scholarly journals Mechanical Forces during Lymph Node Expansion Govern Fibroblastic Reticular Network Remodeling

2021 ◽  
Author(s):  
Harry L Horsnell ◽  
Robert J Tetley ◽  
Henry de Belly ◽  
Spiros Makris ◽  
Agnesska C Benjamin ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Lymph Node ◽  
Adaptive Immune Response ◽  
Tissue Mechanics ◽  
Mechanical Forces ◽  
Cortical Tension ◽  
Lectin Receptor ◽  
Actomyosin Contractility ◽  
The Impact ◽  
Fibroblastic Stroma

After immunogenic challenge, the lymph node rapidly increases in cellularity making space for infiltrating and dividing lymphocytes, expanding the tissue. In the early phases of expansion, the underlying fibroblastic stroma, which organises the lymph node, undergoes elongation and stretching. This is followed by the initiation of fibroblastic stroma proliferation as inflammation proceeds. In the steady state, fibroblastic reticular cells (FRCs) tightly wrap an interconnected network of extracellular matrix fibres. The initial physical deformability of the lymph node is in part determined by Podoplanin (PDPN) signalling in FRCs and is modulated by dendritic cells expressing C-type lectin receptor 2 (CLEC-2). However, the mechanisms changing tissue and cellular mechanical forces of the fibroblastic stroma and the triggers for FRC proliferation and growth are unknown. We examined the contributions of FRC actomyosin contractility and extracellular matrix to lymph node tissue tension. Further, we directly tested the impact of tissue mechanics on the kinetics of lymph node expansion. We show using laser ablation that the FRC network is under mechanical tension generated by actomyosin contractility and that tension changes throughout the course of immunogenic challenge. We find that CLEC-2/PDPN signalling alters the cell intrinsic mechanical state of FRCs by reducing cortical tension and increasing FRC size. We found that FRC network tension is a critical cue in controlling lymph node expansion gating the initiation of FRC proliferation. Together this study demonstrates mechanical forces are generated and sensed through the FRC network to determine lymph node expansion required for an adaptive immune response.

scholarly journals Optogenetic relaxation of actomyosin contractility uncovers mechanistic roles of cortical tension during cytokinesis

2021 ◽  
Author(s):  
Kei Yamamoto ◽  
Haruko Miura ◽  
Motohiko Ishida ◽  
Satoshi Sawai ◽  
Yohei Kondo ◽  
...  
Keyword(s):  
Traction Force ◽  
Tissue Mechanics ◽  
Light Illumination ◽  
Type I ◽  
Contractile Ring ◽  
Cortical Tension ◽  
Regulatory Light Chains ◽  
Actomyosin Contractility ◽  
Nonmuscle Myosin Ii ◽  
Wide Range

Actomyosin contractility generated cooperatively by nonmuscle myosin II and actin filaments plays essential roles in a wide range of biological processes, such as cell motility, cytokinesis, and tissue morphogenesis. However, it is still unknown how actomyosin contractility generates force and maintains cellular morphology. Here, we demonstrate an optogenetic method to induce relaxation of actomyosin contractility. The system, named OptoMYPT, combines a catalytic subunit of the type I phosphatase-binding domain of MYPT1 with an optogenetic dimerizer, so that it allows light-dependent recruitment of endogenous PP1c to the plasma membrane. Blue-light illumination was sufficient to induce dephosphorylation of myosin regulatory light chains and decrease in traction force at the subcellular level. The OptoMYPT system was further employed to understand the mechanics of actomyosin-based cortical tension and contractile ring tension during cytokinesis. We found that the relaxation of cortical tension at both poles by OptoMYPT accelerated the furrow ingression rate, revealing that the cortical tension substantially antagonizes constriction of the cleavage furrow. Based on these results, the OptoMYPT system will provide new opportunities to understand cellular and tissue mechanics.

scholarly journals Optogenetic relaxation of actomyosin contractility uncovers mechanistic roles of cortical tension during cytokinesis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Kei Yamamoto ◽  
Haruko Miura ◽  
Motohiko Ishida ◽  
Yusuke Mii ◽  
Noriyuki Kinoshita ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Tissue Mechanics ◽  
Light Illumination ◽  
Contractile Ring ◽  
Cortical Tension ◽  
Regulatory Light Chains ◽  
Actomyosin Contractility ◽  
Nonmuscle Myosin Ii ◽  
Wide Range ◽  
Subcellular Level

AbstractActomyosin contractility generated cooperatively by nonmuscle myosin II and actin filaments plays essential roles in a wide range of biological processes, such as cell motility, cytokinesis, and tissue morphogenesis. However, subcellular dynamics of actomyosin contractility underlying such processes remains elusive. Here, we demonstrate an optogenetic method to induce relaxation of actomyosin contractility at the subcellular level. The system, named OptoMYPT, combines a protein phosphatase 1c (PP1c)-binding domain of MYPT1 with an optogenetic dimerizer, so that it allows light-dependent recruitment of endogenous PP1c to the plasma membrane. Blue-light illumination is sufficient to induce dephosphorylation of myosin regulatory light chains and a decrease in actomyosin contractile force in mammalian cells and Xenopus embryos. The OptoMYPT system is further employed to understand the mechanics of actomyosin-based cortical tension and contractile ring tension during cytokinesis. We find that the relaxation of cortical tension at both poles by OptoMYPT accelerated the furrow ingression rate, revealing that the cortical tension substantially antagonizes constriction of the cleavage furrow. Based on these results, the OptoMYPT system provides opportunities to understand cellular and tissue mechanics.

