Tissue Fluidity Research Articles

Dynamic regulation of tissue fluidity controls skin repair during wound healing

During wound healing, different pools of stem cells (SCs) contribute to skin repair. However, how SCs become activated and drive the tissue remodeling essential for skin repair is still poorly understood. Here, by developing a mouse model allowing lineage tracing and basal cell lineage ablation, we monitor SC fate and tissue dynamics during regeneration using confocal and intravital imaging. Analysis of basal cell rearrangements shows dynamic transitions from a solid-like homeostatic state to a fluid-like state allowing tissue remodeling during repair, as predicted by a minimal mathematical modeling of the spatiotemporal dynamics and fate behavior of basal cells. The basal cell layer progressively returns to a solid-like state with re-epithelialization. Bulk, single-cell RNA, and epigenetic profiling of SCs, together with functional experiments, uncover a common regenerative state regulated by the EGFR/AP1 axis activated during tissue fluidization that is essential for skin SC activation and tissue repair.

Prickle2 regulates apical junction remodeling and tissue fluidity during vertebrate neurulation.

The process of folding the flat neuroectoderm into an elongated neural tube depends on tissue fluidity, a property that allows epithelial deformation while preserving tissue integrity. Neural tube folding also requires the planar cell polarity (PCP) pathway. Here, we report that Prickle2 (Pk2), a core PCP component, increases tissue fluidity by promoting the remodeling of apical junctions (AJs) in Xenopus embryos. This Pk2 activity is mediated by the unique evolutionarily conserved Ser-Thr-rich region (STR) in the carboxyterminal half of the protein. Mechanistically, the effects of Pk2 require Rac1 and are accompanied by increased cadherin dynamics and destabilization of tricellular junctions, the hotspots of AJ remodeling. Notably, Pk2 depletion leads to the accumulation of mediolaterally oriented cells in the neuroectoderm, whereas the overexpression of Pk2 or Pk1 containing the Pk2-derived STR promotes cell elongation along the anteroposterior axis. We propose that Pk2-dependent regulation of tissue fluidity contributes to anteroposterior tissue elongation in response to extrinsic cues.

Role of tissue fluidization and topological defects in epithelial tubulogenesis

Cellular rearrangements, as primary sources of tissue fluidization, facilitate topological transitions during tissue morphogenesis. We study the role of intrinsic cell properties such as cell polarity and cell-cell adhesion in shaping epithelial tissues using a minimal model of interacting polarized cells. The presence of a vortex in the cell polarization poses the topological constraint that induces an inwards migration with the formation of a conical shape. Local rearrangements at the tip of the cone lead to the onset of tube formation. Switching between collective migration and structural rearrangements is key for balancing the contrasting tendencies, such as the tissue rigidity needed to preserve shape and the tissue fluidity allowing for topological transitions during tissue morphogenesis. Published by the American Physical Society 2024

Vimentin promotes collective cell migration through collagen networks via increased matrix remodeling and spheroid fluidity.

The intermediate filament (IF) protein vimentin is associated with many diseases with phenotypes of enhanced cellular migration and aggressive invasion through the extracellular matrix (ECM) of tissues, but vimentin's role in in-vivo cell migration is still largely unclear. Vimentin is important for proper cellular adhesion and force generation, which are critical to cell migration; yet the vimentin cytoskeleton also hinders the ability of cells to squeeze through small pores in ECM, resisting migration. To identify the role of vimentin in collective cell migration, we generate spheroids of wide-type and vimentin-null mouse embryonic fibroblasts (mEFs) and embed them in a 3D collagen matrix. We find that loss of vimentin significantly impairs the ability of the spheroid to collectively expand through collagen networks and remodel the collagen network. Traction force analysis reveals that vimentin null spheroids exert less contractile force than their wild-type counterparts. In addition, spheroids made of mEFs with only vimentin unit length filaments (ULFs) exhibit similar behavior as vimentin-null spheroids, suggesting filamentous vimentin is required to promote 3D collective cell migration. We find the vimentin-mediated collective cell expansion is dependent on matrix metalloproteinase (MMP) degradation of the collagen matrix. Further, 3D vertex model simulation of spheroid and embedded ECM indicates that wild-type spheroids behave more fluid-like, enabling more active pulling and reconstructing the surrounding collagen network. Altogether, these results signify that VIF plays a critical role in enhancing migratory persistence in 3D matrix environments through MMP transportation and tissue fluidity.

