title: Retinoic acid-loaded polymeric nanoparticles enhance vascular regulation of neural stem cell survival and differentiation after ischaemia.
abstract: Stroke is one of the leading causes of death and disability worldwide. However, current therapies only reach a small percentage of patients and may cause serious side effects. We propose the therapeutic use of retinoic acid-loaded nanoparticles (RA-NP) to safely and efficiently repair the ischaemic brain by creating a favourable pro-angiogenic environment that enhances neurogenesis and neuronal restitution. Our data showed that RA-NP enhanced endothelial cell proliferation and tubule network formation and protected against ischaemia-induced death. To evaluate the effect of RA-NP on vascular regulation of neural stem cell (NSC) survival and differentiation, endothelial cell-conditioned media (EC-CM) were collected. EC-CM from healthy RA-NP-treated cells reduced NSC death and promoted proliferation while EC-CM from ischaemic RA-NP-treated cells decreased cell death, increased proliferation and neuronal differentiation. In parallel, human endothelial progenitor cells (hEPC), which are part of the endogenous repair response to vascular injury, were collected from ischaemic stroke patients. hEPC treated with RA-NP had significantly higher proliferation, which further highlights the therapeutic potential of this formulation. To conclude, RA-NP protected endothelial cells from ischaemic death and stimulated the release of pro-survival, proliferation-stimulating factors and differentiation cues for NSC. RA-NP were shown to be up to 83-fold more efficient than free RA and to enhance hEPC proliferation. These data serve as a stepping stone to use RA-NP as vasculotrophic and neurogenic agents for vascular disorders and neurodegenerative diseases with compromised vasculature.
authors.affiliation: Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal. raquelmargarida@gmail.com libernardino@gmail.com.
authors.forename: R
authors.initials: R
authors.lastname: Ferreira
authors.affiliation: Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal. raquelmargarida@gmail.com libernardino@gmail.com.
authors.forename: M C
authors.initials: MC
authors.lastname: Fonseca
authors.affiliation: Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal. raquelmargarida@gmail.com libernardino@gmail.com.
authors.forename: T
authors.initials: T
authors.lastname: Santos
authors.affiliation: Stroke Unit, Coimbra University and Hospital Centre, Coimbra, Portugal and Biocant - Center of Innovation in Biotechnology, Cantanhede, Portugal.
authors.forename: J
authors.initials: J
authors.lastname: Sargento-Freitas
authors.affiliation: Stroke Unit, Hospital Center of Cova da Beira, Covilhã, Portugal.
authors.forename: R
authors.initials: R
authors.lastname: Tjeng
authors.affiliation: Stroke Unit, Hospital Center of Cova da Beira, Covilhã, Portugal.
authors.forename: F
authors.initials: F
authors.lastname: Paiva
authors.affiliation: Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal. raquelmargarida@gmail.com libernardino@gmail.com and Hospital Center of Cova da Beira, Covilhã, Portugal.
authors.forename: M
authors.initials: M
authors.lastname: Castelo-Branco
authors.affiliation: Biocant - Center of Innovation in Biotechnology, Cantanhede, Portugal and CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Portugal.
authors.forename: L S
authors.initials: LS
authors.lastname: Ferreira
authors.affiliation: Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal. raquelmargarida@gmail.com libernardino@gmail.com.
authors.forename: L
authors.initials: L
authors.lastname: Bernardino
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry; D006801:Humans; D007511:Ischemia / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D018919:Neovascularization, Physiologic / Q000187:drug effects; D058953:Neural Stem Cells / Q000187:drug effects* / Q000473:pathology*; D055495:Neurogenesis / Q000187:drug effects; D011108:Polymers / Q000737:chemistry; D020521:Stroke / Q000188:drug therapy / Q000473:pathology; D014212:Tretinoin / Q000008:administration & dosage*
chemical_list: D004337:Drug Carriers; D011108:Polymers; D014212:Tretinoin