural stem cell transplantation.

Adrenal Medulla↗
PubMed2002

Thrombin regulation of cell function through protease-activated receptors: implications for therapeutic intervention.

The serine protease thrombin is well recognized as being pivotal to the maintenance of hemostasis under both normal and pathological conditions. Its cellular actions are mediated through a unique family of protease-activated receptors (PARs). These receptors represent a novel family of G protein-coupled receptors that undergo proteolytic cleavage of their amino terminus and subsequent autoactivation by a tethered peptide ligand. This paper reviews the consequences of PAR activation in thrombosis, vascular injury, inflammation, tissue injury, and within the tumor microenvironment.

Animals↗
PubMed1974

Phosphate metabolism in intact human erythrocytes: determination by phosphorus-31 nuclear magnetic resonance spectroscopy.

Whole human blood was examined by (31)P nuclear magnetic resonance spectroscopy. Individual phosphates (alpha,beta,gamma) of ATP were identifiable, and two microenvironments appeared to be present for this molecule. When sequential recordings of freshly collected blood were made, 2,3-diphosphoglycerate was observed to decrease in association with a concomitant increase in inorganic orthophosphate. When aged cells containing little 2,3-diphosphoglycerate were incubated in the presence of inosine and pyruvate, 2,3-diphosphoglycerate formation could be demonstrated. These results show that cellular metabolism can be recorded directly in intact cells by (31)P nuclear magnetic resonance.

Adult↗
PubMed1991

Semipermeable polymer tubes provide a microenvironment for in vivo analysis of dorsal root regeneration.

The regeneration of lesioned axons is critically influenced by the local microenvironment. In this study, semipermeable polymer tubes were used to provide a defined microenvironment in vivo to analyze the regeneration of dorsal root axons under various conditions in the adult rat. Cut dorsal root fibers grew across a 2.7 mm gap within enclosed polymer tubes by 4 weeks. The pattern of axonal outgrowth was dramatically influenced by mechanical factors such as the inner surface topography of the polymer tube. Tubes containing various molecular and cellular substrates were also used to study their effect on dorsal root regeneration.

Animals↗
PubMed2005

Persistent NF-kappaB activation in renal epithelial cells in a mouse model of HIV-associated nephropathy.

Human immunodeficiency virus (HIV)-associated nephropathy (HIVAN) is caused, in part, by direct infection of kidney epithelial cells by HIV-1. In the spectrum of pathogenic host-virus interactions, abnormal activation or suppression of host transcription factors is common. NF-kappaB is a necessary host transcription factor for HIV-1 gene expression, and it has been shown that NF-kappaB activity is dysregulated in many naturally infected cell types. We show here that renal glomerular epithelial cells (podocytes) expressing the HIV-1 genome, similar to infected immune cells, also have a dysregulated and persistent activation of NF-kappaB. Although podocytes produce p50, p52, RelA, RelB, and c-Rel, electrophoretic mobility shift assays and immunocytochemistry showed a predominant nuclear accumulation of p50/RelA-containing NF-kappaB dimers in HIV-1-expressing podocytes compared with normal. In addition, the expression level of a transfected NF-kappaB reporter plasmid was significantly higher in HIVAN podocytes. The mechanism of NF-kappaB activation involved increased phosphorylation of IkappaBalpha, resulting in an enhanced turnover of the IkappaBalpha protein. There was no evidence for regulation by IkappaBbeta or the alternate pathway of NF-kappaB activation. Altered activation of this key host transcription factor likely plays a role in the well-described cellular phenotypic changes observed in HIVAN, such as proliferation. Studies with inhibitors of proliferation and NF-kappaB suggest that NF-kappaB activation may contribute to the proliferative mechanism in HIVAN. In addition, because NF-kappaB regulates many aspects of inflammation, this dysregulation may also contribute to disease severity and progression through regulation of proinflammatory processes in the kidney microenvironment.

