Mechanoresponse of Curved Epithelial Monolayers Lining Bowl-Shaped 3D Microwells.

The optimal functioning of many organs relies on the curved architecture of their epithelial tissues. However, the mechanoresponse of epithelia to changes in curvature remains misunderstood. Here, bowl-shaped microwells in hydrogels are designed via photopolymerization to faithfully replicate the shape and dimensions of lobular structures. Leveraging these hydrogel-based microwells, curved epithelial monolayers are engineered, and how in-plane and Gaussian curvatures at the microwell entrance influence epithelial behavior is investigated. Cells and nuclei around the microwell edge display a more pronounced centripetal orientation as the in-plane curvature decreases, and enhanced cell straightness and speed. Moreover, cells reorganize their actin cytoskeleton by forming a supracellular actin cable at the microwell edge, with its size becoming more pronounced as the in-plane curvature decreases. The Gaussian curvature at the microwell entrance enhances the maturation of the supracellular actin cable architecture and leads to a vertical orientation of nuclei toward the bottom of the microwell. Increasing Gaussian curvature results in flattened and elongated nuclear morphologies characterized by highly compacted chromatin states. This approach provides better understanding of the mechanoresponse of curved epithelial monolayers curvatures lining lobular structures. In addition, bowl-shaped microwells offer a powerful platform to study curvature-dependent mechanotransduction pathways in anatomically relevant 3D structures.

Mechanics and functional consequences of nuclear deformations.

As the home of cellular genetic information, the nucleus has a critical role in determining cell fate and function in response to various signals and stimuli. In addition to biochemical inputs, the nucleus is constantly exposed to intrinsic and extrinsic mechanical forces that trigger dynamic changes in nuclear structure and morphology. Emerging data suggest that the physical deformation of the nucleus modulates many cellular and nuclear functions. These functions have long been considered to be downstream of cytoplasmic signalling pathways and dictated by gene expression. In this Review, we discuss an emerging perspective on the mechanoregulation of the nucleus that considers the physical connections from chromatin to nuclear lamina and cytoskeletal filaments as a single mechanical unit. We describe key mechanisms of nuclear deformations in time and space and provide a critical review of the structural and functional adaptive responses of the nucleus to deformations. We then consider the contribution of nuclear deformations to the regulation of important cellular functions, including muscle contraction, cell migration and human disease pathogenesis. Collectively, these emerging insights shed new light on the dynamics of nuclear deformations and their roles in cellular mechanobiology.

Multiscale Mechanobiology in Brain Physiology and Diseases.

Increasing evidence suggests that mechanics play a critical role in regulating brain function at different scales. Downstream integration of mechanical inputs into biochemical signals and genomic pathways causes observable and measurable effects on brain cell fate and can also lead to important pathological consequences. Despite recent advances, the mechanical forces that influence neuronal processes remain largely unexplored, and how endogenous mechanical forces are detected and transduced by brain cells into biochemical and genetic programs have received less attention. In this review, we described the composition of brain tissues and their pronounced microstructural heterogeneity. We discuss the individual role of neuronal and glial cell mechanics in brain homeostasis and diseases. We highlight how changes in the composition and mechanical properties of the extracellular matrix can modulate brain cell functions and describe key mechanisms of the mechanosensing process. We then consider the contribution of mechanobiology in the emergence of brain diseases by providing a critical review on traumatic brain injury, neurodegenerative diseases, and neuroblastoma. We show that a better understanding of the mechanobiology of brain tissues will require to manipulate the physico-chemical parameters of the cell microenvironment, and to develop three-dimensional models that can recapitulate the complexity and spatial diversity of brain tissues in a reproducible and predictable manner. Collectively, these emerging insights shed new light on the importance of mechanobiology and its implication in brain and nerve diseases.

Appreciating the role of cell shape changes in the mechanobiology of epithelial tissues.

The wide range of epithelial cell shapes reveals the complexity and diversity of the intracellular mechanisms that serve to construct their morphology and regulate their functions. Using mechanosensitive steps, epithelial cells can sense a variety of different mechanochemical stimuli and adapt their behavior by reshaping their morphology. These changes of cell shape rely on a structural reorganization in space and time that generates modifications of the tensional state and activates biochemical cascades. Recent studies have started to unveil how the cell shape maintenance is involved in mechanical homeostatic tasks to sustain epithelial tissue folding, identity, and self-renewal. Here, we review relevant works that integrated mechanobiology to elucidate some of the core principles of how cell shape may be conveyed into spatial information to guide collective processes such as epithelial morphogenesis. Among many other parameters, we show that the regulation of the cell shape can be understood as the result of the interplay between two counteracting mechanisms: actomyosin contractility and intercellular adhesions, and that both do not act independently but are functionally integrated to operate on molecular, cellular, and tissue scales. We highlight the role of cadherin-based adhesions in force-sensing and mechanotransduction, and we report recent developments that exploit physics of liquid crystals to connect cell shape changes to orientational order in cell aggregates. Finally, we emphasize that the further intermingling of different disciplines to develop new mechanobiology assays will lead the way toward a unified picture of the contribution of cell shape to the pathophysiological behavior of epithelial tissues.