Secretome of endothelial progenitor cells from stroke patients promotes endothelial barrier tightness and protects against hypoxia-induced vascular leakage
Loiola, Rodrigo Azevedo (Université d'Artois (França))
García-Gabilondo, Miguel (Vall d'Hebron Institut de Recerca (VHIR))
Grayston, Alba (Vall d'Hebron Institut de Recerca (VHIR))
Bugno, Paulina (Pure Biologics (Wroclaw, Polònia))
Kowalska, Agnieszka (Pure Biologics (Wroclaw, Polònia))
Duban-Deweer, Sophie (Université d'Artois (França))
Rizzi, Eleonora (Université d'Artois (França))
Hachani, Johan (Université d'Artois (França))
Sano, Yasuteru (Department of Neurology and Clinical Neuroscience. Yamaguchi University)
Shimizu, Fumitaka (Department of Neurology and Clinical Neuroscience. Yamaguchi University)
Kanda, Takashi (Department of Neurology and Clinical Neuroscience. Yamaguchi University)
Mysiorek, Caroline (Université d'Artois (França))
Mazurek, Maciej Piotr (Pure Biologics (Wroclaw, Polònia))
Rosell Novel, Anna (Vall d'Hebron Institut de Recerca (VHIR))
Gosselet, Fabien (Université d'Artois (França))
Universitat Autònoma de Barcelona

Data:	2021
Resum:	Background: Cell-based therapeutic strategies have been proposed as an alternative for brain repair after stroke, but their clinical application has been hampered by potential adverse effects in the long term. The present study was designed to test the effect of the secretome of endothelial progenitor cells (EPCs) from stroke patients (scCM) on in vitro human models of angiogenesis and vascular barrier. Methods: Two different scCM batches were analysed by mass spectrometry and a proteome profiler. Human primary CD34-derived endothelial cells (CD34-ECs) were used for designing angiogenesis studies (proliferation, migration, and tubulogenesis) or in vitro models of EC monolayer (confluent monolayer ECs-CMECs) and blood-brain barrier (BBB; brain-like ECs-BLECs). Cells were treated with scCM (5 μg/mL) or protein-free endothelial basal medium (scEBM-control). CMECs or BLECs were exposed (6 h) to oxygen-glucose deprivation (OGD) conditions (1% oxygen and glucose-free medium) or normoxia (control-5% oxygen, 1 g/L of glucose) and treated with scCM or scEBM during reoxygenation (24 h). Results: The analysis of different scCM batches showed a good reproducibility in terms of protein yield and composition. scCM increased CD34-EC proliferation, tubulogenesis, and migration compared to the control (scEBM). The proteomic analysis of scCM revealed the presence of growth factors and molecules modulating cell metabolism and inflammatory pathways. Further, scCM decreased the permeability of CMECs and upregulated the expression of the junctional proteins such as occludin, VE-cadherin, and ZO-1. Such effects were possibly mediated through the activation of the interferon pathway and a moderate downregulation of Wnt signalling. Furthermore, OGD increased the permeability of both CMECs and BLECs, while scCM prevented the OGD-induced vascular leakage in both models. These effects were possibly mediated through the upregulation of junctional proteins and the regulation of MAPK/VEGFR2 activity. Conclusion: Our results suggest that scCM promotes angiogenesis and the maturation of newly formed vessels while restoring the BBB function in ischemic conditions. In conclusion, our results highlight the possibility of using EPC-secretome as a therapeutic alternative to promote brain angiogenesis and protect from ischemia-induced vascular leakage.
Ajuts:	European Commission 764958 Generalitat de Catalunya FI17/00073 Generalitat de Catalunya SLT017/20/000197 Agencia Estatal de Investigación PCIN-2017-090 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-1427 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-765
Nota:	This work has been supported under the Euronanomed 8th Joint Call-MAGGBRIS collaborative project by grants from the Spanish Ministry of Science and Innovation (PCIN-2017-090) the French national agency (ANR-ANR-17-ENM3-0005-01), the AC17/00004 grant from Instituto Carlos III (ISCIII) with FEDR funds, and the National Centre for Research and Development (NCBR 15/EuronanoMed/2018). A part of this study has been also funded in the frame of the NANOSTEM project, a Marie Skłodowska-Curie Innovative Training Network (ITN) by receiving grant from the European Union's Horizon 2020 research and innovation programme under grant agreement No. 764958 and the Expression of Interest (EoI) for Collaborative Projects on Regenerative Medicine 2019 P-CMR[C]), and the programs 2017-SGR-1427 and 2017-SGR-765 from the Generalitat de Cataluny. Alba Grayston is supported by the fellowship FI17/00073 from ISCIII with FEDR funds. Miguel Garcia-Gabilondo is supported by the PERIS grant SLT017/20/000197 from Generalitat de Cataluny. The mass spectrometer of the Spectrométrie de Masse de l'Artois (SMART) facilities used in this study was funded by the European Regional Development Fund (ERDF), the Hauts-de-France regional council, and the Université d'Artois (France).
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	Stem cell research & therapy, Vol. 12 Núm. 1 (december 2021) , p. 552, ISSN 1757-6512

DOI: 10.1186/s13287-021-02608-y
PMID: 34702368

23 p, 12.8 MB

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