scholarly journals Mechanosensation and Mechanotransduction by Lymphatic Endothelial Cells Act as Important Regulators of Lymphatic Development and Function

2021 ◽  
Vol 22 (8) ◽  
pp. 3955
Author(s):  
László Bálint ◽  
Zoltán Jakus
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Mechanical Forces ◽  
Lymphatic Endothelial Cells ◽  
Lymphatic Development ◽  
And Function ◽  
The Impact

Our understanding of the function and development of the lymphatic system is expanding rapidly due to the identification of specific molecular markers and the availability of novel genetic approaches. In connection, it has been demonstrated that mechanical forces contribute to the endothelial cell fate commitment and play a critical role in influencing lymphatic endothelial cell shape and alignment by promoting sprouting, development, maturation of the lymphatic network, and coordinating lymphatic valve morphogenesis and the stabilization of lymphatic valves. However, the mechanosignaling and mechanotransduction pathways involved in these processes are poorly understood. Here, we provide an overview of the impact of mechanical forces on lymphatics and summarize the current understanding of the molecular mechanisms involved in the mechanosensation and mechanotransduction by lymphatic endothelial cells. We also discuss how these mechanosensitive pathways affect endothelial cell fate and regulate lymphatic development and function. A better understanding of these mechanisms may provide a deeper insight into the pathophysiology of various diseases associated with impaired lymphatic function, such as lymphedema and may eventually lead to the discovery of novel therapeutic targets for these conditions.

scholarly journals T stage-dependent lymph node and distant metastasis and the accuracy of lymph node assessment in rectal cancer

2021 ◽  
Author(s):  
Henry Ptok ◽  
Frank Meyer ◽  
Roland S. Croner ◽  
Ingo Gastinger ◽  
Benjamin Garlipp
Keyword(s):  
Rectal Cancer ◽  
Overall Survival ◽  
Lymph Node ◽  
Lymph Nodes ◽  
False Negative ◽  
Cumulative Risk ◽  
Distant Metastases ◽  
Number Of Patients ◽  
Tumor Stages ◽  
The Impact

Summary Objective To analyze data obtained in a representative number of patients with primary rectal cancer with respect to lymph node diagnostics and related tumor stages. Methods In pT2-, pT3-, and pT4 rectal cancer lesions, the impact of investigated lymph nodes on the frequency of pN+ status, the cumulative risk of metachronous distant metastases, and overall survival was studied by means of a prospective multicenter observational study over a defined period of time. Results From 2000 to 2011, the proportion of surgical specimens with ≥ 12 investigated lymph nodes increased significantly, from 73.6% to 93.2% (p < 0.001; the number of investigated lymph nodes from 16.2 to 20.8; p < 0.001). Despite this, the percentage of pN+ rectal cancer lesions varied only non-significantly (39.9% to 45.9%; p = 0.130; median, 44.1%). For pT2-, pT3-, and pT4 rectal cancer lesions, there was an increasing proportion of pN+ findings correlating significantly with the number of investigated lymph nodes up to n = 12 investigated lymph nodes. Only in pT3 rectal cancer was there a significant increase in pN+ findings in case of > 12 lymph nodes (p = 0.001), but not in pT2 (p = 0.655) and pT4 cancer lesions (p = 0.256). For pT3pN0cM0 rectal cancer, the risk of metachronous distant metastases and overall survival did not depend on the number of investigated lymph nodes. Conclusion In rectal cancer, at least n = 12 lymph nodes are to be minimally investigated. The investigation of fewer lymph nodes is associated with a higher risk of false-negative pN0 findings. In particular, in pT3 rectal cancer, the investigation of more than 12 lymph nodes lowers the risk of false-negative pN0 findings. An upstaging effect by the investigation of a possibly maximal number of lymph nodes could not be detected.

scholarly journals The Impact of Mechanical Forces in Heart Morphogenesis

2012 ◽  
Vol 5 (1) ◽  
pp. 132-142 ◽  
Author(s):  
Javier T. Granados-Riveron ◽  
J. David Brook
Keyword(s):  
Mechanical Forces ◽  
Heart Morphogenesis ◽  
The Impact

scholarly journals The Dynamic Interaction between Extracellular Matrix Remodeling and Breast Tumor Progression

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1046
Author(s):  
Jorge Martinez ◽  
Patricio C. Smith
Keyword(s):  
Extracellular Matrix ◽  
Type I Collagen ◽  
Cell Metabolism ◽  
Breast Tumors ◽  
Extracellular Matrix Remodeling ◽  
Type I ◽  
Matrix Remodeling ◽  
Desmoplastic Reaction ◽  
The Impact

