In:
PLOS Biology, Public Library of Science (PLoS), Vol. 19, No. 4 ( 2021-4-7), p. e3001166-
Abstract:
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 are 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 with conserved membrane potential and respiration. We found that the transfer of these mitochondria from EVs to mtDNA-deficient L929 Rho 0 cells rescued mitochondrial function and increased Rho 0 cell survival. Furthermore, the incorporation of mitochondria from EVs into inflammatory mononuclear 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 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.
Type of Medium:
Online Resource
ISSN:
1545-7885
DOI:
10.1371/journal.pbio.3001166
DOI:
10.1371/journal.pbio.3001166.g001
DOI:
10.1371/journal.pbio.3001166.g002
DOI:
10.1371/journal.pbio.3001166.g003
DOI:
10.1371/journal.pbio.3001166.g004
DOI:
10.1371/journal.pbio.3001166.g005
DOI:
10.1371/journal.pbio.3001166.g006
DOI:
10.1371/journal.pbio.3001166.g007
DOI:
10.1371/journal.pbio.3001166.g008
DOI:
10.1371/journal.pbio.3001166.g009
DOI:
10.1371/journal.pbio.3001166.s001
DOI:
10.1371/journal.pbio.3001166.s002
DOI:
10.1371/journal.pbio.3001166.s003
DOI:
10.1371/journal.pbio.3001166.s004
DOI:
10.1371/journal.pbio.3001166.s005
DOI:
10.1371/journal.pbio.3001166.s006
DOI:
10.1371/journal.pbio.3001166.s007
DOI:
10.1371/journal.pbio.3001166.s008
DOI:
10.1371/journal.pbio.3001166.s009
DOI:
10.1371/journal.pbio.3001166.s010
DOI:
10.1371/journal.pbio.3001166.s011
DOI:
10.1371/journal.pbio.3001166.r001
DOI:
10.1371/journal.pbio.3001166.r002
DOI:
10.1371/journal.pbio.3001166.r003
DOI:
10.1371/journal.pbio.3001166.r004
DOI:
10.1371/journal.pbio.3001166.r005
DOI:
10.1371/journal.pbio.3001166.r006
DOI:
10.1371/journal.pbio.3001166.r007
DOI:
10.1371/journal.pbio.3001166.r008
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2021
detail.hit.zdb_id:
2126773-X
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