Mechanical Forces Orchestrate Brain Development

doi:10.1016/j.tins.2020.10.012

Trends in Neurosciences

Volume 44, Issue 2, February 2021, Pages 110-121

https://doi.org/10.1016/j.tins.2020.10.012 Get rights and content

Highlights

Mechanotransduction of environmental signals governs important cell functions during brain development.
Recent discoveries have shown that disruption of brain mechanical properties during embryogenesis is associated with neurodevelopmental disorders. Thus, a better understanding of mechanobiology will also enhance our knowledge of brain disorders.
The advent of new technologies will increase our ability to measure and manipulate the physical features of neuronal cells and their environment.

During brain development, progenitors generate successive waves of neurons that populate distinct cerebral regions, where they settle and differentiate within layers or nuclei. While migrating and differentiating, neurons are subjected to mechanical forces arising from the extracellular matrix, and their interaction with neighboring cells. Changes in brain biomechanical properties, during its formation or aging, are converted in neural cells by mechanotransduction into intracellular signals that control key neurobiological processes. Here, we summarize recent findings that support the contribution of mechanobiology to neurodevelopment, with focus on the cerebral cortex. Also discussed are the existing toolbox and emerging technologies made available to assess and manipulate the physical properties of neurons and their environment.

Section snippets

Mechanotransduction and Brain Development

The morphogenic changes that occur during brain development involve cell movement and cell shape remodeling that exert mechanical forces on neighboring cells and their extracellular matrix (ECM). The maturation and differentiation of neurons partly relies on transduction of those mechanical forces into intracellular biochemical signals via a process called mechanotransduction (see Glossary). Several molecular actors have been involved in this process and include for instance, adhesion molecules

Changes in Brain Biomechanical Properties Drive Developmental Processes

The brain is one of the softest tissues of the body, whose mechanical properties rely on both the molecular composition of its ECM (e.g., weak expression of collagen I) and intracellular components (e.g., low content of nuclear lamin A) [5]. The brain ECM proteome (matrisome) is predominantly composed of hyaluronic acid and proteoglycans [6], and its qualitative changes contribute to spatio-temporal modifications of ECM elasticity during development. As a result of the stabilization of their

Mechanotransduction as an Additional Layer of Neuronal Regulation

In general, cells convert biomechanical stimuli into intracellular signals via mechanotransduction. This process is shared by adult neurons, such as the peripheral ones of the somatosensory system that are sensitive to mechanical stretching, compression, vibration, or touch [24], and immature neurons, whose growth cones read mechanical cues [25]. However, in most cases, the underlying mechanisms by which neurons integrate mechanical information remain elusive.

Biomechanical Control of Early Neuronal Functions in Health and Disease

Despite its relative softness, the cerebral cortical wall shows a positive apico-basal stiffness gradient along its differentiation axis [8], which suggests a possible contribution of surrounding mechanical forces to neurogenesis. Indeed, myosin II generates local membrane tensions in response to traction forces causing matrix deformation that, by activating Piezo1 in cultured human neural stem cells (hNSCs), favors the generation of neurons [38]. Additional evidence obtained in rodents, shows

Concluding Remarks

The mechanical properties of the cerebral cortex vary between different locations and over time, and neural cells sense and respond dynamically to these changes. Activation of specific mechanotransduction pathways, instructs local morphogenetic events in neurons ranging from filopodia formation to synaptic maturation. Accumulating data indicate that cell migration contributes to brain morphogenesis. The softness traits of neurons make them susceptible to nuclear deformation upon mechanical

Acknowledgments

The work in the Nguyen laboratory is supported by the F.R.S.-F.N.R.S. (Synet; EOS 0019118F-RG36), the Fonds Leon Fredericq, the Fondation Médicale Reine Elisabeth, the Fondation Simone et Pierre Clerdent, the Belgian Science Policy (IAP-VII network P7/20), and the ERANET Neuron STEM-MCD and NeuroTalk. M.J.-T. and L.N. are respectively postdoctoral researcher, and senior research associates of the F.R.S- F.N.R.S. All figures were created with BioRender.com.

