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Frontiers in Immunology 2023Laminin 332 is a heterotrimeric structural protein of the basal membrane zone (BMZ) of the skin and adjacent mucosal tissues. The importance of laminin 332 for the... (Review)
Review
Laminin 332 is a heterotrimeric structural protein of the basal membrane zone (BMZ) of the skin and adjacent mucosal tissues. The importance of laminin 332 for the structural integrity of the BMZ is demonstrated by mutations in any of the three genes encoding for its three chains causing variants of junctional epidermolysis bullosa. Autoimmunity against laminin 332 is observed in mucous membrane pemphigoid (MMP) and in the rare patients with orf-induced pemphigoid. MMP is an autoimmune blistering disease with predominant mucosal manifestations and autoantibodies against the BMZ of the skin and orifice-close mucous membranes. The main autoantigens of MMP are type XVII collagen (BP180) and laminin 332 targeted in about 80% and 10-20% of patients, respectively. An increasing number of studies has highlighted the association of anti-laminin 332 MMP and malignancies that can be revealed in about a quarter of these patients. This data has led to the recommendation of current guidelines to assay for anti-laminin 332 reactivity in all MMP patients. The present review focuses on anti-laminin 332 MMP describing clinical features, its pathophysiology, and detection of serum anti-laminin 332 IgG. In addition, the available data about the occurrence of malignancies in anti-laminin 332 MMP, the underlying tumor entities, and its biology are detailed.
Topics: Humans; Autoimmunity; Pemphigoid, Bullous; Autoantibodies; Skin; Biological Assay
PubMed: 37638011
DOI: 10.3389/fimmu.2023.1250115 -
Proceedings of the National Academy of... Sep 2023Stem cells in organoids self-organize into tissue patterns with unknown mechanisms. Here, we use skin organoids to analyze this process. Cell behavior videos show that...
Stem cells in organoids self-organize into tissue patterns with unknown mechanisms. Here, we use skin organoids to analyze this process. Cell behavior videos show that the morphological transformation from multiple spheroidal units with morphogenesis competence (CMU) to planar skin is characterized by two abrupt cell motility-increasing events before calming down. The self-organizing processes are controlled by a morphogenetic module composed of molecular sensors, modulators, and executers. Increasing dermal stiffness provides the initial driving force (driver) which activates Yap1 (sensor) in epidermal cysts. Notch signaling (modulator 1) in epidermal cyst tunes the threshold of Yap1 activation. Activated Yap1 induces Wnts and MMPs (epidermal executers) in basal cells to facilitate cellular flows, allowing epidermal cells to protrude out from the CMU. Dermal cell-expressed Rock (dermal executer) generates a stiff force bridge between two CMU and accelerates tissue mixing via activating Laminin and β1-integrin. Thus, this self-organizing coalescence process is controlled by a mechano-chemical circuit. Beyond skin, self-organization in organoids may use similar mechano-chemical circuit structures.
Topics: Skin; Epidermis; Personality; Organoids; Emotions; Adaptor Proteins, Signal Transducing
PubMed: 37643215
DOI: 10.1073/pnas.2221982120 -
BioRxiv : the Preprint Server For... Oct 2023Imaging and characterizing the dynamics of cellular adhesion in blood samples is of fundamental importance in understanding biological function. microscopy methods are...
Imaging and characterizing the dynamics of cellular adhesion in blood samples is of fundamental importance in understanding biological function. microscopy methods are widely used for this task, but typically require diluting the blood with a buffer to allow for transmission of light. However whole blood provides crucial mechanical and chemical signaling cues that influence adhesion dynamics, which means that conventional approaches lack the full physiological complexity of living microvasculature. We propose to overcome this challenge by a new imaging method which we call motion blur microscopy (MBM). By decreasing the source light intensity and increasing the integration time during imaging, flowing cells are blurred, allowing us to identify adhered cells. Combined with an automated analysis using machine learning, we can for the first time reliably image cell interactions in microfluidic channels during whole blood flow. MBM provides a low cost, easy to implement alternative to intravital microscopy, the approach for studying how the whole blood environment shapes adhesion dynamics. We demonstrate the method's reproducibility and accuracy in two example systems where understanding cell interactions, adhesion, and motility is crucial-sickle red blood cells adhering to laminin, and CAR-T cells adhering to E-selectin. We illustrate the wide range of data types that can be extracted from this approach, including distributions of cell size and eccentricity, adhesion times, trajectories and velocities of adhered cells moving on a functionalized surface, as well as correlations among these different features at the single cell level. In all cases MBM allows for rapid collection and processing of large data sets, ranging from thousands to hundreds of thousands of individual adhesion events. The method is generalizable to study adhesion mechanisms in a variety of diseases, including cancer, blood disorders, thrombosis, inflammatory and autoimmune diseases, as well as providing rich datasets for theoretical modeling of adhesion dynamics.
PubMed: 37873474
DOI: 10.1101/2023.10.08.561435 -
Frontiers in Oncology 2023The onset, development, diagnosis, and treatment of cancer involve intricate interactions among various factors, spanning the realms of mechanics, physics, chemistry,... (Review)
Review
The onset, development, diagnosis, and treatment of cancer involve intricate interactions among various factors, spanning the realms of mechanics, physics, chemistry, and biology. Within our bodies, cells are subject to a variety of forces such as gravity, magnetism, tension, compression, shear stress, and biological static force/hydrostatic pressure. These forces are perceived by mechanoreceptors as mechanical signals, which are then transmitted to cells through a process known as mechanical transduction. During tumor development, invasion and metastasis, there are significant biomechanical influences on various aspects such as tumor angiogenesis, interactions between tumor cells and the extracellular matrix (ECM), interactions between tumor cells and other cells, and interactions between tumor cells and the circulatory system and vasculature. The tumor microenvironment comprises a complex interplay of cells, ECM and vasculature, with the ECM, comprising collagen, fibronectins, integrins, laminins and matrix metalloproteinases, acting as a critical mediator of mechanical properties and a key component within the mechanical signaling pathway. The vasculature exerts appropriate shear forces on tumor cells, enabling their escape from immune surveillance, facilitating their dissemination in the bloodstream, dictating the trajectory of circulating tumor cells (CTCs) and playing a pivotal role in regulating adhesion to the vessel wall. Tumor biomechanics plays a critical role in tumor progression and metastasis, as alterations in biomechanical properties throughout the malignant transformation process trigger a cascade of changes in cellular behavior and the tumor microenvironment, ultimately culminating in the malignant biological behavior of the tumor.
