Series |

Series on Mechanobiology

Cell behaviour is governed by the mechanical environment, which influences not only cell-intrinsic properties, but also cellular interactions at the tissue and organism level. Thus, the sensing and transduction of mechanical forces has become an intensely studied aspect of cell biology. Nature Cell Biology presents a series of commissioned Reviews discussing recent advances in the field of mechanobiology, which will be published in the journal over several months. An accompanying online library presents recent research and review articles published in Nature Cell Biology and other Nature journals.

Series Content

Physical forces influence the growth and development of all organisms. In the second Review in the Series on Mechanobiology, Trepat and co-authors describe techniques to measure forces generated by cells, and discuss their use and limitations.

Review Article | | Nature Cell Biology

In this Review, we will discuss how the interplay and feedback between mechanical and biochemical signals control tissue morphogenesis and cell fate specification in embryonic development.

Review Article | | Nature Cell Biology

Editorial & Research Highlights

Mechanobiology — the study of how physical forces control the behaviour of cells and tissues — is a rapidly growing field. In this issue, we launch a Series of specially commissioned Review articles that discuss exciting recent developments in this area.

Editorial | | Nature Cell Biology

Related Nature Cell Biology Research

Cortical tension is thought to be generated by myosin II, and little is known about the role of actin network properties. Chugh et al. demonstrate that actin cortex thickness, determined by actin filament length, influences cortical tension.

Article | | Nature Cell Biology

Epithelial cells form energetically costly cell–cell adhesions in response to mechanical forces. How cells obtain their energy during this event is unclear. Activity of a key regulator of cell metabolism, the AMP-activated protein kinase (AMPK), is now shown to be mechanoresponsive, and thus can bridge adhesion mechanotransduction and energy homeostasis.

News & Views | | Nature Cell Biology

Related Nature Journals Research

The transcriptional co-activator YAP is known to operate downstream of mechanical signals arising from the cell niche. Here the authors demonstrate that YAP controls cell mechanics, force development and adhesion strength by promoting the transcription of genes related to focal adhesions.

Article | Open Access | | Nature Communications

Epidermal growth factor receptor and its isoform HER2 are recruited to nascent cellular adhesion sites and play an important role in the rigidity sensing of cells on stiff substrates, this activity being dependent on Src-mediated phosphorylation.

Article | | Nature Materials

Cytokinesis, which physically separates the dividing cells at the end of epithelial cell division, involves the remodelling of adhesive junctions between the dividing cell and its neighbours. This process depends on the cytoskeletal protein myosin II (MyoII) in the non-dividing neighbouring cells. Yohanns Bellaïche and team investigated how cytokinesis in the dividing cell is coordinated with MyoII activity in its neighbours in living fly tissue and find that mechanical communication is the answer. Specifically, the cytokinetic ring pulls at local adherens junctions causing their elongation, which results in decreased levels of E-cadherin protein at these sites. This is sensed by the contracting neighbouring cells, which then promote actomyosin flows and MyoII accumulation at the base of the ingressing junctions. The authors propose that this mechano-sensing mechanism drives remodelling of adherens junction and highlight the role of actomyosin flows in epithelial cell dynamics.

Letter | | Nature

Pulsatile actomyosin contractility during tissue morphogenesis has been mainly studied in apical domains but less is known about the contribution of the basal domain. Here the authors show differential influence of cell-matrix and cell-cell adhesions in regulating oscillations and tissue elongation.

Article | Open Access | | Nature Communications

Epithelial cell layers serve as barriers for the organs they cover, yet they continuously undergo cell division and cell death. So how do these dynamic processes avoid compromising the barrier function of epithelia? Jody Rosenblatt and colleagues previously reported in Nature that when epithelial cells become too crowded they trigger the stretch-activated channel Piezo1 to effect extrusion of cells that later die. They now ask how epithelia deal with the opposite situation—cell death. It emerges that, following cell death, the low density of surrounding cells also activate Piezo1, driving cell division to rebalance the cell numbers. The authors provide insights into the molecular mechanism through which stretch triggers cell division, and propose that whether Piezo1 signals for cell division or cell extrusion depends on the type of mechanical forces that it experiences.

Letter | | Nature

Actin polymerization in lamellipodia of cells is regulated by the Arp2/3 complex and FMNL family formins. Here the authors show that both FMNL2 and FMNL3 contribute to lamellipodium protrusion and structure, and abolishing FMNL2/3 reduces protrusion force generation and migration, without affecting Arp2/3 incorporation.

