It takes two to remyelinate: A bioengineered platform to study astrocyte-oligodendrocyte crosstalk and potential therapeutic targets in remyelination.

Autor: Rocha DN; Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, 4200-135 Porto, Portugal; Instituto de Engenharia Biomédica (INEB), Universidade do Porto, 4200-135 Porto, Portugal; Faculdade de Engenharia da Universidade do Porto (FEUP), 4200-465 Porto, Portugal., Carvalho ED; Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, 4200-135 Porto, Portugal; Instituto de Engenharia Biomédica (INEB), Universidade do Porto, 4200-135 Porto, Portugal; Faculdade de Engenharia da Universidade do Porto (FEUP), 4200-465 Porto, Portugal., Pires LR; Instituto de Engenharia Biomédica (INEB), Universidade do Porto, 4200-135 Porto, Portugal; Faculdade de Engenharia da Universidade do Porto (FEUP), 4200-465 Porto, Portugal., Gardin C; Maria Cecilia Hospital, GVM Care & Research, Cotignola, 48033 Ravenna, Italy., Zanolla I; Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy., Szewczyk PK; Faculty of Metals Engineering and Industrial Computer Science, AGH University of Science and Technology, 30-059 Krakow, Poland., Machado C; Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, 4200-135 Porto, Portugal., Fernandes R; Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, 4200-135 Porto, Portugal., Stachewicz U; Faculty of Metals Engineering and Industrial Computer Science, AGH University of Science and Technology, 30-059 Krakow, Poland., Zavan B; Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy., Relvas JB; Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, 4200-135 Porto, Portugal; Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, 4200-135 Porto, Portugal; Department of Biomedicine, Faculty of Medicine, Universidade do Porto, 4200-319 Porto, Portugal., Pêgo AP; Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, 4200-135 Porto, Portugal; Instituto de Engenharia Biomédica (INEB), Universidade do Porto, 4200-135 Porto, Portugal; Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, 4050-343 Porto, Portugal. Electronic address: apego@i3s.up.pt.
Jazyk: angličtina
Zdroj: Biomaterials advances [Biomater Adv] 2023 Aug; Vol. 151, pp. 213429. Date of Electronic Publication: 2023 Apr 25.
DOI: 10.1016/j.bioadv.2023.213429
Abstrakt: The loss of the myelin sheath insulating axons is the hallmark of demyelinating diseases. These pathologies often lead to irreversible neurological impairment and patient disability. No effective therapies are currently available to promote remyelination. Several elements contribute to the inadequacy of remyelination, thus understanding the intricacies of the cellular and signaling microenvironment of the remyelination niche might help us to devise better strategies to enhance remyelination. Here, using a new in vitro rapid myelinating artificial axon system based on engineered microfibres, we investigated how reactive astrocytes influence oligodendrocyte (OL) differentiation and myelination ability. This artificial axon culture system enables the effective uncoupling of molecular cues from the biophysical properties of the axons, allowing the detailed study of the astrocyte-OL crosstalk. Oligodendrocyte precursor cells (OPCs) were cultured on poly(trimethylene carbonate-co-ε-caprolactone) copolymer electrospun microfibres that served as surrogate axons. This platform was then combined with a previously established tissue engineered glial scar model of astrocytes embedded in 1 % (w/v) alginate matrices, in which astrocyte reactive phenotype was acquired using meningeal fibroblast conditioned medium. OPCs were shown to adhere to uncoated engineered microfibres and differentiate into myelinating OL. Reactive astrocytes were found to significantly impair OL differentiation ability, after six and eight days in a co-culture system. Differentiation impairment was seen to be correlated with astrocytic miRNA release through exosomes. We found significantly reduction on the expression of pro-myelinating miRNAs (miR-219 and miR-338) and an increase in anti-myelinating miRNA (miR-125a-3p) content between reactive and quiescent astrocytes. Additionally, we show that OPC differentiation inhibition could be reverted by rescuing the activated astrocytic phenotype with ibuprofen, a chemical inhibitor of the small rhoGTPase RhoA. Overall, these findings show that modulating astrocytic function might be an interesting therapeutic avenue for demyelinating diseases. The use of these engineered microfibres as an artificial axon culture system will enable the screening for potential therapeutic agents that promote OL differentiation and myelination while providing valuable insight on the myelination/remyelination processes.
Competing Interests: Declaration of competing interest None of the authors or suggested reviewers have any conflict of interest, financial or otherwise.
(Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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