Glossary

Bin/amphiphysin/Rvs (BAR): family of proteins that contain a Bin/amphiphysin/Rvs (BAR) domain, which includes six subfamilies: N-BAR, BAR, F-BAR, I-BAR, PX-BAR, and BAR-PH. BAR proteins regulate the curvature of the cell membrane, and according to their structure they generate different membrane phenotypes.
Barrier-to-autointegration factor (BAF): mammalian ATP-dependent chromatin remodeling complex that contains DNA and histone-binding domains.
Emerin: LEM domain-containing protein mainly localized in

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Recent research has highlighted the growing significance of the mechanical properties of cells and tissues in the proper execution of physiological functions within an organism; alterations to these properties can potentially result in various diseases. These mechanical properties can be assessed using various techniques that vary in spatial and temporal resolutions as well as applications. Due to the wide range of mechanical behaviors exhibited by cells and tissues, a singular mapping technique may be insufficient in capturing their complexity and nuance. Consequently, by utilizing a combination of methods–multimodal mechanical mapping–researchers can achieve a more comprehensive characterization of mechanical properties, encompassing factors such as stiffness, modulus, viscoelasticity, and forces. Furthermore, different mapping techniques can provide complementary information and enable the exploration of spatial and temporal variations to enhance our understanding of cellular dynamics and tissue mechanics. By capitalizing on the unique strengths of each method while mitigating their respective limitations, a more precise and holistic understanding of cellular and tissue mechanics can be obtained. Here, we spotlight Brillouin microscopy (BM) as a noncontact, noninvasive, and label-free mechanical mapping modality to be coutilized alongside established mechanical probing methods. This review summarizes some of the most widely adopted individual mechanical mapping techniques and highlights several recent multimodal approaches demonstrating their utility. We envision that future studies aim to adopt multimodal techniques to drive advancements in the broader realm of mechanobiology.
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Neural organoids consist of three-dimensional tissue derived from pluripotent stem cells that could recapitulate key features of the human brain. During the past decade, organoid technology has evolved in the field of human brain science by increasing the quality and applicability of its products. Among them, a novel approach involving the design of neural organoids engineered by mechanical forces has emerged. This review describes previous approaches for the generation of neural organoids, the engineering of neural organoids by mechanical forces, and future challenges for the application of mechanical forces in the design of neural organoids.
Unlocking mechanosensitivity: integrins in neural adaptation
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Mechanosensitivity extends beyond sensory cells to encompass most neurons in the brain. Here, we explore recent research on the role of integrins, a diverse family of adhesion molecules, as crucial biomechanical sensors translating mechanical forces into biochemical and electrical signals in the brain. The varied biomechanical properties of neuronal integrins, including their force-dependent conformational states and ligand interactions, dictate their specific functions. We discuss new findings on how integrins regulate filopodia and dendritic spines, shedding light on their contributions to synaptic plasticity, and explore recent discoveries on how they engage with metabotropic receptors and ion channels, highlighting their direct participation in electromechanical transduction. Finally, to facilitate a deeper understanding of these developments, we present molecular and biophysical models of mechanotransduction.
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In multicellular lives, the differentiation of stem cells and progenitor cells is often accompanied by a transition from glycolysis to mitochondrial oxidative phosphorylation (OXPHOS). However, the underlying mechanism of this metabolic transition remains largely unknown. In this study, we investigate the role of mechanical stress in activating OXPHOS during differentiation of the female germline cyst in Drosophila. We demonstrate that the surrounding somatic cells flatten the 16-cell differentiating cyst, resulting in an increase of the membrane tension of germ cells inside the cyst. This mechanical stress is necessary to maintain cytosolic Ca²⁺ concentration in germ cells through a mechanically activated channel, transmembrane channel-like. The sustained cytosolic Ca²⁺ triggers a CaMKI-Fray-JNK signaling relay, leading to the transcriptional activation of OXPHOS in differentiating cysts. Our findings demonstrate a molecular link between cell mechanics and mitochondrial energy metabolism, with implications for other developmentally orchestrated metabolic transitions in mammals.
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Distal metastasis of breast cancer is a primary cause of death, and the lung is a common metastatic target of breast cancer. However, the role of the lung niche in promoting breast cancer progression is not well understood. Engineered three-dimensional (3D) in vitro models capable of bridging this knowledge gap can be specifically designed to mimic crucial characteristics of the lung niche in a more physiologically relevant context than conventional two-dimensional systems. In this study, two 3D culture systems were developed to mimic the late stage of breast cancer progression at a lung metastatic site. These 3D models were created based on a novel decellularized lung extracellular matrix/chondroitin sulfate/gelatin/chitosan composite material and on a porcine decellularized lung matrix (PDLM), with the former tailored with comparable properties (stiffness, pore size, biochemical composition, and microstructure) to that of the in vivo lung matrix. The different microstructure and stiffness of the two types of scaffolds yielded diverse presentations of MCF-7 cells in terms of cell distribution, cell morphology, and migration. Cells showed better extensions with apparent pseudopods and more homogeneous and reduced migration activity on the composite scaffold compared to those on the PDLM scaffold. Furthermore, alveolar-like structures with superior porous connectivity in the composite scaffold remarkably promoted aggressive cell proliferation and viability. In conclusion, a novel lung matrix-mimetic 3D in vitro breast cancer lung metastasis model was developed to clarify the underlying correlativity between lung ECM and breast cancer cells after lung colonization. A better understanding of the effects of biochemical and biophysical environments of the lung matrix on cell behaviors can help elucidate the potential mechanisms of breast cancer progression and further improve target discovery of therapeutic strategies.
Patterning of brain organoids derived from human pluripotent stem cells
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Citation Excerpt :
To address these shortcomings, engineering solutions leveraging recent work in the fields of biomaterials, microfluidics and synthetic biology are increasingly being utilized [58–60]. Bioengineering approaches are uniquely suited for mimicking the complex array of biophysical cues [61,62] and morphogens [63,64] involved in regulating the developing CNS. A recent study used a combination of glass micropatterning of hiPSC cultures to spatially confine their growth with a 4% Matrigel environment to enable the formation of 3D cellular structures (Figure 3b).
The emerging technology of brain organoids deriving from human pluripotent stem cells provides unprecedented opportunities to study human brain development and associated disorders. Various brain organoid protocols have been developed that can recapitulate some key features of cell type diversity, cytoarchitectural organization, developmental processes, functions, and pathologies of the developing human brain. In this review, we focus on patterning of human stem cell-derived brain organoids. We start with an overview of general procedures to generate brain organoids. We then highlight some recently developed brain organoid protocols and chemical cues involved in modeling development of specific human brain regions, subregions, and multiple regions together. We also discuss limitations and potential future improvements of human brain organoid technology.

