Journal
STEM CELL RESEARCH & THERAPY
Volume 12, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s13287-021-02608-y
Keywords
Endothelial progenitor cells; Secretome; Blood-brain barrier; Stroke; Angiogenesis; Cell therapy; Cardiovascular disease; Regenerative medicine
Funding
- Spanish Ministry of Science and Innovation [PCIN-2017-090]
- French national agency [ANR-ANR-17ENM3-0005-01, AC17/00004]
- Instituto Carlos III (ISCIII) with FEDR funds
- National Centre for Research and Development [NCBR 15/EuronanoMed/2018]
- NANOSTEM project
- Marie Sklodowska-Curie Innovative Training Network (ITN)
- European Union's Horizon 2020 research and innovation programme [764958]
- Expression of Interest (EoI) for Collaborative Projects on Regenerative Medicine 2019 P-CMR[C]
- ISCIII [FI17/00073]
- PERIS grant [SLT017/20/000197]
- European Regional Development Fund (ERDF)
- Hauts-de-France regional council
- Universite d'Artois (France)
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The secretome of endothelial progenitor cells from stroke patients (scCM) promotes angiogenesis, migration, and tubulogenesis of endothelial cells while protecting the vascular barrier function, suggesting its potential as a therapeutic alternative for ischemic conditions.
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 mu g/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.
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