Biology subjects

Koster, T.

Publications and source records attributed to Koster, T..

4 recordsLinked to original sources

bioRxiv2026

Differential collagen crosslinking and network organization creates distinct tissue remodeling patterns in fibrosis and COPD

Collagens are key components of the extracellular matrix (ECM) that play a crucial role in maintaining structure, strength, and function of the lungs. Fibrillar collagens are crosslinked by enzymes such as lysyl oxidases and transglutaminases and organized into networks by proteoglycans and glycoproteins. Collagens are the main load-bearing components and along with elastin may impart a non-linear strain hardening behavior to the lung. In disease, collagen crosslinking and organization can be disrupted, possibly due to abnormal levels of enzymes or ECM components. Few studies have examined collagen crosslinking and organization in healthy and diseased human lungs. In this study, alterations in collagen crosslinking and organization were investigated in human lung control, fibrotic and chronic obstructive pulmonary disease (COPD) tissue sections. Ultra-performance liquid chromatography and second harmonic generation microscopy measured pyridinoline crosslinks and the distribution of mature and immature collagens within the decellularized scaffolds, respectively. Fibrotic scaffolds had higher total collagen but less crosslinking per mole of collagen compared with COPD donors. Image analysis by second harmonic generation microscopy showed mature collagens populated airway or blood vessel walls in all three groups and in the parenchyma of fibrotic scaffolds. Immature collagens, on the other hand, were mainly localized to parenchymal regions in control and COPD scaffolds, with fewer immature collagens in fibrotic parenchyma. Additionally, quantification of the mature to immature collagen ratio in defined regions of control and diseased scaffolds showed increased organized collagen in fibrotic tissue. Our study shows that collagen crosslinking and organization are disrupted in fibrotic and COPD lungs and these changes may be compartment specific and can contribute to aberrant mechanical properties of diseased lungs. Our findings highlight that along with total collagen content, collagen crosslinking and organization are equally important while investigating collagen-mediated pathological changes in lung tissue. These changes may have implications for developing ECM-based therapeutics for patients with lung diseases.

molecular biology↗

bioRxiv2025

Contrasting responses of control and fibrotic lung fibroblasts to fibrotic stimuli: the role of osteoprotegerin in extracellular matrix remodeling

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease characterized by dysregulated wound healing, leading to excessive production of extracellular matrix (ECM) proteins, particularly collagen, by activated fibroblasts. Osteoprotegerin (OPG), a soluble protein associated with ECM remodeling in bone, has been found in higher levels in serum and lung tissue of IPF patients compared to controls. However, whether OPG is associated with ECM remodeling by fibroblasts in lung fibrosis remains poorly understood. In this study we assessed differences in OPG levels in ECM-derived hydrogels from non-disease controls and patients with IPF encapsulated with primary human lung fibroblasts from control and patients with IPF (7 days). OPG levels were assessed in a collected culture medium and stained lung tissue sections, and related to biomechanical properties. Fibrotic human lung fibroblasts secreted and deposited more OPG compared to controls, which was observed in both non-diseased and IPF ECM hydrogels. OPG levels correlated significantly with matrix stiffness and collagen fiber structural properties, but only in IPF hydrogels, independent of fibroblast source. Strikingly, we also observed opposite correlations for control and fibrotic fibroblasts in fibrotic hydrogels. Control fibroblasts within a fibrotic microenvironment, secreted less OPG when hydrogel stiffness increased and deposited more OPG when collagen fibers were more aligned. Interestingly, fibrotic fibroblasts secreted more OPG when collagen fiber length increased and when collagen fiber curvature increased. Overall, our findings suggest that control and fibrotic lung fibroblasts exhibited opposite behavior with respect to OPG and ECM remodeling under fibrotic conditions and this may have consequences for matrix stiffness

cell biology↗

bioRxiv2024

At-RS31 orchestrates hierarchical cross-regulation of splicing factors and integrates alternative splicing with TOR-ABA pathways

O_LIAlternative splicing is essential for plants, enabling a single gene to produce multiple transcript variants to boost functional diversity and fine-tune responses to environmental and developmental cues. At-RS31, a plant-specific splicing factor in the Serine/Arginine (SR)-rich protein family, responds to light and the Target of Rapamycin (TOR) signaling pathway, yet its downstream targets and regulatory impact remain unknown. C_LIO_LITo identify At-RS31 targets, we applied individual-nucleotide resolution crosslinking and immunoprecipitation (iCLIP) and RNAcompete assays. Transcriptomic analyses of At-RS31 mutant and overexpressing plants further revealed its effects on alternative splicing. C_LIO_LIiCLIP identified 4,034 At-RS31 binding sites across 1,421 genes, enriched in CU-rich and CAGA RNA motifs. Comparative iCLIP and RNAcompete data indicate that the RS domain of At-RS31 may influence its binding specificity in planta, underscoring the value of combining in vivo and in vitro approaches. Transcriptomic analysis showed that At-RS31 modulates diverse splicing events, particularly intron retention and exitron splicing, and influences other splicing modulators, acting as a hierarchical regulator. C_LIO_LIBy regulating stress-response genes and genes in both TOR and abscisic acid (ABA) signaling pathways, At-RS31 may help integrate these signals, balancing plant growth with environmental adaptability through alternative splicing. C_LI

plant biology↗

bioRxiv2023

Three dimensional fibrotic extracellular matrix directs microenvironment fiber remodeling by fibroblasts

Idiopathic pulmonary fibrosis (IPF), for which effective treatments are limited, results in excessive and disorganized deposition of an aberrant extracellular matrix (ECM). An altered ECM microenvironment is postulated to contribute to disease perpetuation in a feed-forward manner through inducing profibrotic behavior by lung fibroblasts, the main producers and regulators of ECM. Here, we examined this hypothesis in a 3D in vitro model system by growing primary human lung fibroblasts in ECM-derived hydrogels from non-fibrotic (control) or IPF lung tissue. Culture of fibroblasts in fibrotic hydrogels did not trigger a change in the overall amount of collagen or glycosaminoglycans but did cause a drastic change in fiber organization compared to culture in control hydrogels. Mechanical properties of fibrotic hydrogels were modified by fibroblasts while control hydrogels were not. These results illustrate how the 3D microenvironment plays a crucial role in directing cells to exhibit pro-fibrotic responses by providing biochemical and/or biomechanical cues.

pathology↗