bims-ecemfi 2025-01-05 papers

Sci Adv. 2025 Jan 03. 11(1): eadr5023

Extracellular fluid viscosity regulates human mesenchymal stem cell lineage and function.

Alice Amitrano, Qinling Yuan, Bhawana Agarwal, Anindya Sen, Yoseph W Dance, Yi Zuo, Jude M Phillip, Luo Gu, Konstantinos Konstantopoulos.

Human mesenchymal stem cells (hMSCs) respond to mechanical stimuli, including stiffness and viscoelasticity. To date, it is unknown how extracellular fluid viscosity affects hMSC function on substrates of different stiffness and viscoelasticity. While hMSCs assume an adipogenic phenotype on gels of low stiffness and prescribed stress relaxation times, elevated fluid viscosity is sufficient to bias hMSCs toward an osteogenic phenotype. Elevated viscosity induces Arp2/3-dependent actin remodeling, enhances NHE1 activity, and promotes hMSC spreading via up-regulation of integrin-linked kinase. The resulting increase in membrane tension triggers the activation of transient receptor potential cation vanilloid 4 to facilitate calcium influx, thereby stimulating RhoA/ROCK and driving YAP-dependent RUNX2 translocation to the nucleus, leading to osteogenic differentiation. hMSCs on soft gels at elevated relative to basal viscosity favor an M2 macrophage phenotype. This study establishes fluid viscosity as a key physical cue that imprints osteogenic memory in hMSCs and promotes an immunosuppressive phenotype.

DOI: https://doi.org/10.1126/sciadv.adr5023

Adv Mater. 2025 Jan 02. e2410452

Tunable Bicontinuous Macroporous Cell Culture Scaffolds via Kinetically Controlled Phase Separation.

Oksana Y Dudaryeva, Lucien Cousin, Leila Krajnovic, Gian Gröbli, Virbin Sapkota, Lauritz Ritter, Dhananjay Deshmukh, Yifan Cui, Robert W Style, Riccardo Levato, Céline Labouesse, Mark W Tibbitt.

3D scaffolds enable biological investigations with a more natural cell conformation. However, the porosity of synthetic hydrogels is often limited to the nanometer scale, which confines the movement of 3D encapsulated cells and restricts dynamic cell processes. Precise control of hydrogel porosity across length scales remains a challenge and the development of porous materials that allow cell infiltration, spreading, and migration in a manner more similar to natural ECM environments is desirable. Here, a straightforward and reliable method is presented for generating kinetically-controlled macroporous biomaterials using liquid-liquid phase separation between poly(ethylene glycol) (PEG) and dextran. Photopolymerization-induced phase separation resulted in macroporous hydrogels with tunable pore size. Varying light intensity and hydrogel composition controlled polymerization kinetics, time to percolation, and complete gelation, which defined the average pore diameter (Ø = 1-200 µm) and final gel stiffness of the formed hydrogels. Critically, for biological applications, macroporous hydrogels are prepared from aqueous polymer solutions at physiological pH and temperature using visible light, allowing for direct cell encapsulation. Human dermal fibroblasts in a range of macroporous gels are encapsulated with different pore sizes. Porosity improved cell spreading with respect to bulk gels and allowed migration in the porous biomaterials.

Keywords: Biomaterials; Phase separation; Porosity; hydrogels; kinetic control

DOI: https://doi.org/10.1002/adma.202410452

Biomech Model Mechanobiol. 2024 Dec 31.

Stress relaxation rates of myocardium from failing and non-failing hearts.

Marissa Gionet-Gonzales, Gianna Gathman, Jonah Rosas, Kyle Y Kunisaki, Dominique Gabriele P Inocencio, Niki Hakami, Gregory N Milburn, Angela A Pitenis, Kenneth S Campbell, Beth L Pruitt, Ryan S Stowers.

The heart is a dynamic pump whose function is influenced by its mechanical properties. The viscoelastic properties of the heart, i.e., its ability to exhibit both elastic and viscous characteristics upon deformation, influence cardiac function. Viscoelastic properties change during heart failure (HF), but direct measurements of failing and non-failing myocardial tissue stress relaxation under constant displacement are lacking. Further, how consequences of tissue remodeling, such as fibrosis and fat accumulation, alter the stress relaxation remains unknown. To address this gap, we conducted stress relaxation tests on porcine myocardial tissue to establish baseline properties of cardiac tissue. We found porcine myocardial tissue to be fast relaxing, characterized by stress relaxation tests on both a rheometer and microindenter. We then measured human left ventricle (LV) epicardium and endocardium tissue from non-failing, ischemic HF and non-ischemic HF patients by microindentation. Analyzing by patient groups, we found that ischemic HF samples had slower stress relaxation than non-failing endocardium. Categorizing the data by stress relaxation times, we found that slower stress relaxing tissues were correlated with increased collagen deposition and increased α-smooth muscle actin (α-SMA) stress fibers, a marker of fibrosis and cardiac fibroblast activation, respectively. In the epicardium, analyzing by patient groups, we found that ischemic HF had faster stress relaxation than non-ischemic HF and non-failing. When categorizing by stress relaxation times, we found that faster stress relaxation correlated with Oil Red O staining, a marker for adipose tissue. These data show that changes in stress relaxation vary across the different layers of the heart during ischemic versus non-ischemic HF. These findings reveal how the viscoelasticity of the heart changes, which will lead to better modeling of cardiac mechanics for in vitro and in silico HF models.

Keywords: Heart failure; Mechanobiology; Stress relaxation; Viscoelasticity

DOI: https://doi.org/10.1007/s10237-024-01909-4