Desmoplastic tumors correspond to a unique tissue structure characterized by the abnormal deposition of extracellular matrix. Breast tumors are a typical example of this type of lesion, a property that allows its palpation and early detection. Fibrillar type I collagen is a major component of tumor desmoplasia and its accumulation is causally linked to tumor cell survival and metastasis. For many years, the desmoplastic phenomenon was considered to be a reaction and response of the host tissue against tumor cells and, accordingly, designated as “desmoplastic reaction”. This notion has been challenged in the last decades when desmoplastic tissue was detected in breast tissue in the absence of tumor. This finding suggests that desmoplasia is a preexisting condition that stimulates the development of a malignant phenotype. With this perspective, in the present review, we analyze the role of extracellular matrix remodeling in the development of the desmoplastic response. Importantly, during the discussion, we also analyze the impact of obesity and cell metabolism as critical drivers of tissue remodeling during the development of desmoplasia. New knowledge derived from the dynamic remodeling of the extracellular matrix may lead to novel targets of interest for early diagnosis or therapy in the context of breast tumors.

scholarly journals Cell-derived Extracellular Matrix as maintaining Biomaterial for adipogenic differentiation

2020 ◽  
Vol 6 (3) ◽  
pp. 410-413
Author(s):  
Petra J. Kluger ◽  
Svenja Nellinger ◽  
Simon Heine ◽  
Ann-Cathrin Volz
Keyword(s):  
Tissue Engineering ◽  
Extracellular Matrix ◽  
Adipogenic Differentiation ◽  
Cellular Activity ◽  
Adipose Tissue Engineering ◽  
Physical Support ◽  
Supporting Effect ◽  
Brdu Assay ◽  
The Impact

AbstractThe extracellular matrix (ECM) naturally surrounds cells in humans, and therefore represents the ideal biomaterial for tissue engineering. ECM from different tissues exhibit different composition and physical characteristics. Thus, ECM provides not only physical support but also contains crucial biochemical signals that influence cell adhesion, morphology, proliferation and differentiation. Next to native ECM from mature tissue, ECM can also be obtained from the in vitro culture of cells. In this study, we aimed to highlight the supporting effect of cell-derived- ECM (cdECM) on adipogenic differentiation. ASCs were seeded on top of cdECM from ASCs (scdECM) or pre-adipocytes (acdECM). The impact of ECM on cellular activity was determined by LDH assay, WST I assay and BrdU assay. A supporting effect of cdECM substrates on adipogenic differentiation was determined by oil red O staining and subsequent quantification. Results revealed no effect of cdECM substrates on cellular activity. Regarding adipogenic differentiation a supporting effect of cdECM substrates was obtained compared to control. With these results, we confirm cdECM as a promising biomaterial for adipose tissue engineering.

scholarly journals Impact of Pancreatic Resection on Survival in Locally Advanced Resectable Gastric Cancer

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1289
Author(s):  
Shih-Chun Chang ◽  
Chi-Ming Tang ◽  
Puo-Hsien Le ◽  
Chia-Jung Kuo ◽  
Tsung-Hsing Chen ◽  
...  
Keyword(s):  
Lymph Node ◽  
Pancreatic Resection ◽  
Locally Advanced ◽  
Survival Rates ◽  
Disease Free Survival ◽  
Complication Rates ◽  
Lymph Node Yield ◽  
Whipple’S Operation ◽  
Whipple's Operation ◽  
The Impact

Whether gastric adenocarcinoma (GC) patients with adjacent organ invasion (T4b) benefit from aggressive surgery involving pancreatic resection (PR) remains unclear. This study aimed to clarify the impact of PR on survival in patients with locally advanced resectable GC. Between 1995 and 2017, patients with locally advanced GC undergoing radical-intent gastrectomy with and without PR were enrolled and stratified into four groups: group 1 (G1), pT4b without pancreatic resection (PR); group 2 (G2), pT4b with PR; group 3 (G3), positive duodenal margins without Whipple’s operation; and group 4 (G4), cT4b with Whipple’s operation. Demographics, clinicopathological features, and outcomes were compared between G1 and G2 and G3 and G4. G2 patients were more likely to have perineural invasion than G1 patients (80.6% vs. 50%, p < 0.001). G4 patients had higher lymph node yield (40.8 vs. 31.3, p = 0.002), lower nodal status (p = 0.029), lower lymph node ratios (0.20 vs. 0.48, p < 0.0001) and higher complication rates (45.2% vs. 26.3%, p = 0.047) than G3 patients. The 5-year disease-free survival (DFS) and overall survival (OS) rates were significantly longer in G1 than in G2 (28.1% vs. 9.3%, p = 0.003; 32% vs. 13%, p = 0.004, respectively). The 5-year survival rates did not differ between G4 and G3 (DFS: 14% vs. 14.4%, p = 0.384; OS: 12.6% vs. 16.4%, p = 0.321, respectively). In conclusion, patients with T4b lesion who underwent PR had poorer survival than those who underwent resection of other adjacent organs. Further Whipple’s operation did not improve survival in pT3–pT4 GC with positive duodenal margins.

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