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1.
Nat Commun ; 14(1): 3020, 2023 05 25.
Article in English | MEDLINE | ID: mdl-37230982

ABSTRACT

The origins of wound myofibroblasts and scar tissue remains unclear, but it is assumed to involve conversion of adipocytes into myofibroblasts. Here, we directly explore the potential plasticity of adipocytes and fibroblasts after skin injury. Using genetic lineage tracing and live imaging in explants and in wounded animals, we observe that injury induces a transient migratory state in adipocytes with vastly distinct cell migration patterns and behaviours from fibroblasts. Furthermore, migratory adipocytes, do not contribute to scar formation and remain non-fibrogenic in vitro, in vivo and upon transplantation into wounds in animals. Using single-cell and bulk transcriptomics we confirm that wound adipocytes do not convert into fibrogenic myofibroblasts. In summary, the injury-induced migratory adipocytes remain lineage-restricted and do not converge or reprogram into a fibrosing phenotype. These findings broadly impact basic and translational strategies in the regenerative medicine field, including clinical interventions for wound repair, diabetes, and fibrotic pathologies.


Subject(s)
Cicatrix , Skin , Animals , Cicatrix/pathology , Skin/pathology , Myofibroblasts/pathology , Adipocytes/pathology , Wound Healing , Fibroblasts/pathology , Fibrosis
2.
PLoS Biol ; 19(2): e3001132, 2021 Feb.
Article in English | MEDLINE | ID: mdl-33596206

ABSTRACT

[This corrects the article DOI: 10.1371/journal.pbio.3000708.].

3.
PLoS Biol ; 18(12): e3000708, 2020 12.
Article in English | MEDLINE | ID: mdl-33290409

ABSTRACT

Regulation of quiescence and cell cycle entry is pivotal for the maintenance of stem cell populations. Regulatory mechanisms, however, are poorly understood. In particular, it is unclear how the activity of single stem cells is coordinated within the population or if cells divide in a purely random fashion. We addressed this issue by analyzing division events in an adult neural stem cell (NSC) population of the zebrafish telencephalon. Spatial statistics and mathematical modeling of over 80,000 NSCs in 36 brain hemispheres revealed weakly aggregated, nonrandom division patterns in space and time. Analyzing divisions at 2 time points allowed us to infer cell cycle and S-phase lengths computationally. Interestingly, we observed rapid cell cycle reentries in roughly 15% of newly born NSCs. In agent-based simulations of NSC populations, this redividing activity sufficed to induce aggregated spatiotemporal division patterns that matched the ones observed experimentally. In contrast, omitting redivisions leads to a random spatiotemporal distribution of dividing cells. Spatiotemporal aggregation of dividing stem cells can thus emerge solely from the cells' history.


Subject(s)
Cell Differentiation/physiology , Neural Stem Cells/metabolism , Telencephalon/growth & development , Adult Stem Cells/metabolism , Animals , Cell Cycle/physiology , Cell Division/physiology , Cell Proliferation/physiology , Models, Theoretical , Neural Stem Cells/cytology , Neural Stem Cells/physiology , Neurogenesis/physiology , Signal Transduction/physiology , Telencephalon/cytology , Telencephalon/metabolism , Zebrafish/growth & development , Zebrafish Proteins/metabolism
4.
Nat Commun ; 11(1): 5653, 2020 11 06.
Article in English | MEDLINE | ID: mdl-33159076

ABSTRACT

Scars are more severe when the subcutaneous fascia beneath the dermis is injured upon surgical or traumatic wounding. Here, we present a detailed analysis of fascia cell mobilisation by using deep tissue intravital live imaging of acute surgical wounds, fibroblast lineage-specific transgenic mice, and skin-fascia explants (scar-like tissue in a dish - SCAD). We observe that injury triggers a swarming-like collective cell migration of fascia fibroblasts that progressively contracts the skin and form scars. Swarming is exclusive to fascia fibroblasts, and requires the upregulation of N-cadherin. Both swarming and N-cadherin expression are absent from fibroblasts in the upper skin layers and the oral mucosa, tissues that repair wounds with minimal scar. Impeding N-cadherin binding inhibits swarming and skin contraction, and leads to reduced scarring in SCADs and in animals. Fibroblast swarming and N-cadherin thus provide therapeutic avenues to curtail fascia mobilisation and pathological fibrotic responses across a range of medical settings.