Helical vasculogenesis driven by cell chirality.

The cellular helical structure is well known for its crucial role in development and disease. Nevertheless, the underlying mechanism governing this phenomenon remains largely unexplored, particularly in recapitulating it in well-controlled engineering systems. Leveraging advanced microfluidics, we present compelling evidence of the spontaneous emergence of helical endothelial tubes exhibiting robust right-handedness governed by inherent cell chirality. To strengthen our findings, we identify a consistent bias toward the same chirality in mouse vascular tissues. Manipulating endothelial cell chirality using small-molecule drugs produces a dose-dependent reversal of the handedness in engineered vessels, accompanied by non-monotonic changes in vascular permeability. Moreover, our three-dimensional cell vertex model provides biomechanical insights into the chiral morphogenesis process, highlighting the role of cellular torque and tissue fluidity in its regulation. Our study unravels an intriguing mechanism underlying vascular chiral morphogenesis, shedding light on the broader implications and distinctive perspectives of tubulogenesis within biological systems.

Acinar-ductal cell rearrangement drives branching morphogenesis of the murine pancreas in an IGF/PI3K-dependent manner

During organ formation, progenitor cells need to acquire different cell identities and organize themselves into distinct structural units. How these processes are coordinated and how tissue architecture(s) is preserved despite the dramatic cell rearrangements occurring in developing organs remain unclear. Here, we identified cellular rearrangements between acinar and ductal progenitors as a mechanism to drive branching morphogenesis in the pancreas while preserving the integrity of the acinar-ductal functional unit. Using exvivo and invivo mouse models, we found that pancreatic ductal cells form clefts by protruding and pulling on the acinar basement membrane, which leads to acini splitting. Newly formed acini remain connected to the bifurcated branches generated by ductal cell rearrangement. Insulin growth factor (IGF)/phosphatidylinositol 3-kinase (PI3K) pathway finely regulates this process by controlling pancreatic ductal tissue fluidity, with a simultaneous impact on branching and cell fate acquisition. Together, our results explain how acinar structure multiplication and branch bifurcation are synchronized during pancreas organogenesis.

Tension Remodeling Regulates Topological Transitions in Epithelial Tissues.

Cell neighbor exchanges play a critical role in regulating tissue fluidity during epithelial morphogenesis and repair. In vivo, these neighbor exchanges are often hindered by the formation of transiently stable fourfold vertices, which can develop into complex multicellular rosettes where five or more cell junctions meet. Despite their importance, the mechanical origins of multicellular rosettes have remained elusive, and current cellular models lack the ability to explain their formation and maintenance. Here we present a dynamic vertex model of epithelial tissues with strain-dependent tension remodeling and mechanical memory dissipation. We show that an increase in cell junction tension upon contraction and reduction in tension upon extension can stabilize higher-order vertices, temporarily stalling cell rearrangements. On the other hand, inducing mechanical memory dissipation via relaxation of junction strain and stress promotes the resolution of higher-order vertices, facilitating cell neighbor exchanges. We demonstrate that by tuning the rates of tension remodeling and mechanical memory dissipation, we can control topological transitions and tissue material properties, recapitulating complex cellular topologies seen in developing organisms.

Effects of kidney perfusion on renal stiffness and tissue fluidity measured with tomoelastography in an MRI-compatible ex vivo model.

Stiffness plays a vital role in diagnosing renal fibrosis. However, perfusion influences renal stiffness in various chronic kidney diseases. Therefore, we aimed to characterize the effect of tissue perfusion on renal stiffness and tissue fluidity measured by tomoelastography based on multifrequency magnetic resonance elastography in an ex vivo model. Five porcine kidneys were perfused ex vivo in an MRI-compatible normothermic machine perfusion setup with adjusted blood pressure in the 50/10-160/120mmHg range. Simultaneously, renal cortical and medullary stiffness and fluidity were obtained by tomoelastography. For the cortex, a statistically significant (p < 0.001) strong positive correlation was observed between both perfusion parameters (blood pressure and resulting flow) and stiffness (r = 0.95, 0.91), as well as fluidity (r = 0.96, 0.92). For the medulla, such significant (p < 0.001) correlations were solely observed between the perfusion parameters and stiffness (r = 0.88, 0.71). Our findings demonstrate a strong perfusion dependency of renal stiffness and fluidity in an ex vivo setup. Moreover, changes in perfusion are rapidly followed by changes in renal mechanical properties-highlighting the sensitivity of tomoelastography to fluid pressure and the potential need for correcting mechanics-derived imaging biomarkers when addressing solid structures in renal tissue.

