RT Journal Article
SR Electronic
T1 Neural stem cells traffic functional mitochondria via extracellular vesicles to correct mitochondrial dysfunction in target cells
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.01.29.923441
DO 10.1101/2020.01.29.923441
A1 Luca Peruzzotti-Jametti
A1 Joshua D. Bernstock
A1 Giulia Manferrari
A1 Rebecca Rogall
A1 Erika Fernandez-Vizarra
A1 James C Williamson
A1 Alice Braga
A1 Aletta van den Bosch
A1 Tommaso Leonardi
A1 Ágnes Kittel
A1 Cristiane Benincá
A1 Nunzio Vicario
A1 Sisareuth Tan
A1 Carlos Bastos
A1 Iacopo Bicci
A1 Nunzio Iraci
A1 Jayden A. Smith
A1 Paul J Lehner
A1 Edit Iren Buzas
A1 Nuno Faria
A1 Massimo Zeviani
A1 Christian Frezza
A1 Alain Brisson
A1 Nicholas J Matheson
A1 Carlo Viscomi
A1 Stefano Pluchino
YR 2020
UL http://biorxiv.org/content/early/2020/01/29/2020.01.29.923441.abstract
AB Neural stem cell (NSC) transplantation induces recovery in animal models of central nervous system (CNS) diseases. Although the replacement of lost endogenous cells was originally proposed as the primary healing mechanism of NSC grafts, it is now clear that transplanted NSCs operate via multiple mechanisms, including the horizontal exchange of therapeutic cargoes to host cells via extracellular vesicles (EVs).EVs are membrane particles trafficking nucleic acids, proteins, metabolites and metabolic enzymes, lipids and entire organelles. However, the function and the contribution of these cargoes to the broad therapeutic effects of NSCs is yet to be fully understood. Mitochondrial dysfunction is an established feature of several inflammatory and degenerative CNS disorders, most of which are potentially treatable with exogenous stem cell therapeutics.Herein we investigated the hypothesis that NSCs release and traffic functional mitochondria via EVs to restore mitochondrial function in target cells.Untargeted proteomics revealed a significant enrichment of mitochondrial proteins spontaneously released by NSCs in EVs. Morphological and functional analyses confirmed the presence of ultrastructurally intact mitochondria within EVs (Mito-EVs) with conserved membrane potential and respiration. We found that the transfer of Mito-EVs to mtDNA-deficient L929 Rho0 cells rescued mitochondrial function and increased Rho0 cell survival. Furthermore, the incorporation of Mito-EVs into inflammatory professional phagocytes restored normal mitochondrial dynamics and cellular metabolism and reduced the expression of pro-inflammatory markers in target cells. When transplanted in an animal model of multiple sclerosis, exogenous NSCs actively transferred mitochondria to mononuclear phagocytes and induced a significant amelioration of clinical deficits.Our data provide the first evidence that NSCs deliver functional mitochondria to target cells via Mito-EVs, paving the way for the development of novel (a)cellular approaches aimed at restoring mitochondrial dysfunction not only in multiple sclerosis, but also in degenerative neurological diseases.