bims-ecemfi 2024-12-22 papers

Math Biosci. 2024 Dec 17. pii: S0025-5564(24)00222-0. [Epub ahead of print] 109362

Competing elastic and viscous gradients determine directional cell migration.

Pablo Saez, Pallavi U Shirke, Jyoti R Seth, Jorge Alegre-Cebollada, Abhijit Majumder.

Cell migration regulates central life processes including embryonic development, tissue regeneration, and tumor invasion. To establish the direction of migration, cells follow exogenous cues. Durotaxis, the directed cell migration toward elastic stiffness gradients, is the classical example of mechanical taxis. However, whether gradients of the relaxation properties in the extracellular matrix may also induce tactic responses (viscotaxis) is not well understood. Moreover, whether and how durotaxis and viscotaxis interact with each other has never been investigated. Here, we integrate clutch models for cell adhesions with an active gel theory of cell migration to reveal the mechanisms that govern viscotaxis. We show that viscotaxis is enabled by an asymmetric expression of cell adhesions that further polarize the intracellular motility forces to establish the cell front, similar to durotaxis. More importantly, when both relaxation and elastic gradients coexist, durotaxis appears more efficient in controlling directed cell migration, which we confirm with experimental results. However, the presence of opposing relaxation gradients to an elastic one can arrest or shift the migration direction. Our model rationalizes for the first time the mechanisms that govern viscotaxis and its competition with durotaxis through a mathematical model.

Keywords: Active gel models; Cell adhesion; Clutch model; Durotaxis; Mechanotransduction; Viscotaxis

DOI: https://doi.org/10.1016/j.mbs.2024.109362

Biophys J. 2024 Dec 16. pii: S0006-3495(24)04071-2. [Epub ahead of print]

Probabilistic analysis of spatial viscoelastic cues in 3D cell culture using magnetic microrheometry.

Ossi Arasalo, Arttu J Lehtonen, Mari Kielosto, Markus Heinonen, Juho Pokki.

Breast tumors are typically surrounded by extracellular matrix (ECM) that is heterogeneous, not just structurally but also mechanically. Conventional rheometry is inadequate for describing cell-size-level spatial differences in ECM mechanics that are evident at micrometer scales. Optical tweezers and passive microrheometry provide a microscale resolution for the purpose but are incapable of measuring ECM viscoelasticity (the liquid-like viscous and solid-like elastic characteristics) at stiffness levels as found in breast-tumor biopsies. Magnetic microrheometry records data on varying microscale viscoelasticity within 3D ECM-mimicking materials up to the biopsy-relevant stiffness. However, the measurement-probe-based microrheometry data has limitations in spatial resolution. Here, we present a probabilistic modeling method-providing analysis of sparse, probe-based spatial information on microscale viscoelasticity in ECM obtained from magnetic microrheometry-in two parts. First, we validated the method's applicability for analysis of a controlled stiffness difference, based on two collagen type 1 concentrations in one sample, showing a detectable stiffness gradient in the interface of the changing concentrations. Second, we used the method to quantify and visualize differences in viscoelasticity within 3D cell cultures containing breast-cancer-associated fibroblasts, and collagen type 1 (both typically present in the tumor ECM). The fibroblasts' presence stiffens the collagen material, which aligns with previous research. Importantly, we provided probabilistic quantification of related spatial-heterogeneity differences in viscoelasticity recorded by magnetic microrheometry, for the first time. The fibroblasts culturing leads to an initially higher spatial heterogeneity in the collagen stiffness. In summary, this method reports on enhanced spatial mapping of viscoelasticity in breast-cancer 3D cultures, with the future potential for matching of spatial viscoelasticity distribution in the 3D cultures with the one in biopsies.

DOI: https://doi.org/10.1016/j.bpj.2024.12.010

Phys Rev E. 2024 Nov;110(5-1): 054414

Emergence of biphasic versus monotonic response of actin retrograde flow and cell traction force with varying substrate rigidity.

Partho Sakha De, Rumi De.

