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Biology subjects

Luber, M.

Publications and source records attributed to Luber, M..

3 recordsLinked to original sources

Structural order emerges without mechanical order inside living cells

Intracellular organization is vital for cell function, and disruption of organelle positioning is connected to severe diseases, such as cancer. Given the small length scale of cells and the importance of Brownian motion, maintaining intracellular organization requires mechanical interactions to remain stable. Here, we test the common view that intracellular organization is reflected in intracellular mechanical properties. Using the recently introduced active mechanical fingerprint, we quantify intracellular mechanical properties and active forces to create mechanical maps of patterned RPE1 cells. The organization of actin, microtubules, the Golgi apparatus, the endoplasmic reticulum, and the nucleus reveals pronounced structural polarization across the cell population. To overcome limitations of simple averages, we use a Wasserstein barycenter to calculate an optimal intracellular organization that explains all measurements with minimal cellular distortion. To our surprise, and in contrast to previous reports, we find neither a statistically significant spatial mechanical pattern nor any relevant correlation between the tested structures and intracellular mechanical properties. While there is clear local mechanical anisotropy, the large heterogeneity of mechanical values outweighs any intracellular mechanical gradient. This is further supported by large cell-to-cell variability. Thus, despite having the same genome, cells function properly while their intracellular mechanical properties vary over two orders of magnitude.

biophysics↗

Stretched Exponential Modeling Reveals Drug-Specific Kinetics in Human Engineered Skeletal Muscle

Understanding muscle tissue is key not only for advancing our knowledge in biophysical function of the human body, but can also open new paths to better description of pathological states, improve treatment and training and even provide insights for drug development. While using excised muscles is an excellent way to study muscular function, this limits access to non-human tissue, as human muscle tissue donation is very limited. The past decade has seen a rise in 3D in vitro models of human skeletal muscle, however many current experimental approaches to create such models often struggle with the high variability of primary cells or the limited translational relevance in cases where murine lines are used. Furthermore, the state-of-the-art functional analysis is typically focusing at peak force, which overlooks critical kinetic information. In this study, we present an systematic approach to generate functional engineered skeletal muscle tissues (ESMs), measure the contraction force dynamics and model these with a new approach to extract the effect of a series of standard pharmacological modulators. Within 14 days, LHCN-M2 ESMs mature into aligned, multinucleated myofibers expressing key sarcomeric markers and exhibiting robust excitation-contraction coupling. To decode these dynamics, we introduce a novel mathematical model based on stretched exponential functions. This framework accurately captures the heterogeneous contraction and relaxation phases across diverse phenotypes using only six interpretable parameters. We validated the platforms sensitivity using a library of pharmacological modulators. Our kinetic modeling revealed a distinct parameter fingerprint for different drug classes such as the specific changes of contraction kinetics that peak force alone could not detect. Additionally the presence of the necessary drug targets as well as the state of maturation were investigated by proteomic profiling. Together, study provides a scalable, high-fidelity human platform for high-content pharmacological screening and muscle biophysics.

biophysics↗

Distinct myeloid precursors and their interaction with mesenchymal cells orchestrate the spreading of psoriatic disease from the skin to the joints

Psoriatic disease initially affects the skin, but later extends to the joints. Herein, we describe a two-step process that orchestrates spreading of inflammation from the skin to the joints. Induction of psoriatic skin disease in photoconvertible mice, followed by sequencing and computational characterization of skin-derived cells in the joints, identified a unique population of CD2+ MHC-II+ CCR2+ myeloid precursors that built up a skin-derived myeloid cell compartment in the joints. Single-cell cross-species reference mapping and mitochondrial variant tracing showed an orthologue human cell population. Interactome analyses in the joints showed that in a second step, resident regulatory CD200+ fibroblasts critically regulate the priming of the CD2+ MHC-II+ CCR2+ myeloid precursors, which subsequently regulate the IL-17 expression in T cells. Hence, spreading of inflammation requires a distinct migratory myeloid precursor population and a permissive local tissue environment, similar to tumour metastasis. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=121 SRC="FIGDIR/small/665302v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@38c440org.highwire.dtl.DTLVardef@dc574dorg.highwire.dtl.DTLVardef@1e79f72org.highwire.dtl.DTLVardef@19508cf_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