PubMed: 37901315
DOI: 10.3389/fonc.2023.1273154 -
Neural Regeneration Research Dec 2023The blood-brain barrier is a unique property of central nervous system blood vessels that protects sensitive central nervous system cells from potentially harmful blood... (Review)
Review
The blood-brain barrier is a unique property of central nervous system blood vessels that protects sensitive central nervous system cells from potentially harmful blood components. The mechanistic basis of this barrier is found at multiple levels, including the adherens and tight junction proteins that tightly bind adjacent endothelial cells and the influence of neighboring pericytes, microglia, and astrocyte endfeet. In addition, extracellular matrix components of the vascular basement membrane play a critical role in establishing and maintaining blood-brain barrier integrity, not only by providing an adhesive substrate for blood-brain barrier cells to adhere to, but also by providing guidance cues that strongly influence vascular cell behavior. The extracellular matrix protein laminin is one of the most abundant components of the basement membrane, and several lines of evidence suggest that it plays a key role in directing blood-brain barrier behavior. In this review, we describe the basic structure of laminin and its receptors, the expression patterns of these molecules in central nervous system blood vessels and how they are altered in disease states, and most importantly, how genetic deletion of different laminin isoforms or their receptors reveals the contribution of these molecules to blood-brain barrier function and integrity. Finally, we discuss some of the important unanswered questions in the field and provide a "to-do" list of some of the critical outstanding experiments.
PubMed: 37449589
DOI: 10.4103/1673-5374.373677 -
Journal of Experimental & Clinical... May 2023Increasing evidence indicates that the tumor microenvironment (TME) is a crucial determinant of cancer progression. However, the clinical and pathobiological...
BACKGROUND
Increasing evidence indicates that the tumor microenvironment (TME) is a crucial determinant of cancer progression. However, the clinical and pathobiological significance of stromal signatures in the TME, as a complex dynamic entity, is still unclear in esophageal squamous cell carcinoma (ESCC).
METHODS
Herein, we used single-cell transcriptome sequencing data, imaging mass cytometry (IMC) and multiplex immunofluorescence staining to characterize the stromal signatures in ESCC and evaluate their prognostic values in this aggressive disease. An automated quantitative pathology imaging system determined the locations of the lamina propria, stroma, and invasive front. Subsequently, IMC spatial analyses further uncovered spatial interaction and distribution. Additionally, bioinformatics analysis was performed to explore the TME remodeling mechanism in ESCC. To define a new molecular prognostic model, we calculated the risk score of each patient based on their TME signatures and pTNM stages.
RESULTS
We demonstrate that the presence of fibroblasts at the tumor invasive front was associated with the invasive depth and poor prognosis. Furthermore, the amount of α-smooth muscle actin (α-SMA) fibroblasts at the tumor invasive front positively correlated with the number of macrophages (MØs), but negatively correlated with that of tumor-infiltrating granzyme B immune cells, and CD4 and CD8 T cells. Spatial analyses uncovered a significant spatial interaction between α-SMA fibroblasts and CD163 MØs in the TME, which resulted in spatially exclusive interactions to anti-tumor immune cells. We further validated the laminin and collagen signaling network contributions to TME remodeling. Moreover, compared with pTNM staging, a molecular prognostic model, based on expression of α-SMA fibroblasts at the invasive front, and CD163 MØs, showed higher accuracy in predicting survival or recurrence in ESCC patients. Regression analysis confirmed this model is an independent predictor for survival, which also identifies a high-risk group of ESCC patients that can benefit from adjuvant therapy.
CONCLUSIONS
Our newly defined biomarker signature may serve as a complement for current clinical risk stratification approaches and provide potential therapeutic targets for reversing the fibroblast-mediated immunosuppressive microenvironment.
Topics: Humans; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Carcinoma, Squamous Cell; CD8-Positive T-Lymphocytes; Prognosis; Fibroblasts; Tumor Microenvironment
PubMed: 37254126
DOI: 10.1186/s13046-023-02697-y -
Frontiers in Cell and Developmental... 2024Nidogen, also known as entactin, is a multifunctional glycoprotein that plays a crucial role in the maintenance of the basement membrane (BM), morphogenesis and neuronal... (Review)
Review
Nidogen, also known as entactin, is a multifunctional glycoprotein that plays a crucial role in the maintenance of the basement membrane (BM), morphogenesis and neuronal plasticity. This review aims to provide an overview of the structural features, molecular interactions and diverse functions associated with Nidogen. As a bridging molecule within the BM, Nidogen acts as a linchpin connecting various extracellular matrix (ECM) components. Its involvement in tissue development, homeostasis, and pathological conditions underscores its biological and medical significance. We discuss the current state of knowledge regarding Nidogen's role in tissue maintenance, cell adhesion, migration, and signaling, shedding light on its intricate contributions to physiological and pathological processes.
PubMed: 38550383
DOI: 10.3389/fcell.2024.1380542