AIDS-Associated Nephropathy↗
PubMed1997

Chondrocytes are regulated by cellular adhesion through CD44 and hyaluronic acid pathway.

The articular cartilage consists of resident chondrocytes embedded within the extracellular matrix which contains several components such as collagen and hyaluronic acids (HA). CD44 is a major cell surface receptor for HA and is homologous to cartilage-link proteins. Although CD44 is present in cartilage, it is not clear if chondrocytes adhere to HA through CD44 or whether such adhesion changes the function of chondrocytes. We studied the molecular mechanisms of CD44-related chondrocyte adhesion to HA and the effects of such adhesion on chondrocyte function. Experiments were performed using the human chondrosarcoma-derived chondrocyte-like cell line HCS-2/8. Our results showed that (a) HCS-2/8 cells highly expressed CD44; (b) HCS-2/8 cells efficiently adhered to HA without any stimuli; (c) monoclonal antibody (mAb)-blocking studies indicated that adhesion of HCS-2/8 cells to HA was mainly mediated by the CD44/HA pathway; (d) cellular adhesion to HA increased the proliferation of HCS-2/8 cells, independent of transforming growth factor-beta (TGF-beta), but this was inhibited by CD44 mAb; (e) the adhesion of chondrocytes to HA also induced c-myc mRNA expression and this was also inhibited by CD44 mAb; and (f) the adhesion of cells to HA augmented TGF-beta mRNA expression, a process also reduced by CD44 mAb. Thus, HCS-2/8 cells effectively adhered to HA through cell surface CD44. The adhesion was also involved in cellular signaling which induced cellular proliferation and expression of c-myc mRNA as well as TGF-beta mRNA expression within the cells. Our results indicate that CD44 on chondrocytes plays an important role in normal and abnormal functions of cartilage through its adhesion to HA, which induces a variety of stimulatory signals to regulate chondrocyte proliferation as well as matrix synthesis in cartilage microenvironment.

Antibodies, Monoclonal↗
PubMed2003

Common lymphoid progenitors, early B-lineage precursors, and IL-7: characterizing the trophic and instructive signals underlying early B cell development.

Precursors for B lymphocytes develop from semirestricted lymphoid progenitors in the bone marrow. Here we review current knowledge on the cellular stages underlying early B cell development from multipotent progenitor cells, and discuss the factors implicated in the regulation of this process. In particular, we will focus on the role of cytokine receptor signaling in early lymphocyte ontogeny and lymphoid lineage commitment, with an emphasis on the role of interleukin- 7 (IL-7) in early lymphocyte development within the bone marrow microenvironment. We will also discuss recent evidence that lymphocytes and subsets of dendritic cells develop from a common pathway, speculating that IL-7 may regulate cell fate decisions in multipotent B/dendritic cell precursors by driving these cells to differentiate into B-lineage-committed cells.

Animals↗
PubMed1984

Chronic myelocytic leukemia: ultrastructural histopathology of bone marrow from patients in the chronic phase.

We investigated the ultrastructural changes in the hematopoietic microenvironment of the bone marrow obtained from 15 untreated patients with chronic myelocytic leukemia (CML) in the chronic phase by transmission and scanning electron microscopy using the cryofracture technique. Examination of the undecalcified bone marrow specimens confirmed extensive hyperplastic granulopoiesis. In the stroma, fat cells were scarce or absent. Macrophages were increased and scattered throughout the marrow. The cytoplasm contained abundant cellular debris and crystals of the Charcot-Leyden type. Slender reticular cells were inconspicuously located between proliferating myeloid cells. A few foci of fibrosis were occasionally observed. The sinus endothelium generally retained its continuity, and no features suggesting complete deterioration of the sinus were evident. However, certain alterations in the sinus wall were noted in the process of leukemia cell migration. Many cells migrated transcellularly into the circulation through transient large openings in the sinus endothelium.

Biopsy↗