Changes in Tissue Fluidity Predict Tumor Aggressiveness In Vivo.

Cancer progression is caused by genetic changes and associated with various alterations in cell properties, which also affect a tumor's mechanical state. While an increased stiffness has been well known for long for solid tumors, it has limited prognostic power. It is hypothesized that cancer progression is accompanied by tissue fluidization, where portions of the tissue can change position across different length scales. Supported by tabletop magnetic resonance elastography (MRE) on stroma mimicking collagen gels and microscopic analysis of live cells inside patient derived tumor explants, an overview is provided of how cancer associated mechanisms, including cellular unjamming, proliferation, microenvironment composition, and remodeling can alter a tissue's fluidity and stiffness. In vivo, state-of-the-art multifrequency MRE can distinguish tumors from their surrounding host tissue by their rheological fingerprints. Most importantly, a meta-analysis on the currently available clinical studies is conducted and universal trends are identified. The results and conclusions are condensed into a gedankenexperiment about how a tumor can grow and eventually metastasize into its environment from a physics perspective to deduce corresponding mechanical properties. Based on stiffness, fluidity, spatial heterogeneity, and texture of the tumor front a roadmap for a prognosis of a tumor's aggressiveness and metastatic potential is presented.

An Eulerian Nonlinear Elastic Model for Compressible and Fluidic Tissue with Radially Symmetric Growth

Cell proliferation, apoptosis, and myosin-dependent contraction can generate elastic stress and strain in living tissues, which may be dissipated by internal rearrangement through cell topological transition and cytoskeletal reorganization. Moreover, cells and tissues can change their sizes in response to mechanical cues. The present work demonstrates the role of tissue compressibility and internal rearranging activities on its size and mechanics regulation in the context of differential growth induced by a field of growth-promoting chemical factors. We develop a mathematical model based on finite elasticity and growth theory and the reference map techniques to describe the coupled tissue growth and mechanics in the Eulerian frame. We incorporate the tissue rearrangement by introducing a rearranging rate to the reference map evolution, leading to elastic-energy dissipation when tissue growth and deformation are in radial symmetry. By linearizing the model, we show that the stress follows the Maxwell-type viscoelastic relaxation. The rearrangement rate, which we call tissue fluidity, sets the stress relaxation time, and the ratio between the shear modulus and the fluidity sets the tissue viscosity. By nonlinear simulation of growing tissue spheroids and discs with graded growth rates along the radius, we find that the tissue compressibility and fluidity influence their equilibrium size. By comparing the nonlinear simulations with the linear analytical solutions, we show the size change as a nonlinear effect due to the advection of the tissue density flow, which only occurs when both tissue compressibility and fluidity are small. We apply the model to study tumor spheroid growth and epithelial disc growth when a reaction-diffusion process determines the growth-promoting factor field.

Adhesion regulation and the control of cellular rearrangements: From emulsions to developing tissues

Cell rearrangements are critical for tissue remodeling during diverse biological processes, such as morphogenesis or cancer progression. They control tissue fluidity and can lead to irreversible shape changes in cohesive tissues. However, the completion of such rearrangements is strongly conditioned by intercellular adhesion, that can prevent their completion or conversely promote them along a given pattern. In this review we explore how intercellular adhesion impacts cell rearrangements at the local scale and how it translates into macroscopic mechanical properties in biological tissues. We first describe general principles obtained from the study of dispersed materials, such as emulsions, in which the mechanical properties and interaction potential between individual particles can be described in a quantitative manner. We then review the effect of varying cell-cell adhesion on rearrangements in vitro model tissues, from cell aggregates to 2D epithelial-like cellular layers. We finally consider developing tissues in which adhesion between the cells is strongly tuned and localized in order to allow for function and shape emergence in the embryo.

Calcium sparks enhance the tissue fluidity within epithelial layers and promote apical extrusion of transformed cells.

