Background

Mesenchymal stem (stromal) cells (MSCs) are present in a variety of tissue sources and possess multi-lineage differentiation potential. Due to their angiogenic, anti-apoptotic, regenerative, and immunomodulatory properties, a variety of clinical trials including the work from our team [1] have studied the therapeutic applications of MSCs for a wide range of diseases [2, 3]. More recently, MSCs have been tested for the treatment of coronavirus disease 2019 (COVID-19) [4]. At present, there are two registered studies examining MSC-derived extracellular vesicles (MSC-EVs) as a candidate for treating severe COVID-19 (NCT04491240, NCT04276987) [5]. The beneficial effects of MSCs were originally attributed to their ability to home to the damaged tissues and differentiate into many cell types. However, further studies demonstrated that only a small percentage of the transplanted MSCs actually engrafted in target tissues [6]. Based on the findings that conditioned medium from MSCs mimicked the effects of whole cells, it was proposed that the paracrine-secreted elements from MSCs were accountable for the mechanism [7]. These secreted elements are collectively referred to as secretome, which is composed of cytokines, growth factors, MSC-EVs, etc. [8]. Recent studies demonstrated that MSC-EVs separated from secretome were able to replicate the effects of MSCs, indicating a major role of MSC-EVs in the paracrine mechanism [9]. Potter et al. showed that both MSC-EVs and MSCs attenuated lung vascular permeability in a mouse model of hemorrhagic shock and trauma. However, MSC secretome but not MSC-EVs decreased thrombin-induced endothelial cell permeability in vitro, indicating differences in the molecular mechanisms between MSCs and MSC-EVs [10]. Carreras-Planella et al. reported that the immunomodulatory effect of MSC secretome on B cells was not mediated by MSC-EVs, but rather by protein-enriched fraction [11]. In addition, Mitchell et al. found that MSC secretome and MSC-EVs acted synergistically to stimulate muscle generation in a cardiotoxin-induced muscle injury model [12]. The present review article will describe the general properties of MSC-EVs and mechanisms of macrophage polarization and emphasize the impacts of MSC-EVs on macrophage polarization in diseases of cardiovascular, pulmonary, digestive, renal, and central nervous systems.

Table 1 Studies demonstrating the effects of MSC-EVs on macrophage polarization
Full size table

EVs

EVs are a generic term for membrane-contained particles that are naturally released by the cells and do not contain a functional nucleus according to International Society for Extracellular Vesicles (ISEV) [13]. EVs are traditionally divided into three subtypes based on the vesicle sizes and mechanisms of biogenesis: exosomes (50–150 nm diameter), microvesicles (100–1000 nm diameter), and apoptotic bodies (50–4000 nm diameter). Exosomes are formed after fusion of multivesicular bodies (MVB), a type of late endosomes in the endolysosomal pathway, with the plasma membrane. In contrast, both microvesicles and apoptotic bodies are generated by direct outward budding from the cell surface [14]. However, there is a lack of specific markers or distinctive methodologies to differentiate the three subtypes of EVs as they share overlap** size, density, and membrane proteins [15]. ISEV has now suggested to categorize EVs upon biochemical markers or size such as small EVs (< 100 nm or < 200 nm) and medium/large EVs (> 200 nm) [13].

EVs are produced by almost all types of cells and were originally thought to be a method for cells to dispose unwanted components [16]. They are now increasingly recognized as important mediators of intercellular communication and have opened up a new field of research. EVs are composed of a lipid bilayer containing proteins/peptides, lipids, and genetic material such as mRNA, microRNA (miRNA), and DNA. There are evidences to support that EVs also enclose mitochondria, ribosomes, and proteasomes [17]. These cargoes differ significantly depending on their cell of origin and are selectively sorted into EVs. It is well-established that EVs could exert the effects of parental cells via transfer of miRNA and functional proteins [18]. miRNAs are single-stranded and non-coding RNAs with 19–24 nucleotide in size. It is estimated that miRNAs may regulate up to 30% of protein-encoding genes in mammalian cells [19]. The transferred miRNAs are able to interact with target mRNAs via canonical binding, leading to target degradation or translational repression [20]. The transferred miRNAs can also use a non-canonical pathway through activation of Toll-like receptor 7 (TLR7)/Toll-like receptor-8 (TLR8) to regulate immune responses [21]. The sorting of miRNAs into EVs involves miRNA motifs such as GGCU [22] and the miRNA-associated proteins such as Argonaute 2 and Alix [23]. The sorting of proteins into EVs utilizes endosomal sorting complex required for transport (ESCRT)-dependent machinery as well as ESCRT-independent pathway [24].