Article | Open Access | | Nature Communications

Cellular mechanical forces are regulated by Rho GTPases. Here the authors develop an optogenetic system to control the spatiotemporal activity of RhoA, and show that directing a RhoA activator to the plasma membrane causes contraction and YAP nuclear localization, whereas directing it to the mitochondria causes relaxation.

Article | Open Access | | Nature Communications

Increased cellular expression of RAB5A, an important regulator of endocytic processes, brings epithelial cells from a jammed state to coordinated motion, and can facilitate wound closure, gastrulation and migration in constrained environments.

Article | | Nature Materials

Interaction of fibronectin with αv-class and α5β1 integrins results in formation of cell adhesion complexes, but the initial events (<120 s) remain unclear. Here, the authors show that αv-class integrins bind fibronectin faster than α5β1 integrins and subsequently signal to α5ß1 integrins to strengthen the adhesion.

Article | Open Access | | Nature Communications

The Hering–Breuer inflation reflex, described some 150 years ago, is thought to protect the lung from overinflation thanks to stretch-activated sensory neurons that innervate the lung, but the actual molecular and cellular mechanisms involved have remained unknown. Ardem Patapoutian and colleagues find that this reflex is absent in adult mice that lack the mechanosensitive ion channel Piezo2, which was previously implicated in the skin's sense of touch. Surprisingly, Piezo2 is also required for initial lung inflation at birth, thus establishing a role for mechanotransduction in respiratory control in both newborn and adult mice.

Article | | Nature

The role of force in activating integrin cell adhesion receptors is not known. Here the authors develop fluorescent tension sensors for αL and β2 integrins and show that in migrating T cells force is transduced across the β2 integrin, and that this correlates with an active conformational state.

Article | Open Access | | Nature Communications

Mechanosensation by biological membranes can be relayed by mechanical tension to ion channels. Here the authors show that phospholipase D (PLD) is activated by mechanical disruption of lipid rafts which allows PLD to mix with its substrate in the lipid membrane, and propose a kinetic model of force transduction.

Article | Open Access | | Nature Communications

YAP and TAZ, effectors of the Hippo signalling pathway, have previously been reported to be sensors for mechanical stimuli. Now Yu Huang and colleagues show that these molecules sense mechanical forces generated by blood flow and play a role in atherosclerosis pathogenesis. Atherosclerotic plaques form in regions of disturbed blood flow. The authors show that disturbed flow increases YAP/TAZ activity and increases expression of proinflammatory genes, whereas steady unidirectional shear flow inhibits YAP/TAZ activity through integrin activation. The authors show that in mice, endothelial cell-specific knockdown of YAP retards atherosclerotic plaque formation. This work points to the integrin–Gα13–RhoA–YAP pathway as a possible target against atherosclerosis.

Letter | | Nature

How cells in mouse blastocyst sort themselves out to generate the inner cell mass, and how the embryos respond to manipulation during early development remain unexplained. Previous studies have indicated the importance of differential cell adhesion or oriented cell division along an apical–basal axis in the sorting phenomenon. Jean-Léon Maître et al. use a combination of biophysical measurement, modelling and both genetic and experimental manipulation of contractile components to analyse inner cell mass formation in the early mouse embryo. They suggest that cell polarization generates cells of different contractilities, which trigger their sorting to inner and outer position. The contractile forces are shown to modulate the sub-cellular localization of Yap, a transcriptional regulator known to influence cell fate.

Letter | | Nature

There is a growing appreciation that mechanical forces have important roles in many aspects of biology. This review provides a survey of methods for measuring the forces exerted by cells and discusses technical barriers to their implementation.

Review Article | | Nature Methods

The primary cilium is a single organelle protruding from the cell surface. Given this antenna-like structure, its function has been assumed to be sensing of the surrounding environment. Specifically, the main assumption has been that calcium-permeable ion channels within the cilium sense and respond to mechanical forces — a hypothesis that has been used to explain a large range of biological responses, from control of left–right axis determination during embryonic development to adult progression of polycystic kidney disease and some cancers. David Clapham and colleagues, however, present evidence that refutes this hypothesis. They measured Ca2+ signals in primary cilia following a mechanical force in mice engineered to express a sensor protein that fluoresces in response to Ca2+. They find no evidence of force-driven Ca2+ influx in primary cilia and conclude that if mechanosensation originates in primary cilia, it is not via calcium signalling.

Letter | | Nature