A biomechanical switch regulates the transition towards homeostasis in oesophageal epithelium

McGinn, Jamie; Hallou, Adrien; Han, Seungmin; Krizic, Kata; Ulyanchenko, Svetlana; Iglesias-Bartolomé, Ramiro; England, Frances J.; Verstreken, Christophe M.; Chalut, Kevin J.; Jensen, Kim B.; Simons, Benjamin D.; Alcolea, Maria P.

doi:10.1038/s41556-021-00679-w

Cited by 40 publications

(39 citation statements)

References 110 publications

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“…Other studies have shown that tissue scale properties emerge from cellular scale mechanics in the transition from developing to adult tissues 44 . We have directly addressed this concept in immunologically relevant adult mammalian tissue during homeostasis and immune challenge.…”

Section: Discussionmentioning

confidence: 99%

Lymph node homeostasis and adaptation to immune challenge resolved by fibroblast network mechanics

et al. 2022

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Emergent physical properties of tissues are not readily understood by reductionist studies of their constituent cells. Here, we show molecular signals controlling cellular, physical, and structural properties and collectively determine tissue mechanics of lymph nodes, an immunologically relevant adult tissue. Lymph nodes paradoxically maintain robust tissue architecture in homeostasis yet are continually poised for extensive expansion upon immune challenge. We find that in murine models of immune challenge, cytoskeletal mechanics of a cellular meshwork of fibroblasts determine tissue tension independently of extracellular matrix scaffolds. We determine that C-type lectin-like receptor 2 (CLEC-2)–podoplanin signaling regulates the cell surface mechanics of fibroblasts, providing a mechanically sensitive pathway to regulate lymph node remodeling. Perturbation of fibroblast mechanics through genetic deletion of podoplanin attenuates T cell activation. We find that increased tissue tension through the fibroblastic stromal meshwork is required to trigger the initiation of fibroblast proliferation and restore homeostatic cellular ratios and tissue structure through lymph node expansion.

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Section: Discussionmentioning

confidence: 99%

Lymph node homeostasis and adaptation to immune challenge resolved by fibroblast network mechanics

et al. 2022

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“…There is a growing body of literature in which scRNA-Seq technology is leveraged for molecular characterization of squamous epithelial tissues 27 , 28 , including the normal and diseased esophagus 24 , 29 – 35 . Our study represents a significant advance in the field of squamous epithelial biology, analyzing the transcriptome of 44,679 esophageal keratinocytes to resolve the cellular landscape of normal murine esophageal epithelium.…”

Section: Discussionmentioning

confidence: 99%

Single cell transcriptomic analysis reveals cellular diversity of murine esophageal epithelium

et al. 2022

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Although morphologic progression coupled with expression of specific molecular markers has been characterized along the esophageal squamous differentiation gradient, the molecular heterogeneity within cell types along this trajectory has yet to be classified at the single cell level. To address this knowledge gap, we perform single cell RNA-sequencing of 44,679 murine esophageal epithelial, to identify 11 distinct cell populations as well as pathways alterations along the basal-superficial axis and in each individual population. We evaluate the impact of aging upon esophageal epithelial cell populations and demonstrate age-associated mitochondrial dysfunction. We compare single cell transcriptomic profiles in 3D murine organoids and human esophageal biopsies with that of murine esophageal epithelium. Finally, we employ pseudotemporal trajectory analysis to develop a working model of cell fate determination in murine esophageal epithelium. These studies provide comprehensive molecular perspective on the cellular heterogeneity of murine esophageal epithelium in the context of homeostasis and aging.

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“…For example, the onset of migration of neural crest cells in Xenopus appears controlled by the stiffening of the underlying mesoderm resulting from axis elongation [16]. An example of a more mature tissue is the epithelium of the ju-venile oesophagus in mice, whose transition from growth to homeostasis is mediated by the mechanotransduction of progressively increasing mechanical strain at the organ level [17].…”

Section: Introductionmentioning

confidence: 99%

Force propagation between epithelial cells depends on active coupling and mechano-structural polarization

Ruppel

Wörthmüller

Misiak

et al. 2022

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Cell-generated forces play a major role in coordinating the large-scale behavior of cell assemblies, in particular during development, wound healing and cancer. Mechanical signals propagate faster than biochemical signals, but can have similar effects, especially in epithelial tissues with strong cell-cell adhesion. However, a quantitative description of the transmission chain from force generation in a sender cell, force propagation across cell-cell boundaries, and the concomitant response of receiver cells is missing. For a quantitative analysis of this important situation, here we propose a minimal model system of two epithelial cells on an H-pattern (“cell doublet”). After optogenetically activating RhoA, a major regulator of cell contractility, in the sender cell, we measure the mechanical response of the receiver cell by traction force and monolayer stress microscopies. In general, we find that the receiver cells shows an active response so that the cell doublet forms a coherent unit. However, force propagation and response of the receiver cell also strongly depends on the mechano-structural polarization in the cell assembly, which is controlled by cell-matrix adhesion to the adhesive micropattern. We find that the response of the receiver cell is stronger when the mechano-structural polarization axis is oriented perpendicular to the direction of force propagation, reminiscent of the Poisson effect in passive materials. We finally show that the same effects are at work in small tissues. Our work demonstrates that cellular organization and active mechanical response of a tissue is key to maintain signal strength and leads to the emergence of elasticity, which means that signals are not dissipated like in a viscous system, but can propagate over large distances.

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A biomechanical switch regulates the transition towards homeostasis in oesophageal epithelium

Cited by 40 publications

References 110 publications

Lymph node homeostasis and adaptation to immune challenge resolved by fibroblast network mechanics

Lymph node homeostasis and adaptation to immune challenge resolved by fibroblast network mechanics

Single cell transcriptomic analysis reveals cellular diversity of murine esophageal epithelium

Force propagation between epithelial cells depends on active coupling and mechano-structural polarization

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