The transmission of cytoskeletal forces to the extracellular matrix through focal adhesion complexes is essential for a multitude of biological processes, such as cell migration, cell differentiation, tissue development, and cancer progression, among others. During migration, focal adhesions arrest the actin retrograde flow towards the cell interior, allowing the cell front to move forward. Here, we address a puzzling observation of the existence of two distinct phenomena: a biphasic vs a monotonic relationship of the retrograde flow and cell traction force with substrate rigidity. In the former, maximum traction force and minimum retrograde flow velocity are observed at an intermediate optimal substrate stiffness; while in the latter, the actin retrograde flow decreases and traction force increases with increasing substrate stiffness. We propose a theoretical model for cell-matrix adhesions at the leading edge of a migrating cell, incorporating a novel approach in force loading rate sensitive binding and reinforcement of focal adhesions assembly and the subsequent force-induced slowing down of actin flow. Our model exhibits both biphasic and monotonic responses of the retrograde flow and cell traction force with increasing substrate rigidity, owing to the cell's ability to sense and adapt to the fast-growing forces. Furthermore, our analysis shows how competition between different timescales regulated by loading rate sensitivity influences the biphasic versus monotonic behavior and the emergence of optimal substrate rigidity in the biphasic scenario. We also elucidate how the viscoelastic properties of the substrate regulate these nonlinear responses and predict the loss of cell sensitivity to variation in substrate rigidity when adhesions are subjected to high forces.

DOI: https://doi.org/10.1103/PhysRevE.110.054414

Phys Rev E. 2024 Nov;110(5-1): 054410

Active curling of epithelial monolayers dominated by actin cytoskeleton mechanics.

Huan Wang, Jiu-Tao Hang, Guang-Kui Xu.

Active curling of epithelial tissues, as an indispensable component of developmental morphogenesis, occurs frequently both in vivo and in vitro microenvironments. Deciphering the mechanisms underlying the active curling of epithelial monolayers is crucial for understanding many physiological and pathological processes. Here, a multiscale structure-based cell monolayer model and an active constitutive relation are established to characterize this spontaneous curling of the epithelial tissue. It is shown that the asymmetric distribution of Myosin II along the apicobasal axis generates an active moment that drives spontaneous curling of the suspended epithelial tissue. The time-dependent deflection and rotation angle of the active curling are analytically solved, proving that the curling is driven by the active bending moment directly associated with the apicobasal asymmetric contractile force. Moreover, we demonstrate that the rotation angle is proportional to the apicobasal force ratio and inversely proportional to the thickness of epithelial tissues. In addition, we derive an approximate analytical relation between the out-of-plane curling behavior and in-plane stress, in good agreement with the experimental data and our simulation results. This study provides a pathway to elucidate the mechanical mechanism underlying complex morphological development as well as the physiological and pathological phenomena of epithelial tissues.

DOI: https://doi.org/10.1103/PhysRevE.110.054410

Adv Mater. 2024 Dec 17. e2410802

Matrix Viscoelasticity Controls Differentiation of Human Blood Vessel Organoids into Arterioles and Promotes Neovascularization in Myocardial Infarction.

Dayu Sun, Kunyu Zhang, Feiyang Zheng, Guanyuan Yang, Mingcan Yang, Youqian Xu, Yinhua Qin, Mingxin Lin, Yanzhao Li, Ju Tan, Qiyu Li, Xiaohang Qu, Gang Li, Liming Bian, Chuhong Zhu.

Stem cell-derived blood vessel organoids are embedded in extracellular matrices to stimulate vessel sprouting. Although vascular organoids in 3D collagen I-Matrigel gels are currently available, they are primarily capillaries composed of endothelial cells (ECs), pericytes, and mesenchymal stem-like cells, which necessitate mature arteriole differentiation for neovascularization. In this context, the hypothesis that matrix viscoelasticity regulates vascular development is investigated in 3D cultures by encapsulating blood vessel organoids within viscoelastic gelatin/β-CD assembly dynamic hydrogels or methacryloyl gelatin non-dynamic hydrogels. The vascular organoids within the dynamic hydrogel demonstrate enhanced angiogenesis and differentiation into arterioles containing smooth muscle cells. The dynamic hydrogel mechanical microenvironment promotes vascular patterning and arteriolar differentiation by elevating notch receptor 3 signaling in mesenchymal stem cells and downregulating platelet-derived growth factor B expression in ECs. Transplantation of vascular organoids in vivo, along with the dynamic hydrogel, leads to the reassembly of arterioles and restoration of cardiac function in infarcted hearts. These findings indicate that the viscoelastic properties of the matrix play a crucial role in controlling the vascular organization and differentiation processes, suggesting an exciting potential for its application in regenerative medicine.

Keywords: angiogenesis; arteriole differentiation; blood vessel organoids; dynamic hydrogels; myocardial infarction; neovascularization; viscoelasticity

DOI: https://doi.org/10.1002/adma.202410802