Neural stem cells traffic functional mitochondria via extracellular vesicles

被引：109

作者：

Peruzzotti-Jametti, Luca ^{[1
,2
]}

Bernstock, Joshua D. ^{[1
,2
,3
]}

Willis, Cory M. ^{[1
,2
]}

Manferrari, Giulia ^{[1
,2
]}

Rogall, Rebecca ^{[1
,2
]}

Fernandez-Vizarra, Erika ^{[4
]}

Williamson, James C. ^{[5
,6
]}

Braga, Alice ^{[1
,2
]}

van den Bosch, Aletta ^{[1
,2
]}

Leonardi, Tommaso ^{[1
,2
,7
]}

Krzak, Grzegorz ^{[1
,2
]}

Kittel, Agnes ^{[8
,9
,10
]}

Beninca, Cristiane ^{[4
]}

Vicario, Nunzio ^{[1
,2
,11
]}

Tan, Sisareuth ^{[1
,2
]}

Bastos, Carlos ^{[13
]}

Bicci, Iacopo ^{[1
,2
]}

Iraci, Nunzio ^{[11
]}

Smith, Jayden A. ^{[14
]}

Peacock, Ben ^{[15
]}

Muller, Karin H. ^{[16
]}

Lehner, Paul J. ^{[5
,6
]}

Buzas, Edit Iren ^{[9
,10
]}

Faria, Nuno ^{[13
]}

Zeviani, Massimo ^{[4
]}

Frezza, Christian ^{[7
,17
]}

Brisson, Alain ^{[1
,2
,12
]}

Matheson, Nicholas J. ^{[18
]}

Viscomi, Carlo ^{[4
]}

Pluchino, Stefano ^{[1
,2
,14
]}

机构：

[1] Univ Cambridge, Dept Clin Neurosci, Cambridge, England

[2] Univ Cambridge, NIHR Biomed Res Ctr, Cambridge, England

[3] Natl Inst Hlth NINDS NIH, Bethesda, MD USA

[4] Univ Cambridge, MRC Mitochondrial Biol Unit, Cambridge, England

[5] Univ Cambridge, Cambridge Inst Therapeut Immunol & Infect Dis CIT, Cambridge, England

[6] NHS Blood & Transplant, Cambridge, England

[7] Ist Italiano Tecnol IIT, Ctr Genom Sci IIT SEMM, Milan, Italy

[8] Semmelweis Univ, Budapest, Hungary

[9] HCEMM Kft HU, Budapest, Hungary

[10] ELKH SE, Budapest, Hungary

[11] Univ Catania, Dept Biomed & Biotechnol Sci BIOMETEC, Catania, Italy

[12] Univ Bordeaux, IPB, CNRS, UMR CBMN, Bordeaux, France

[13] Univ Cambridge, Dept Vet Med, Cambridge, England

[14] Cambridge Innovat Technol Consulting CITC Ltd, Cambridge, England

[15] NanoFCM Co Ltd, Nottingham, England

[16] Cambridge Adv Imaging Ctr CAIC, Cambridge, England

[17] Univ Cambridge, Hutchison MRC Res Ctr, MRC Canc Unit, Cambridge, England

[18] Univ Cambridge, Dept Med, Cambridge, England

来源：

PLOS BIOLOGY | 2021年 / 19卷 / 04期

基金：

英国工程与自然科学研究理事会; 英国生物技术与生命科学研究理事会; 英国惠康基金; 英国医学研究理事会; 欧洲研究理事会;

关键词：

STROMAL CELLS; HIGH-RESOLUTION; TRANSPORT; TRANSPLANTATION; INHIBITOR; MICROGLIA; EXTRUSION; MECHANISM; MITOPHAGY; PLATELETS;

D O I：

10.1371/journal.pbio.3001166

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页数：42

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