Fibroblast state switching orchestrates dermal maturation and wound healing

Rognoni, Emanuel; Pisco, Angela Oliveira; Hiratsuka, Toru; Sipilä, Kalle; Belmonte, Julio M.; Mobasseri, S A; Philippeos, Christina; Dilão, Rui; Watt, Fiona M.

doi:10.15252/msb.20178174

Cited by 126 publications

(102 citation statements)

References 46 publications

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“…This is because in the model ECM contributes to dermal volume changes substantially more as compared to fibroblasts. This assumption is in line with the observations that ECM occupies larger proportion of a given dermal volume in adult mouse skin as compared to fibroblasts. These results also suggest that epidermal signals (primarily I) can supplement dermal signals and contribute to maintaining dermal skin compartment in homeostasis.…”

Section: Resultssupporting

confidence: 89%

“…Indeed, a recently reported mathematical model of wound healing that utilized Cellular Potts model accounted for two fibroblast subtypes—proliferative and collagen‐producing fibroblasts. In the model, the switch between two fibroblast types was positively regulated by ECM and was required to achieve dermal scar maturation.…”

Section: Discussionmentioning

confidence: 99%

“…Another study implemented hybrid model to study how collagen fibres organize during wound healing and their role in scarring. The Cellular Potts model also has been used to investigate sprouting and branching during angiogenesis and, more recently, to examine proliferation and migration of skin wound fibroblasts.…”

Section: Introductionmentioning

confidence: 99%

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A multiscale hybrid mathematical model of epidermal‐dermal interactions during skin wound healing

Wang

Guerrero‐Juarez

Qiu

et al. 2019

Experimental Dermatology

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Following injury, skin activates a complex wound healing programme. While cellular and signalling mechanisms of wound repair have been extensively studied, the principles of epidermal‐dermal interactions and their effects on wound healing outcomes are only partially understood. To gain new insight into the effects of epidermal‐dermal interactions, we developed a multiscale, hybrid mathematical model of skin wound healing. The model takes into consideration interactions between epidermis and dermis across the basement membrane via diffusible signals, defined as activator and inhibitor. Simulations revealed that epidermal‐dermal interactions are critical for proper extracellular matrix deposition in the dermis, suggesting these signals may influence how wound scars form. Our model makes several theoretical predictions. First, basal levels of epidermal activator and inhibitor help to maintain dermis in a steady state, whereas their absence results in a raised, scar‐like dermal phenotype. Second, wound‐triggered increase in activator and inhibitor production by basal epidermal cells, coupled with fast re‐epithelialization kinetics, reduces dermal scar size. Third, high‐density fibrin clot leads to a raised, hypertrophic scar phenotype, whereas low‐density fibrin clot leads to a hypotrophic phenotype. Fourth, shallow wounds, compared to deep wounds, result in overall reduced scarring. Taken together, our model predicts the important role of signalling across dermal‐epidermal interface and the effect of fibrin clot density and wound geometry on scar formation. This hybrid modelling approach may be also applicable to other complex tissue systems, enabling the simulation of dynamic processes, otherwise computationally prohibitive with fully discrete models due to a large number of variables.

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Section: Resultssupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

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A multiscale hybrid mathematical model of epidermal‐dermal interactions during skin wound healing

Wang

Guerrero‐Juarez

Qiu

et al. 2019

Experimental Dermatology

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“…MSCs have the potential to differentiate in vivo and in vitro into myofibroblasts, adipocytes, chondrogenic, and osteogenic cells (Agley et al, 2013; Contreras et al, 2019c; Oishi et al, 2013; Uezumi et al, 2014b; Uezumi et al, 2011; Wosczyna et al, 2012). These PDGFRα + MSCs are found in most tissues, including bone marrow, heart, kidney, muscle, nerves, liver, lung, and skin in which they play crucial roles (Carr et al, 2019; Lemos and Duffield, 2018; Lynch and Watt, 2018; Rognoni et al, 2018). Despite their required normal activity during muscle regeneration (Joe et al, 2010; Heredia et al, 2013; Mathew et al, 2011; Fiore et al, 2016; Wosczyna et al, 2019), we and others have reported dysregulated behavior of these precursor cells in models of acute and chronic muscle damage, muscular dystrophy (MD), neurodegenerative diseases, and aging (Acuña et al, 2014; Contreras et al, 2016; Contreras et al, 2019c; González et al, 2017; Kopinke et al, 2017; Madaro et al, 2018; Mahmoudi et al, 2019; Lemos et al, 2015; Lukjanenko et al, 2019; Uezumi et al, 2014a).…”

Section: Introductionmentioning

confidence: 99%

TGF-β-driven downregulation of the Wnt/β-Catenin transcription factor TCF7L2/TCF4 in PDGFRα⁺fibroblasts