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Trends in Neurosciences

ReviewMechanical Forces Orchestrate Brain Development

Highlights

Section snippets

Mechanotransduction and Brain Development

Changes in Brain Biomechanical Properties Drive Developmental Processes

Mechanotransduction as an Additional Layer of Neuronal Regulation

Biomechanical Control of Early Neuronal Functions in Health and Disease

Concluding Remarks

Acknowledgments

Glossary

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Mol. Cell

Stem Cell Reports

NeuroImage

Neurobiol. Stress

Neuroimage Clin.

Methods

Neuron

Cell

Integrin mechano-chemical signaling generates plasma membrane nanodomains that promote cell spreading

Cell

Mechanosensing controlled directly by tyrosine kinases

Nano Lett.

Cadherin adhesion and mechanotransduction

Annu. Rev. Cell Dev. Biol.

Chromatin and lamin A determine two different mechanical response regimes of the cell nucleus

MBoC

Nuclear Lamin-A scales with tissue stiffness and enhances matrix-directed differentiation

Science

How the extracellular matrix shapes neural development

Open Biol.

Systematic profiling of spatiotemporal tissue and cellular stiffness in the developing brain

Development

Regulation of neuritogenesis in hippocampal neurons using stiffness of extracellular microenvironment

PLoS ONE

Defining the adult neural stem cell niche proteome identifies key regulators of adult neurogenesis

Cell Stem Cell

How forces fold the cerebral cortex

J. Neurosci.

Deconstructing cortical folding: genetic, cellular, and mechanical determinants

Nat. Rev. Neurosci.

Dynamic patterns of cortical expansion during folding of the preterm human brain

Proc. Natl. Acad. Sci. U. S. A.

Transcriptomes of germinal zones of human and mouse fetal neocortex suggest a role of extracellular matrix in progenitor self-renewal

Proc. Natl. Acad. Sci. U. S. A.

Human brain organoids on a chip reveal the physics of folding

Nat. Phys.

Extracellular matrix components HAPLN1, lumican, and collagen I, cause hyaluronic acid-dependent folding of the developing human neocortex

Neuron

Discrete domains of gene expression in germinal layers distinguish the development of gyrencephaly

EMBO J.

Regulation of cerebral cortex folding by controlling neuronal migration via FLRT adhesion molecules

Cell

Molecular mechanisms of mechanotransduction in mammalian sensory neurons

Nat. Rev. Neurosci.

Mechanochemical regulation of growth cone motility

Front. Cell. Neurosci.

Integrin activation by talin, kindlin, and mechanical forces

Nat. Cell Biol.

Fibronectin forms the most extensible biological fibers displaying switchable force-exposed cryptic binding sites

Proc. Natl. Acad. Sci. U. S. A.

Mechanical regulation of a molecular clutch defines force transmission and transduction in response to matrix rigidity

Nat. Cell Biol.

Paxillin facilitates timely neurite initiation on soft-substrate environments by interacting with the endocytic machinery

eLife

Proteomic dissection of nanotopography-sensitive mechanotransductive signaling hubs that foster neuronal differentiation in PC12 Cells

Front. Cell. Neurosci.

Netrin-1 attracts axons through FAK-dependent mechanotransduction

Review
Mechanical Forces Orchestrate Brain Development