MSC-EVs

MSC-EVs display both characteristic surface markers for MSCs (CD29, CD73, and CD105) and classical markers for EVs (CD63, CD9 and CD81) [25]. MSC-EVs acquired from different sources have similar therapeutic effects, indicating comparable compositions of diverse EVs [26]. By comparison of proteomics of published MSC-EVs, a specific protein signature was identified with 22 members, involving functions such as cell adhesion [27]. However, a consensus miRNA signature among MSC-EVs from different sources has not been reported. Transfer of miRNAs and functional proteins from MSC-EVs to target cells has been reported as the mechanisms underlying the beneficial effects. For example, MSC-EVs transferred miR-223 to cardiomyocytes, resulting in downregulation of proinflammatory genes in a mouse model of polymicrobial sepsis [28]. Uptake of EVs from MSCs with miRNA-181-5p overexpression by hepatic stellate cells ameliorated liver fibrosis via activation of autophagy in mice [29]. In addition, treatment of stroke rats with MSC-EVs enriched with miR-17–92 cluster promoted functional recovery of brain via targeting PTEN [61]. The hypoxia inducible factors (HIF) played differential roles in macrophage polarization with HIF-1α promoting the inducible nitric oxide synthase and M1 state and HIF-2α enhancing arginase 1 expression and the M2 state [62]. Additionally, Krüppel-like factor 4 (KLF4) and KLF2 promoted M2 polarization by coordinating with STAT6 and inhibiting the NF-κB/HIF-1α functions, respectively [63, 64]. Furthermore, peroxisome proliferator-activated receptor γ (PPARγ), another transcription factor, skewed M2 phenotype and regulated genes in oxidative metabolism by inhibiting NF-κB and AP-1 pathways [65].

miRNAs are able to regulate M1 and M2 macrophage polarization at the post-transcriptional level by targeting various transcription factors and adaptor proteins. In M1-polarized macrophages induced by LPS plus IFN-γ treatment, the expression of miR-181a, miR-155, miR-204, and miR-451 was upregulated, whereas the levels of miR-146a, miR-143, and miR-145 were downregulated compared with M2 polarized macrophages treated with IL-4 [66]. Thulin et al. documented that miR-9 skewed M1 polarization by targeting nuclear receptor PPARδ, resulting in inhibition of PPARδ activity and thereby preventing the B cell lymphoma-6 (BCL-6)-mediated anti-inflammatory effects [67]. Ying et al. reported that miR-127 targeted BCL-6 and downregulated its expression, which augmented the activation of c-Jun N-terminal kinase (JNK) and the development of M1 macrophages [

Availability of data and materials

Not applicable.

Abbreviations

EVs:

Extracellular vesicles

MSCs:

Mesenchymal stem (stromal) cells

MSC-EVs:

MSC-derived EVs

COVID-19:

Coronavirus disease 2019

ISEV:

International Society for Extracellular Vesicles

miRNA:

MicroRNA

MVB:

Multivesicular bodies

TLR:

Toll-like receptor

IFN-γ:

Interferon gamma

TNF-α:

Tumor necrosis factor alpha

ESCRT:

Endosomal sorting complex required for transport

EMMPRIN:

Extracellular matrix metalloproteinase inducer

MHC:

Major histocompatibility complex

TGF-β:

Transforming growth factor beta

IL-1RA:

IL-1 receptor antagonist

STAT1:

Signal transducer and activator of transcription 1

NF-κB:

Nuclear factor-κB

LPS:

Lipopolysaccharide

HIF:

Hypoxia inducible factor

KLF4:

Krüppel-like factor 4

PPAR:

Peroxisome proliferator-activated receptor

BCL-6:

B cell lymphoma-6

JNK:

c-Jun N-terminal kinase

IRF4:

