Activin A and ALK4 Identified as Novel Regulators of Epithelial to Mesenchymal Transition (EMT) in Human Epicardial Cells

The epicardium, the mesothelial layer covering the heart, is a crucial cell source for cardiac development and repair. It provides cells and biochemical signals to the heart to facilitate vascularization and myocardial growth. An essential element of epicardial behavior is epicardial epithelial to mesenchymal transition (epiMT), which is the initial step for epicardial cells to become motile and invade the myocardium. To identify targets to optimize epicardium-driven repair of the heart, it is vital to understand which pathways are involved in the regulation of epiMT. Therefore, we established a cell culture model for human primary adult and fetal epiMT, which allows for parallel testing of inhibitors and stimulants of specific pathways. Using this approach, we reveal Activin A and ALK4 signaling as novel regulators of epiMT, independent of the commonly accepted EMT inducer TGFβ. Importantly, Activin A was able to induce epicardial invasion in cultured embryonic mouse hearts. Our results identify Activin A/ALK4 signaling as a modulator of epicardial plasticity which may be exploitable in cardiac regenerative medicine.

Roles of mechanosensitive channel Piezo1/2 proteins in skeleton and other tissues

Mechanotransduction is a fundamental ability that allows living organisms to receive and respond to physical signals from both the external and internal environments. The mechanotransduction process requires a range of special proteins termed mechanotransducers to convert mechanical forces into biochemical signals in cells. The Piezo proteins are mechanically activated nonselective cation channels and the largest plasma membrane ion channels reported thus far. The regulation of two family members, Piezo1 and Piezo2, has been reported to have essential functions in mechanosensation and transduction in different organs and tissues. Recently, the predominant contributions of the Piezo family were reported to occur in the skeletal system, especially in bone development and mechano-stimulated bone homeostasis. Here we review current studies focused on the tissue-specific functions of Piezo1 and Piezo2 in various backgrounds with special highlights on their importance in regulating skeletal cell mechanotransduction. In this review, we emphasize the diverse functions of Piezo1 and Piezo2 and related signaling pathways in osteoblast lineage cells and chondrocytes. We also summarize our current understanding of Piezo channel structures and the key findings about PIEZO gene mutations in human diseases.

Mechanical Aspects of Angiogenesis

Angiogenesis is of high clinical relevance as it plays a crucial role in physiological (e.g., tissue regeneration) and pathological processes (e.g., tumor growth). Besides chemical signals, such as VEGF, the relationship between cells and the extracellular matrix (ECM) can influence endothelial cell behavior during angiogenesis. Previously, in terms of the connection between angiogenesis and mechanical factors, researchers have focused on shear forces due to blood flow. However, it is becoming increasingly important to include the direct influence of the ECM on biological processes, such as angiogenesis. In this context, we focus on the stiffness of the surrounding ECM and the adhesion of cells to the ECM. Furthermore, we highlight the mechanical cues during the main stages of angiogenesis: cell migration, tip and stalk cells, and vessel stabilization. It becomes clear that the different stages of angiogenesis require various chemical and mechanical cues to be modulated by/modulate the stiffness of the ECM. Thus, changes of the ECM during tumor growth represent additional potential dysregulations of angiogenesis in addition to erroneous biochemical signals. This awareness could be the basis of therapeutic approaches to counteract specific processes in tumor angiogenesis.

Aurora B Tension Sensing Mechanisms in the Kinetochore Ensure Accurate Chromosome Segregation

The accurate segregation of chromosomes is essential for the survival of organisms and cells. Mistakes can lead to aneuploidy, tumorigenesis and congenital birth defects. The spindle assembly checkpoint ensures that chromosomes properly align on the spindle, with sister chromatids attached to microtubules from opposite poles. Here, we review how tension is used to identify and selectively destabilize incorrect attachments, and thus serves as a trigger of the spindle assembly checkpoint to ensure fidelity in chromosome segregation. Tension is generated on properly attached chromosomes as sister chromatids are pulled in opposing directions but resisted by centromeric cohesin. We discuss the role of the Aurora B kinase in tension-sensing and explore the current models for translating mechanical force into Aurora B-mediated biochemical signals that regulate correction of chromosome attachments to the spindle.

