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Biology subjects

Stramer, B.

Publications and source records attributed to Stramer, B..

6 recordsLinked to original sources

Derivation and simulation of a computational model of active cell populations: How overlap avoidance, deformability, cell-cell junctions and cytoskeletal forces affect alignment

Collective alignment of cell populations is a commonly observed phenomena in biology. An important example are aligning fibroblasts in healthy or scar tissue. In this work we derive and simulate a mechanistic agent-based model of the collective behaviour of actively moving and interacting cells, with a focus on understanding collective alignment. The derivation strategy is based on energy minimisation. The model ingredients are motivated by data on the behaviour of different populations of aligning fibroblasts and include: Self-propulsion, overlap avoidance, deformability, cell-cell junctions and cytoskeletal forces. We find that there is an optimal ratio of self-propulsion speed and overlap avoidance that maximises collective alignment. Further we find that deformability aids alignment, and that cell-cell junctions by themselves hinder alignment. However, if cytoskeletal forces are transmitted via cell-cell junctions we observe strong collective alignment over large spatial scales.

cell biology↗

Characterisation and correction of polarisation effects in fluorescently labelled fibres

Many biological structures take the form of fibres and filaments, and quantitative analysis of fibre organisation is important for understanding their functions in both normal physiological conditions and disease. In order to visualise these structures, fibres can be fluorescently labelled and imaged, with specialised image analysis methods available for quantifying the degree and strength of fibre alignment. Here we show that fluorescently labelled fibres can display polarised emission, with the strength of this effect varying depending on structure and fluorophore identity. This can bias automated analysis of fibre alignment and mask the true underlying structural organisation. We present a method for quantifying and correcting these polarisation effects without requiring polarisation resolved microscopy, and demonstrate its efficacy when applied to images of fluorescently labelled collagen gels, allowing for more reliable characterisation of fibre microarchitecture.

cell biology↗

Convergent Insulin and TGF-β signalling drives cancer cachexia by promoting aberrant fatbody ECM accumulation in a Drosophila tumour model

Cancer cachexia is a wasting disease suffered by advanced stage cancer patients and ultimately causes [~]30% of cancer mortalities. Clinical observations have shown that extracellular matrix (ECM) remodelling which leads to fibrosis in the adipose tissue is a key feature of cancer cachexia. However, the molecular regulators of adipose ECM remodelling are not known and how this leads to muscle wasting is unclear. In this study, using a Drosophila cachexia model, we found that in the adipose tissue of both wildtype and tumour bearing animals, insulin and TGF-{beta} signalling converge via a BMP antagonist short gastrulation (sog) to regulate ECM remodelling. In tumour bearing animals, the aberrant ECM accumulation in the fatbody, contributes towards muscle detachment by preventing ECM secretion and subsequently depleting muscles of fatbody-secreted ECM proteins. Strikingly, activation of insulin signalling, inhibition of TGF-{beta} signalling, or modulation of ECM secretion via SPARC or Rab10 in the fatbody, was able to rescue tissue wasting in the presence of tumour. Together, our study highlights the importance of adipose ECM remodelling in the context of cancer cachexia.

developmental biology↗

Extracellular matrix assembly stress drives Drosophila central nervous system morphogenesis

The forces controlling tissue morphogenesis are attributed to cellular-driven activities and any role for extracellular matrix (ECM) is assumed to be passive. However, all polymer networks, including ECM, can theoretically develop autonomous stresses during their assembly. Here we examine the morphogenetic function of an ECM prior to reaching homeostatic equilibrium by analyzing de novo ECM assembly during Drosophila ventral nerve cord (VNC) condensation. Asymmetric VNC shortening and a rapid decrease in surface area correlate with exponential assembly of Collagen-IV (Col4) surrounding the tissue. Concomitantly, a transient developmentally-induced Col4 gradient leads to coherent long-range flow of ECM, which equilibrates the Col4 network. Finite element analysis and perturbation of Col4 network formation through the generation of dominant Col4-truncations that affect assembly, reveals that VNC morphodynamics is driven by a sudden increase in ECM-driven surface tension. These data highlight that ECM assembly stress and associated network instabilities can actively participate in tissue morphogenesis.

developmental biology↗

The glycocalyx affects force loading-dependent mechanotransductive topography sensing at the nanoscale

The cell/microenvironment interface is the starting point of integrin-mediated mechanotransduction, but many details of mechanotransductive signal integration remain elusive due to the complexity of the involved (extra)cellular structures, such as the glycocalyx. We used nano-bio-interfaces reproducing the complex nanotopographical features of the extracellular matrix to analyse the glycocalyx impact on PC12 cell mechanosensing at the nanoscale (e.g., by force spectroscopy with functionalised probes). Our data demonstrates that the glycocalyx configuration affects spatio-temporal nanotopography-sensitive mechanotransductive events at the cell/microenvironment interface. Opposing effects of glycocalyx removal were observed, when comparing flat and specific nanotopographical conditions. The excessive retrograde actin flow speed and force loading are strongly reduced on certain nanotopographies upon removal of the native glycocalyx, while on the flat substrate we observe the opposite trend. Our results highlight the importance of the glycocalyx configuration in a molecular clutch force loading-dependent cellular mechanism for mechanosensing of microenvironmental nanotopographical features.

biophysics↗

EphB2 and ERK signaling are required for heterotypic contact inhibition of locomotion to drive cell sorting

Interactions between different cell-types can induce distinct contact inhibition of locomotion (CIL) responses that are hypothesized to control population-wide behaviors during embryogenesis [1, 2]. However, our understanding of the signals that lead to cell-type specific repulsion, and the precise capacity of heterotypic CIL responses to drive emergent behaviors is lacking. Using a new in vitro model of heterotypic CIL between epithelial and mesenchymal cells, we show that fibrosarcoma cells (HT1080), but not fibroblasts (NIH3T3), are actively repelled by epithelial cells in culture. We show that knocking down EphB2 in fibrosarcoma cells specifically leads to disruption of the repulsion phase of CIL in response to interactions with epithelial cells. Furthermore, this heterotypic interaction requires ERK activation, downstream of EphB2 signaling. We also examine the population-wide effects when these various cell combinations, and their specific heterotypic CIL responses, are allowed to interact in culture. Mixtures of fibrosarcoma and epithelial cells - unlike fibroblasts and epithelial cells - lead to complete sorting and segregation of the two populations, and inhibiting their distinct CIL response by knocking down EphB2 or ERK in fibrosarcoma cells disrupts this emergent sorting behavior. Our understanding of the mechanisms underlying developmental behaviors such as cell sorting is lacking as predominant sorting hypotheses, such as differential adhesion, have recently been found inadequate in predicting the sorting of mesenchymal cells [3, 4]. These data suggest that heterotypic CIL responses, in conjunction with processes such as differential adhesion, may aid the sorting of cell populations during embryogenesis.

cell biology↗