In vertebrates, newly emerging transformed cells are often apically extruded from epithelial layers through cell competition with surrounding normal epithelial cells. However, the underlying molecular mechanism remains elusive. Here, using phospho-SILAC screening, we show that phosphorylation of AHNAK2 is elevated in normal cells neighboring RasV12 cells soon after the induction of RasV12 expression, which is mediated by calcium-dependent protein kinase C. In addition, transient upsurges of intracellular calcium, which we call calcium sparks, frequently occur in normal cells neighboring RasV12 cells, which are mediated by mechanosensitive calcium channel TRPC1 upon membrane stretching. Calcium sparks then enhance cell movements of both normal and RasV12 cells through phosphorylation of AHNAK2 and promote apical extrusion. Moreover, comparable calcium sparks positively regulate apical extrusion of RasV12-transformed cells in zebrafish larvae as well. Hence, calcium sparks play a crucial role in the elimination of transformed cells at the early phase of cell competition.

Self-Organization of Tissue Growth by Interfacial Mechanical Interactions in Multilayered Systems.

Morphogenesis is a spatially and temporally regulated process involved in various physiological and pathological transformations. In addition to the associated biochemical factors, the physical regulation of morphogenesis has attracted increasing attention. However, the driving force of morphogenesis initiation remains elusive. Here, it is shown that during the growth of multilayered tissues, a morphogenetic process can be self‐organized by the progression of compression gradient stemmed from the interfacial mechanical interactions between layers. In tissues with low fluidity, the compression gradient is progressively strengthened during growth and induces stratification by triggering symmetric‐to‐asymmetric cell division reorientation at the critical tissue size. In tissues with high fluidity, compression gradient is dynamic and induces cell rearrangement leading to 2D in‐plane morphogenesis instead of 3D deformation. Morphogenesis can be tuned by manipulating tissue fluidity, cell adhesion forces, and mechanical properties to influence the progression of compression gradient during the development of cultured cell sheets and chicken embryos. Together, the dynamics of compression gradient arising from interfacial mechanical interaction provides a conserved mechanism underlying morphogenesis initiation and size control during tissue growth.

Interplay between substrate rigidity and tissue fluidity regulates cell monolayer spreading.

Coordinated and cooperative motion of cells is essential for embryonic development, tissue morphogenesis, wound healing and cancer invasion. A predictive understanding of the emergent mechanical behaviors in collective cell motion is challenging due to the complex interplay between cell-cell interactions, cell-matrix adhesions and active cell behaviors. To overcome this challenge, we develop a predictive cellular vertex model that can delineate the relative roles of substrate rigidity, tissue mechanics and active cell properties on the movement of cell collectives. We apply the model to the specific case of collective motion in cell aggregates as they spread into a two-dimensional cell monolayer adherent to a soft elastic matrix. Consistent with recent experiments, we find that substrate stiffness regulates the driving forces for the spreading of cellular monolayer, which can be pressure-driven or crawling-based depending on substrate rigidity. On soft substrates, cell monolayer spreading is driven by an active pressure due to the influx of cells coming from the aggregate, whereas on stiff substrates, cell spreading is driven primarily by active crawling forces. Our model predicts that cooperation of cell crawling and tissue pressure drives faster spreading, while the spreading rate is sensitive to the mechanical properties of the tissue. We find that solid tissues spread faster on stiff substrates, with spreading rate increasing with tissue tension. By contrast, the spreading of fluid tissues is independent of substrate stiffness and is slower than solid tissues. We compare our theoretical results with experimental results on traction force generation and spreading kinetics of cell monolayers, and provide new predictions on the role of tissue fluidity and substrate rigidity on collective cell motion.

Tissue fluidity mediated by adherens junction dynamics promotes planar cell polarity-driven ommatidial rotation

The phenomenon of tissue fluidity—cells’ ability to rearrange relative to each other in confluent tissues—has been linked to several morphogenetic processes and diseases, yet few molecular regulators of tissue fluidity are known. Ommatidial rotation (OR), directed by planar cell polarity signaling, occurs during Drosophila eye morphogenesis and shares many features with polarized cellular migration in vertebrates. We utilize in vivo live imaging analysis tools to quantify dynamic cellular morphologies during OR, revealing that OR is driven autonomously by ommatidial cell clusters rotating in successive pulses within a permissive substrate. Through analysis of a rotation-specific nemo mutant, we demonstrate that precise regulation of junctional E-cadherin levels is critical for modulating the mechanical properties of the tissue to allow rotation to progress. Our study defines Nemo as a molecular tool to induce a transition from solid-like tissues to more viscoelastic tissues broadening our molecular understanding of tissue fluidity.