Autofluorescence of stingray skeletal cartilage: hyperspectral imaging as a tool for histological characterization

Tessellated cartilage is a distinctive composite tissue forming the bulk of the skeleton of cartilaginous fishes (e.g. sharks and rays), built from unmineralized cartilage covered at the surface by a thin layer of mineralized tiles called tesserae. The finescale structure and composition of elasmobranch tessellated cartilage has largely been investigated with electron microscopy, micro-computed tomography and histology, but many aspects of tissue structure and composition remain uncharacterized. In our study, we demonstrate that the tessellated cartilage of a stingray exhibits a strong and diverse autofluorescence, a native property of the tissue which can be harnessed as an effective label-free imaging technique. The autofluorescence signal was excited using a broad range of wavelengths in confocal and light sheet microscopy, comparing several sample preparations (fresh; demineralized and paraffin-embedded; non-demineralized and plastic-embedded) and imaging the tissue at different scales. Autofluorescence varied with sample preparation with the signal in both plastic- and paraffin-embedded samples strong enough to allow visualization of finescale (≥ 1 μm) cellular and matrix structures, such as cell nuclei and current and former mineralization fronts, identifiable by globular mineralized tissue. A defined pericellular matrix (PCM) surrounding chondrocytes was also discernible, described here for the first time in elasmobranchs. The presence of a PCM suggests similarities with mammalian cartilage regarding how chondrocytes interact with their environment, the PCM in mammals acting as a transducer for biomechanical and biochemical signals. A posterior analysis of hyperspectral images by an MCR-ALS unmixing algorithm allowed identification of several distinct fluorescence signatures associated to specific regions in the tissue. Some fluorescence signatures identified could be correlated with collagen type II, the most abundant structural molecule of cartilage. Other fluorescence signatures, however, remained unidentified, spotlighting tissue regions that deserve deeper characterization and suggesting the presence of molecules still unidentified in elasmobranch skeletal cartilage. Our results show that autofluorescence can be a powerful exploratory imaging tool for characterizing less-studied skeletal tissues, such as tessellated cartilage. The images obtained are largely comparable with more commonly used techniques, but without the need for complicated sample preparations or external staining reagents standard in histology and electron microscopy (TEM, SEM).

Mechanical Patterning in Animal Morphogenesis

Morphogenesis is one of the most remarkable examples of biological pattern formation. Despite substantial progress in the field, we still do not understand the organizational principles responsible for the robust convergence of the morphogenesis process across scales to form viable organisms under variable conditions. Achieving large-scale coordination requires feedback between mechanical and biochemical processes, spanning all levels of organization and relating the emerging patterns with the mechanisms driving their formation. In this review, we highlight the role of mechanics in the patterning process, emphasizing the active and synergistic manner in which mechanical processes participate in developmental patterning rather than merely following a program set by biochemical signals. We discuss the value of applying a coarse-grained approach toward understanding this complex interplay, which considers the large-scale dynamics and feedback as well as complementing the reductionist approach focused on molecular detail. A central challenge in this approach is identifying relevant coarse-grained variables and developing effective theories that can serve as a basis for an integrated framework for understanding this remarkable pattern-formation process. Expected final online publication date for the Annual Review of Cell and Developmental Biology, Volume 37 is October 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Cell migration guided by long-lived spatial memory

Living cells actively migrate in their environment to perform key biological functions—from unicellular organisms looking for food to single cells such as fibroblasts, leukocytes or cancer cells that can shape, patrol or invade tissues. Cell migration results from complex intracellular processes that enable cell self-propulsion, and has been shown to also integrate various chemical or physical extracellular signals. While it is established that cells can modify their environment by depositing biochemical signals or mechanically remodelling the extracellular matrix, the impact of such self-induced environmental perturbations on cell trajectories at various scales remains unexplored. Here, we show that cells can retrieve their path: by confining motile cells on 1D and 2D micropatterned surfaces, we demonstrate that they leave long-lived physicochemical footprints along their way, which determine their future path. On this basis, we argue that cell trajectories belong to the general class of self-interacting random walks, and show that self-interactions can rule large scale exploration by inducing long-lived ageing, subdiffusion and anomalous first-passage statistics. Altogether, our joint experimental and theoretical approach points to a generic coupling between motile cells and their environment, which endows cells with a spatial memory of their path and can dramatically change their space exploration.

Role of Physical Activity in Bone–Muscle Crosstalk: Biological Aspects and Clinical Implications

Bone and muscle tissues influence each other through the integration of mechanical and biochemical signals, giving rise to bone–muscle crosstalk. They are also known to secrete osteokines, myokines, and cytokines into the circulation, influencing the biological and pathological activities in local and distant organs and cells. In this regard, even osteoporosis and sarcopenia, which were initially thought to be two independent diseases, have recently been defined under the term “osteosarcopenia”, to indicate a synergistic condition of low bone mass with muscle atrophy and hypofunction. Undoubtedly, osteosarcopenia is a major public health concern, being associated with high rates of morbidity and mortality. The best current defence against osteosarcopenia is prevention based on a healthy lifestyle and regular exercise. The most appropriate type, intensity, duration, and frequency of exercise to positively influence osteosarcopenia are not yet known. However, combined programmes of progressive resistance exercises, weight-bearing impact exercises, and challenging balance/mobility activities currently appear to be the most effective in optimising musculoskeletal health and function. Based on this evidence, the aim of our review was to summarize the current knowledge about the role of exercise in bone–muscle crosstalk, highlighting how it may represent an effective alternative strategy to prevent and/or counteract the onset of osteosarcopenia.