Interferon regulatory factor 4

C/EBP:

CCAAT/enhancer binding protein

SOCS1:

Suppressor of cytokine signaling 1

ERK:

Extracellular signal-regulated kinase

HMGA2:

High-mobility group A2

NFKB1:

Nuclear factor kappa B subunit 1

LPS/GalN:

Lipopolysaccharide and D-galactosamine

NLRP3:

NOD-, LRR- and pyrin domain-containing protein 3

CCR2:

C-C motif chemokine receptor-2

CCL2:

C-C motif chemokine ligand 2

References

  1. Zheng G, Huang L, Tong H, Shu Q, Hu Y, Ge M, Deng K, Zhang L, Zou B, Cheng B, Xu J. Treatment of acute respiratory distress syndrome with allogeneic adipose-derived mesenchymal stem cells: a randomized, placebo-controlled pilot study. Respir Res. 2014;15:39.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Florea V, Rieger AC, DiFede DL, El-Khorazaty J, Natsumeda M, Banerjee MN, Tompkins BA, Khan A, Schulman IH, Landin AM, et al. Dose comparison study of allogeneic mesenchymal stem cells in patients with ischemic cardiomyopathy (the TRIDENT study). Circ Res. 2017;121:1279–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Smets F, Dobbelaere D, McKiernan P, Dionisi-Vici C, Broue P, Jacquemin E, Lopes AI, Goncalves I, Mandel H, Pawlowska J, et al. Phase I/II trial of liver derived mesenchymal stem cells in pediatric liver based metabolic disorders: a prospective, open label, multicenter, partially randomized, safety study of one cycle of heterologous human adult liver-derived progenitor cells (HepaStem(R)) in urea cycle disorders and Crigler-Najjar syndrome patients. Transplantation. 2019;103:1903–15.

  4. Leng Z, Zhu R, Hou W, Feng Y, Yang Y, Han Q, Shan G, Meng F, Du D, Wang S, et al. Transplantation of ACE2(-) mesenchymal stem cells improves the outcome of patients with COVID-19 pneumonia. Aging Dis. 2020;11:216–28.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Tsuchiya A, Takeuchi S, Iwasawa T, Kumagai M, Sato T, Motegi S, Ishii Y, Koseki Y, Tomiyoshi K, Natsui K, et al. Therapeutic potential of mesenchymal stem cells and their exosomes in severe novel coronavirus disease 2019 (COVID-19) cases. Inflamm Regen. 2020;40:14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Gao J, Dennis JE, Muzic RF, Lundberg M, Caplan AI. The dynamic in vivo distribution of bone marrow-derived mesenchymal stem cells after infusion. Cells Tissues Organs. 2001;169:12–20.

    Article  CAS  PubMed  Google Scholar 

  7. Gnecchi M, He H, Liang OD, Melo LG, Morello F, Mu H, Noiseux N, Zhang L, Pratt RE, Ingwall JS, Dzau VJ. Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nat Med. 2005;11:367–8.

    Article  CAS  PubMed  Google Scholar 

  8. Eleuteri S, Fierabracci A. Insights into the secretome of mesenchymal stem cells and its potential applications. Int J Mol Sci. 2019;20.

  9. Nooshabadi VT, Mardpour S, Yousefi-Ahmadipour A, Allahverdi A, Izadpanah M, Daneshimehr F, Ai J, Banafshe HR, Ebrahimi-Barough S. The extracellular vesicles-derived from mesenchymal stromal cells: a new therapeutic option in regenerative medicine. J Cell Biochem. 2018.

  10. Potter DR, Miyazawa BY, Gibb SL, Deng X, Togaratti PP, Croze RH, Srivastava AK, Trivedi A, Matthay M, Holcomb JB, et al. Mesenchymal stem cell-derived extracellular vesicles attenuate pulmonary vascular permeability and lung injury induced by hemorrhagic shock and trauma. J Trauma Acute Care Surg. 2018;84:245–56.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Carreras-Planella L, Monguio-Tortajada M, Borras FE, Franquesa M. Immunomodulatory effect of MSC on B cells is independent of secreted extracellular vesicles. Front Immunol. 2019;10:1288.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Mitchell R, Mellows B, Sheard J, Antonioli M, Kretz O, Chambers D, Zeuner MT, Tomkins JE, Denecke B, Musante L, et al. Secretome of adipose-derived mesenchymal stem cells promotes skeletal muscle regeneration through synergistic action of extracellular vesicle cargo and soluble proteins. Stem Cell Res Ther. 2019;10:116.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Thery C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, Andriantsitohaina R, Antoniou A, Arab T, Archer F, Atkin-Smith GK, et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles. 2018;7:1535750.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Hessvik NP, Llorente A. Current knowledge on exosome biogenesis and release. Cell Mol Life Sci. 2018;75:193–208.

