Cytoskeletal tension regulates mesodermal spatial organization and subsequent vascular fate

Abstract

Morphogenesis during human development relies on the interplay between physiochemical cues that are mediated in part by cellular density and cytoskeletal tension. Here, we interrogated these factors on vascular lineage specification during human-induced pluripotent stem-cell (hiPSC) fate decision. We found that independent of chemical cues, spatially presented physical cues induce the self-organization of Brachyury-positive mesodermal cells, in a RhoA/Rho-associated kinase (ROCK)-dependent manner. Using unbiased support vector machine (SVM) learning, we found that density alone is sufficient to predict mesodermal fate. Furthermore, the long-withstanding presentation of spatial confinement during hiPSC differentiation led to an organized vascular tissue, reminiscent of native blood vessels, a process dependent on cell density as found by SVM analysis. Collectively, these results show how tension and density relate to vascular identity mirroring early morphogenesis. We propose that such a system can be applied to study other aspects of the stem-cell niche and its role in embryonic patterning.

Mechanosensing by Gli1+ cells contributes to the orthodontic force‐induced bone remodelling

“…Force has been demonstrated to influence cellular processes including cell shape changes, proliferation, migration and differentiation 22,29,30 . Extensive studies have presented that cells sense the mechanical force through cell membrane or cytoskeleton then converts the mechanical signals into biochemical signals to induce downstream gene transcription, thereby leading to cell adaptive behaviour 22,31,32 .…”

“…Studies have exhibited several factors that serve as mechanical sensors in cells including TGF‐β, Integrins, Runx2 and Yap (yes‐associated protein)/ Taz (transcriptional coactivator with PDZ‐binding motif) 30,40,41 . Among them, Yap is a classical transcription factor that transduces mechanical signals by transferring into nucleus, then activating gene expression to mediate cell behaviour 31 .…”

Mechanics regulate human embryonic stem cell self-organization to specify mesoderm

“…After confirming that hESCs plated on the patterned substrates did not spontaneously differentiate ( Figure S3), we monitored the force-generating behavior of the hESC colonies. We determined that specific tissue geometries previously shown to promote localized tension within an epithelial cell colony (Gomez et al, 2010;Kilian et al, 2010;Lee et al, 2016;Nelson et al, 2005;Smith et al, 2018) similarly induced high tension in the hESC colonies. For instance, shapes such as squares and triangles fostered the highest cell tension development in the colony corners, whereas circles developed comparatively moderate levels of tension around their colony periphery ( Figure 3C).…”

Understanding the Mechanobiology of Early Mammalian Development through Bioengineered Models

“…Much less is known about how local forces and mechanical properties affect implanted embryos that develop in utero, even though these are the embryos that might intuitively be considered as the most susceptible to mechanical and geometrical influences due to their embedded development. Recent literature has identified evolutionaryconserved mechanics-linked dependencies of genes involved in key milestones of mammalian development (Brunet et al, 2013;Pukhlyakova et al, 2018); links between embryonic confinement, local stresses, and body axis establishment (Hiramatsu et al, 2013); geometrical effects on the sorting of cell populations (Blin et al, 2018;Smith et al, 2018); and links between architectural features of the embryo and the establishment and maintenance of early signaling gradients (Zhang et al, 2018b). Nonetheless, experimental validation of such dependencies in mouse is still limited by its inaccessibility and the small litter sizes available for experimentation.…”