Microgravity Modifies the Phenotype of Fibroblast and Promotes Remodeling of the Fibroblast-Keratinocyte Interaction in a 3D Co-Culture Model.

Valeria Fedeli,Simona Dinicola,Paola Pedata,Mariano Bizzarri,Simona Ceccarelli,Luisa Gesualdi,Angela Catizone,Saleh H Alwasel,Abdel Halim Harrath,Alessandra Cucina,Gianmarco Fabrizi,Giulia Ricci,Noemi Monti

doi:10.3390/ijms23042163

Abstract

Microgravity impairs tissue organization and critical pathways involved in the cell–microenvironment interplay, where fibroblasts have a critical role. We exposed dermal fibroblasts to simulated microgravity by means of a Random Positioning Machine (RPM), a device that reproduces conditions of weightlessness. Molecular and structural changes were analyzed and compared to control samples growing in a normal gravity field. Simulated microgravity impairs fibroblast conversion into myofibroblast and inhibits their migratory properties. Consequently, the normal interplay between fibroblasts and keratinocytes were remarkably altered in 3D co-culture experiments, giving rise to several ultra-structural abnormalities. Such phenotypic changes are associated with down-regulation of α-SMA that translocate in the nucleoplasm, altogether with the concomitant modification of the actin-vinculin apparatus. Noticeably, the stress associated with weightlessness induced oxidative damage, which seemed to concur with such modifications. These findings disclose new opportunities to establish antioxidant strategies that counteract the microgravity-induced disruptive effects on fibroblasts and tissue organization.

Highlights

IntroductionWeightlessness can impair human physiology by acting at the systemic level and by affecting a bewildering number of critical and genomic pathways within cells and tissues [6,7]
In agreement with proliferation and apoptosis data, fibroblasts subjected to microgravity showed a decrease in the S phase of the cell cycle (p < 0.05) and an increase in the G2/M phase (p < 0.05) compared to fibroblasts grown under normal gravity conditions (Figure 1C)
Dermal Fibroblasts Exposed to Simulated Microgravity for 24 h We investigated if μG exposure could impair specific cytoskeleton (CSK) targets involved in enabling cell-surface and Namely, actin-vinculin coIn human dermal fibroblastscontact exposed to displacement

Summary

Introduction

Weightlessness can impair human physiology by acting at the systemic level and by affecting a bewildering number of critical and genomic pathways within cells and tissues [6,7]. It is worth noting that epithelial cells—in both normal and pathological conditions—dynamically interact with the extracellular matrix (ECM) and a wide array of mesenchymal cells, including fibroblasts. Those interactions play a critical role in several processes, including cell proliferation and differentiation, tissue repair (wound healing), fibrosis, and cancer transformation, driving cells toward distinct phenotypic fates [9,10]. Fibroblast–epithelial interactions modulate tissue repair, homeostasis, inflammation, proliferation, and remodeling, through the mechanotransduction of physical stimuli and the modification of the ECM composition, participating in the morphology of epithelial cells and tissues [11]

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Conclusion