Tight Junction ZO Proteins Maintain Tissue Fluidity, Ensuring Efficient Collective Cell Migration.

Tight junctions (TJs) are essential components of epithelial tissues connecting neighboring cells to provide protective barriers. While their general function to seal compartments is well understood, their role in collective cell migration is largely unexplored. Here, the importance of the TJ zonula occludens (ZO) proteins ZO1 and ZO2 for epithelial migration is investigated employing video microscopy in conjunction with velocimetry, segmentation, cell tracking, and atomic force microscopy/spectroscopy. The results indicate that ZO proteins are necessary for fast and coherent migration. In particular, ZO1 and 2 loss (dKD) induces actomyosin remodeling away from the central cortex towards the periphery of individual cells, resulting in altered viscoelastic properties. A tug‐of‐war emerges between two subpopulations of cells with distinct morphological and mechanical properties: 1) smaller and highly contractile cells with an outward bulging apical membrane, and 2) larger, flattened cells, which, due to tensile stress, display a higher proliferation rate. In response, the cell density increases, leading to crowding‐induced jamming and more small cells over time. Co‐cultures comprising wildtype and dKD cells migrate inefficiently due to phase separation based on differences in contractility rather than differential adhesion. This study shows that ZO proteins are necessary for efficient collective cell migration by maintaining tissue fluidity and controlling proliferation.

Cell and Nucleus Shape as an Indicator of Tissue Fluidity in Carcinoma

Tissue, cell, and nucleus morphology change during tumor progression. In 2D confluent cell cultures, different tissue states, such as fluid (unjammed) and solid (jammed), are correlated with cell shapes. These results do not have to apply a priori to three dimensions. Cancer cell motility requires and corresponds to a fluidization of the tumor tissue on the bulk level. Here, we investigate bulk tissue fluidity in 3D and determine how it correlates with cell and nucleus shape. In patient samples of mamma and cervix carcinoma, we find areas where cells can move or are immobile. We compare 3D cell spheroids composed of cells from a cancerous and a noncancerous cell line. Through bulk mechanical spheroid-fusion experiments and single live-cell tracking, we show that the cancerous sample is fluidized by active cells moving through the tissue. The healthy, epithelial sample with immobile cells behaves more solidlike. 3D segmentations of the samples show that the degree of tissue fluidity correlates with elongated cell and nucleus shapes. This correlation links cell shapes to cell motility and bulk mechanical behavior. We find two active states of matter in solid tumors: an amorphous glasslike state with characteristics of 3D cell jamming and a disordered fluid state. Individual cell and nucleus shape may serve as a marker for metastatic potential to foster personalized cancer treatment.

Ectoderm to mesoderm transition by down-regulation of actomyosin contractility.

Collective migration of cohesive tissues is a fundamental process in morphogenesis and is particularly well illustrated during gastrulation by the rapid and massive internalization of the mesoderm, which contrasts with the much more modest movements of the ectoderm. In the Xenopus embryo, the differences in morphogenetic capabilities of ectoderm and mesoderm can be connected to the intrinsic motility of individual cells, very low for ectoderm, high for mesoderm. Surprisingly, we find that these seemingly deep differences can be accounted for simply by differences in Rho-kinases (Rock)-dependent actomyosin contractility. We show that Rock inhibition is sufficient to rapidly unleash motility in the ectoderm and confer it with mesoderm-like properties. In the mesoderm, this motility is dependent on two negative regulators of RhoA, the small GTPase Rnd1 and the RhoGAP Shirin/Dlc2/ArhGAP37. Both are absolutely essential for gastrulation. At the cellular and tissue level, the two regulators show overlapping yet distinct functions. They both contribute to decrease cortical tension and confer motility, but Shirin tends to increase tissue fluidity and stimulate dispersion, while Rnd1 tends to favor more compact collective migration. Thus, each is able to contribute to a specific property of the migratory behavior of the mesoderm. We propose that the "ectoderm to mesoderm transition" is a prototypic case of collective migration driven by a down-regulation of cellular tension, without the need for the complex changes traditionally associated with the epithelial-to-mesenchymal transition.