Subject(s)
Cicatrix/metabolism , Fascia/injuries , Fibroblasts/metabolism , Wounds and Injuries/metabolism , Adult , Aged , Animals , Cadherins/metabolism , Cell Movement , Cicatrix/physiopathology , Fascia/cytology , Fascia/metabolism , Female , Fibroblasts/cytology , Humans , Male , Mice , Mice, Inbred C57BL , Middle Aged , Skin/cytology , Skin/injuries , Skin/metabolism , Skin/physiopathology , Wound Healing , Wounds and Injuries/physiopathology , Young Adult
5.
Elife ; 72018 03 29.
Article in English | MEDLINE | ID: mdl-29595471

ABSTRACT

Despite the intrinsically stochastic nature of damage, sensory organs recapitulate normal architecture during repair to maintain function. Here we present a quantitative approach that combines live cell-lineage tracing and multifactorial classification by machine learning to reveal how cell identity and localization are coordinated during organ regeneration. We use the superficial neuromasts in larval zebrafish, which contain three cell classes organized in radial symmetry and a single planar-polarity axis. Visualization of cell-fate transitions at high temporal resolution shows that neuromasts regenerate isotropically to recover geometric order, proportions and polarity with exceptional accuracy. We identify mediolateral position within the growing tissue as the best predictor of cell-fate acquisition. We propose a self-regulatory mechanism that guides the regenerative process to identical outcome with minimal extrinsic information. The integrated approach that we have developed is simple and broadly applicable, and should help define predictive signatures of cellular behavior during the construction of complex tissues.


Subject(s)
Mechanoreceptors/physiology , Regeneration , Animals , Cell Lineage , Intravital Microscopy , Larva , Machine Learning , Microscopy, Video , Zebrafish
6.
Cytometry A ; 93(3): 314-322, 2018 03.
Article in English | MEDLINE | ID: mdl-29125897

ABSTRACT

Proliferating stem cells in the adult body are the source of constant regeneration. In the brain, neural stem cells (NSCs) divide to maintain the stem cell population and generate neural progenitor cells that eventually replenish mature neurons and glial cells. How much spatial coordination of NSC division and differentiation is present in a functional brain is an open question. To quantify the patterns of stem cell divisions, one has to (i) identify the pool of NSCs that have the ability to divide, (ii) determine NSCs that divide within a given time window, and (iii) analyze the degree of spatial coordination. Here, we present a bioimage informatics pipeline that automatically identifies GFP expressing NSCs in three-dimensional image stacks of zebrafish brain from whole-mount preparations. We exploit the fact that NSCs in the zebrafish hemispheres are located on a two-dimensional surface and identify between 1,500 and 2,500 NSCs in six brain hemispheres. We then determine the position of dividing NSCs in the hemisphere by EdU incorporation into cells undergoing S-phase and calculate all pairwise NSC distances with three alternative metrics. Finally, we fit a probabilistic model to the observed spatial patterns that accounts for the non-homogeneous distribution of NSCs. We find a weak positive coordination between dividing NSCs irrespective of the metric and conclude that neither strong inhibitory nor strong attractive signals drive NSC divisions in the adult zebrafish brain. © 2017 International Society for Advancement of Cytometry.


Subject(s)
Image Processing, Computer-Assisted/methods , Neural Stem Cells/cytology , Neurogenesis/physiology , Telencephalon/cytology , Telencephalon/diagnostic imaging , Animals , Cell Division/physiology , Cell Proliferation/physiology , Green Fluorescent Proteins/biosynthesis , Zebrafish
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