de la Fuente, J. M. | bioRxiv Science

bioRxiv2024

Efficient targeting of heart lesions with cardiac myofibroblasts: Combined gene and cell therapy enhanced by magnetic steering

1The cardiac scar is a collagen-rich area, which is populated by myofibroblasts and has proven little amenable for therapeutic interventions. Herein, we have established an efficient targeting strategy for cardiac lesions by genetically manipulating embryonic cardiac myofibroblasts (mFB) in vitro, load the cells with magnetic nanoparticles and inject these into infarcted mouse hearts using magnetic steering. This yields strongly increased numbers ([~]4 fold compared to other cell types) of engrafted mFB. The injected mFB and endogenous myofibroblast (endoFB) population remain separate in the scar, but grafted mFB enhance the proliferation rate of endoFB by [~]4 fold. We also tested the functional impact of this approach by grafting lentiviral (LV)-transduced Connexin43 (Cx43) overexpressing mFB into the cardiac lesion. Prominent engraftment of Cx43+ mFB provides strong protection against post-infarct ventricular tachycardia (VT) in vivo, as VT incidence is reduced by [~]50 % at two and eight weeks after cell injection. Thus, ex vivo gene and subsequent in vivo cell therapy combined with magnetic steering of cardiac mFB enable efficient functional targeting of the cardiac scar.

physiology↗

bioRxiv2022

Stiffness-dependent active wetting enables optimal collective cell durotaxis

The directed migration of cellular clusters enables morphogenesis, wound healing, and collective cancer invasion. Gradients of substrate stiffness are known to direct the migration of cellular clusters in a process called collective durotaxis, but underlying mechanisms remain unclear. Here, we unveil a connection between collective durotaxis and the wetting properties of cellular clusters. We show that clusters of cancer cells dewet soft substrates and wet stiff ones. At intermediate stiffness, at the crossover from low to high wettability, clusters on uniform-stiffness substrates become maximally motile, and clusters on stiffness gradients exhibit optimal durotaxis. Durotactic velocity increases with cluster size, stiffness gradient, and actomyosin activity. We demonstrate this behavior on substrates coated with the cell-cell adhesion protein E-cadherin and then establish its generality on substrates coated with extracellular matrix. We develop a physical model of three-dimensional active wetting that explains this mode of collective durotaxis in terms of a balance between in-plane active traction and tissue contractility, and out-of-plane surface tension. Finally, we show that the distribution of cluster displacements has a heavy tail, with infrequent but large cellular hops that contribute to durotactic migration. Our study demonstrates a physical mechanism of collective durotaxis, through both cell-cell and cell-substrate adhesion ligands, based on the wetting properties of active droplets.

biophysics↗