In Vivo Quantification of Water Diffusion, Stiffness, and Tissue Fluidity in Benign Prostatic Hyperplasia and Prostate Cancer.

Water diffusion, tissue stiffness, and viscosity characterize the biophysical behavior of tumors. However, little is known about how these parameters correlate in prostate cancer (PCa). Therefore, we paired tomoelastography of the prostate with diffusion-sensitive magnetic resonance imaging for the quantitative mapping of biophysical parameters in benign prostatic hyperplasia (BPH) and PCa. Multifrequency magnetic resonance imaging elastography with tomoelastography processing was performed at 60, 70, and 80 Hz using externally placed compressed-air drivers. Shear-wave speed (SWS) and loss angle (φ) were analyzed as surrogate markers of stiffness and viscosity-related fluidity in the normal peripheral zone (PZ), hyperplastic transition zone (TZ), which is consistent with BPH, and PCa lesions. The SWS and φ were correlated with the normalized apparent diffusion coefficient (nADC). Thirty-nine men (median age/range, 67/49-88 years), 25 with BPH and 14 with biopsy-proven PCa, were prospectively enrolled in this institutional review board-approved study. The SWS in PCa (3.1 ± 0.6 m/s) was higher than in TZ (2.8 ± 0.3 m/s, P = 0.004) or tended to be higher than in PZ (2.8 ± 0.4 m/s, P = 0.025). Similarly, φ in PCa (1.1 ± 0.1 rad) was higher than in TZ (0.9 ± 0.2 m/s, P < 0.001) and PZ (0.9 ± 0.1 rad, P < 0.001), whereas nADC in PCa (1.3 ± 0.3) was lower than in TZ (2.2 ± 0.4, P < 0.001) and PZ (3.1 ± 0.7, P < 0.001). Pooled nADC was inversely correlated with φ (R = -0.6, P < 0.001) but not with SWS. TZ and PZ only differed in nADC (P < 0.001) but not in viscoelastic properties. Diagnostic differentiation of PCa from normal prostate tissues, as assessed by area under the curve greater than 0.9, was feasible using nADC and φ but not SWS. Tomoelastography provides quantitative maps of tissue mechanical parameters of the prostate. Prostate cancer is characterized by stiff tissue properties and reduced water diffusion, whereas, at the same time, tissue fluidity is increased, suggesting greater mechanical friction inside the lesion. This biophysical signature correlates with known histopathological features including increased cell density and fibrous protein accumulation.

Fluidity and elasticity form a concise set of viscoelastic biomarkers for breast cancer diagnosis based on Kelvin-Voigt fractional derivative modeling.

Cancer progression involves biomechanical changes within transformed cells and the surrounding extracellular matrix (ECM). The viscoelastic features of fluidity and elasticity that are based on a novel Kelvin-Voigt fractional derivative (KVFD) model were found capable of discriminating normal, benign and malignant breast biopsy tissues on the cellular scale. The improved specificity of KVFD model parameters derives from greater accuracy of fitting the entire approaching force-indentation measurement curve ([Formula: see text] > 0.99) compared with traditional elastic models ([Formula: see text] < 0.86). Moreover, model parameters can be interpreted in terms of histopathological features. First, statistical comparisons reveal there are significant differences (p < 0.001) in elasticity E0, fluidity [Formula: see text], and viscosity [Formula: see text] among healthy, benign, and malignant groups. Malignant breast tissues show low-value, broad-distributions in E0 and with high fluidity [Formula: see text] as compared with healthy and benign tissues. Second, histograms of E0 and [Formula: see text] provide distinctive features by fitting to Gaussian mixture (GM) models. The histograms of E0 and [Formula: see text] are best fit by two kernels GM for malignant tissues, indicating that the cells are soft but with high fluidity and the ECM is stiff but with low fluidity. However, the data suggest one-kernel GM model for benign tissue and a patched uniform distribution for healthy tissue. Third, using fluidity [Formula: see text] as the test statistic, the area under the receiver operator characteristiccurve (AUC) is 0.701 ± 0.012 (p < 0.0001) for control versus malignant and 0.706 ± 0.013 (p < 0.0001) for benign versus malignant group. Variations in tissue fluidity and elasticity offer a concise set of viscoelastic biomarkers that correlate well with histopathological features.