Moghaddam, A. O. | Search bioRxiv

bioRxiv2026

The effect of microstructural variations in tendon and ligament on diffusion tensor MRI

The fibrous microstructure of tendons and ligaments is an important determinant of their mechanical behavior and integrity. Diffusion tensor imaging (DTI) is a magnetic resonance imaging (MRI) technique that enables the inference of microstructural features within fibrous tissues and has recently been used to characterize the microstructure of dense connective tissues such as tendon and ligament. However, the effect of microstructural variations in tendon and ligament on DTI metrics remains unclear. To address this gap, we simulated diffusion MRI of second harmonic generation (SHG) image-informed square lattice fiber networks to determine which microstructural features have the strongest influence on DTI metrics. Then, we performed a second set of diffusion MRI simulations for randomly dispersed fibers within synthetic tendon volumes to relate DTI metrics to the influential microstructural features, including fiber dispersion. All DTI metrics were insensitive to collagen fiber crimp. Fiber dispersion did not affect mean diffusivity, decreased axial diffusivity, increased radial diffusivity, and decreased fractional anisotropy. These results provide valuable insight into the relationships between DTI metrics and microstructural properties of tendon and ligament, which is particularly relevant for inferring microstructural changes in impaired tissue using DTI. Furthermore, our findings are an important step in the translation of DTI for clinical and computational studies of dense connective tissues such as tendon and ligament.

bioengineering↗

bioRxiv2024

Data-Driven Image Analysis to Determine Antibody-Induced Dissociation of Cell-Cell Adhesion and Antibody Pathogenicity in Pemphigus Vulgaris

Pemphigus vulgaris (PV) is a blistering autoimmune disease that affects the skin and mucous membranes. The precise mechanisms by which PV antibodies induce a complete loss of cohesion of keratinocytes are not fully understood. But it is accepted that the process starts with antibody binding to desmosomal targets which leads to its disassembly and subsequent structural changes to cell-cell adhesions. In vitro immunofluorescence imaging of desmosome molecules has been used to characterize this initial phase, often qualitatively. However, there remains an untapped potential of image analysis in providing us more in-depth knowledge regarding ultrastructural changes after antibody binding. Currently, there is no such effort to establish a quantitative framework from immunofluorescence images in PV pathology. We take on this effort here in a comprehensive study to examine the effects of antibodies on key adhesion molecules and the cytoskeletal network, aiming to establish a correlation of ultrastructural changes in cell-cell adhesion with antibody pathogenicity. Specifically, we introduced a data-driven approach to quantitatively evaluate perturbations in adhesion molecules, including desmoglein 3, E-cadherin, as well as the cytoskeleton, following antibody treatment. We identify distinct immunofluorescence imaging signatures that mark the impact of antibody binding on the remodeling of the adhesion molecules and introduce a pathogenicity score to compare the relative effects of different antibodies. From this analysis, we showed that the biophysical response of keratinocytes to distinct PV associated antibodies is highly specific, allowing for accurate prediction of their pathogenicity. For instance, the high pathogenicity scores of the PVIgG and AK23 antibodies show strong agreement with their reported PV pathology. Our data-driven approach offers a more detailed framework for the action of autoantibodies in pemphigus and has the potential to pave the way for the development of effective novel diagnostic methods and therapeutic strategies. SIGNIFICANCEPemphigus vulgaris (PV) presents a critical unmet medical challenge due to its autoimmune-induced disruption of skin cell adhesion. Our study presents a data-driven approach to quantitatively analyze changes in adhesion molecules and the cytoskeleton upon exposure to various PV antibodies. By introducing a pathogenicity score, we pinpoint the specific impacts of different antibodies on various proteins, build association among these antibodies, and reveal the contribution of previously overlooked non-desmosomal antibodies, broadening the understanding of PV pathology. Although centered on PV, our method offers a versatile framework applicable for evaluating the effects of other antibodies and drugs, paving the way for new diagnostic tools for personalized medicine.

biophysics↗

bioRxiv2024

Sustained Strain Applied at High Rates Drives Dynamic Tensioning in Epithelial Cells

Epithelial cells experience long lasting loads of different magnitudes and rates. How they adapt to these loads strongly impacts tissue health. Yet, much remains unknown about the evolution of cellular stress in response to sustained strain. Here, by subjecting cell pairs to sustained strain, we report a bimodal stress response, where in addition to the typically observed stress relaxation, a subset of cells exhibits a dynamic tensioning process with significant elevation in stress within 100s, resembling active pulling-back in muscle fibers. Strikingly, the fraction of cells exhibiting tensioning increases with increasing strain rate. The tensioning response is accompanied by actin remodeling, and perturbation to actin abrogates it, supporting cell contractilitys role in the response. Collectively, our data show that epithelial cells adjust their tensional states over short timescales in a strain-rate dependent manner to adapt to sustained strains, demonstrating that the active pulling-back behavior could be a common protective mechanism against environmental stress.

biophysics↗