Contreras¹,

Soliman

Théret

et al. 2020

Preprint

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Mesenchymal stromal/stem cells (MSCs) are multipotent progenitors essential ororganogenesis, tissue homeostasis, regeneration, and scar formation. Tissue injury upregulates TGF-β signaling, which modulates myofibroblast fate, extracellular matrix remodeling, and fibrosis. However, the molecular determinants of MSCs differentiation and survival remain poorly understood. The canonical Wnt Tcf/Lef transcription factors regulate development and stemness, but the mechanisms by which injury-induced cues modulate their expression remain underexplored. Here, we studied the cell-specific gene expression of Tcf/Lef and, more specifically, we investigated whether damage-induced TGF-β impairs the expression and function of TCF7L2, using several models of MSCs, including skeletal muscle fibro-adipogenic progenitors. We show that Tcf/Lefs are differentially expressed and that TGF-β reduces the expression of TCF7L2 in MSCs but not in myoblasts. We also found that the ubiquitin-proteasome system regulates TCF7L2 proteostasis and participates in TGF-β-mediated TCF7L2 protein downregulation. Finally, we show that TGF-β requires HDACs activity to repress the expression of TCF7L2. Thus, our work found a novel interplay between TGF-β and Wnt canonical signaling cascades in PDGFRα+ fibroblasts and suggests that this mechanism could be targeted in tissue repa ir and regeneration.Summary statementTGF-β signaling suppresses the expression of the Wnt transcription factor TCF7L2 and compromises TCF7L2-dependent functions in tissue-resident PDGFRα+ fibroblasts.

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“…The ability of cells to navigate complex three-dimensional (3D) extracellular matrix (ECM) is essential in the physiology of health and disease. One example of a process important for health is fibroblasts moving through the ECM to heal wounds [1]. On the other hand, one of the hallmarks of cancer is the migration of metastatic cancer cells across the ECM [2].…”

Section: Introductionmentioning

confidence: 99%

Computational estimates of mechanical constraints on cell migration through the extracellular matrix

Maxian

Mogilner

Strychalski

2020

Preprint

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Cell migration through three-dimensional (3D) extracellular matrix (ECM) underlies important physiological phenomena and is based on a variety of mechanical strategies depending on the cell type and the properties of the ECM. By using computer simulations, we investigate two such migration mechanisms -'push-pull' (forming a finger-like protrusion, adhering to an ECM node, and pulling the cell body forward) and 'rear-squeezing' (pushing the cell body through the ECM by contracting the cell cortex and ECM at the cell rear). We present a computational model that accounts for both elastic deformation and forces of the ECM, an active cell cortex and nucleus, and for hydrodynamic forces and flow of the extracellular fluid, cytoplasm and nucleoplasm. We find that relations between three mechanical parameters -the cortex's contractile force, nuclear elasticity and ECM rigidity -determine the effectiveness of cell migration through the dense ECM. The cell can migrate persistently even if its cortical contraction cannot deform a near-rigid ECM, but then the contraction of the cortex has to be able to sufficiently deform the nucleus. The cell can also migrate even if it fails to deform a stiff nucleus, but then it has to be able to sufficiently deform the ECM. Simulation results show that nuclear stiffness limits the cell migration more than the ECM rigidity. Simulations of the rear-squeezing mechanism of motility results in more robust migration with larger cell displacements than those with the push-pull mechanism over a range of parameter values. Author summaryComputational simulations of models representing two different mechanisms of 3D cell migration in an extracellular matrix are presented. One mechanism represents a mesenchymal mode, characterized by finger-like actin protrusions, while the second mode is more amoeboid in that rear contraction of the cortex propels the cell forward. In both mechanisms, the cell generates a thin actin protrusion on the cortex that attaches to an ECM node. The cell is then either pulled (mesenchymal) or pushed (amoeboid) forward. Results show both mechanisms result in successful migration over a range of simulated parameter values as long as the contractile tension of the cortex exceeds either the nuclear stiffness or ECM stiffness, but not necessarily both. However, January 20, 2020 1/25 the distance traveled by the amoeboid migration mode is more robust to changes in parameter values, and is larger than in simulations of the mesenchymal mode. Additionally cells experience a favorable fluid pressure gradient when migrating in the amoeboid mode, and an adverse fluid pressure gradient in the mesenchymal mode.

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Fibroblast state switching orchestrates dermal maturation and wound healing

Cited by 126 publications

References 46 publications

A multiscale hybrid mathematical model of epidermal‐dermal interactions during skin wound healing

A multiscale hybrid mathematical model of epidermal‐dermal interactions during skin wound healing

TGF-β-driven downregulation of the Wnt/β-Catenin transcription factor TCF7L2/TCF4 in PDGFRα⁺fibroblasts

Computational estimates of mechanical constraints on cell migration through the extracellular matrix

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Fibroblast state switching orchestrates dermal maturation and wound healing

Cited by 126 publications

References 46 publications

A multiscale hybrid mathematical model of epidermal‐dermal interactions during skin wound healing

A multiscale hybrid mathematical model of epidermal‐dermal interactions during skin wound healing

TGF-β-driven downregulation of the Wnt/β-Catenin transcription factor TCF7L2/TCF4 in PDGFRα+fibroblasts

Computational estimates of mechanical constraints on cell migration through the extracellular matrix

Contact Info

Product

Resources

About

TGF-β-driven downregulation of the Wnt/β-Catenin transcription factor TCF7L2/TCF4 in PDGFRα⁺fibroblasts