    Article  CAS  PubMed  Google Scholar 

  15. Holm MM, Kaiser J, Schwab ME. Extracellular vesicles: multimodal envoys in neural maintenance and repair. Trends Neurosci. 2018.

  16. Yanez-Mo M, Siljander PR, Andreu Z, Zavec AB, Borras FE, Buzas EI, Buzas K, Casal E, Cappello F, Carvalho J, et al. Biological properties of extracellular vesicles and their physiological functions. J Extracell Vesicles. 2015;4:27066.

    Article  PubMed  Google Scholar 

  17. Islam MN, Das SR, Emin MT, Wei M, Sun L, Westphalen K, Rowlands DJ, Quadri SK, Bhattacharya S, Bhattacharya J. Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat Med. 2012;18:759–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Qiu G, Zheng G, Ge M, Wang J, Huang R, Shu Q, Xu J. Mesenchymal stem cell-derived extracellular vesicles affect disease outcomes via transfer of microRNAs. Stem Cell Res Ther. 2018;9:320.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–97.

    Article  CAS  PubMed  Google Scholar 

  20. Gregory RI, Chendrimada TP, Cooch N, Shiekhattar R. Human RISC couples microRNA biogenesis and posttranscriptional gene silencing. Cell. 2005;123:631–40.

    Article  CAS  PubMed  Google Scholar 

  21. Bayraktar R, Bertilaccio MTS, Calin GA. The interaction between two worlds: microRNAs and toll-like receptors. Front Immunol. 2019;10:1053.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Santangelo L, Giurato G, Cicchini C, Montaldo C, Mancone C, Tarallo R, Battistelli C, Alonzi T, Weisz A, Tripodi M. The RNA-binding protein SYNCRIP is a component of the hepatocyte exosomal machinery controlling microRNA sorting. Cell Rep. 2016;17:799–808.

    Article  CAS  PubMed  Google Scholar 

  23. Iavello A, Frech VS, Gai C, Deregibus MC, Quesenberry PJ, Camussi G. Role of Alix in miRNA packaging during extracellular vesicle biogenesis. Int J Mol Med. 2016;37:958–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hurley JH. ESCRTs are everywhere. EMBO J. 2015;34:2398–407.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. T LR, Sanchez-Abarca LI, Muntion S, Preciado S, Puig N, Lopez-Ruano G, Hernandez-Hernandez A, Redondo A, Ortega R, Rodriguez C, et al: MSC surface markers (CD44, CD73, and CD90) can identify human MSC-derived extracellular vesicles by conventional flow cytometry. Cell Commun Signal 2016, 14:2.

  26. Willis GR, Fernandez-Gonzalez A, Anastas J, Vitali SH, Liu X, Ericsson M, Kwong A, Mitsialis SA, Kourembanas S. Mesenchymal stromal cell exosomes ameliorate experimental bronchopulmonary dysplasia and restore lung function through macrophage immunomodulation. Am J Respir Crit Care Med. 2018;197:104–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. van Balkom BWM, Gremmels H, Giebel B, Lim SK. Proteomic signature of mesenchymal stromal cell-derived small extracellular vesicles. Proteomics. 2019;19:e1800163.

    Article  PubMed  CAS  Google Scholar 

  28. Wang X, Gu H, Qin D, Yang L, Huang W, Essandoh K, Wang Y, Caldwell CC, Peng T, Zingarelli B, Fan GC. Exosomal miR-223 contributes to mesenchymal stem cell-elicited Cardioprotection in Polymicrobial Sepsis. Sci Rep. 2015;5:13721.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Qu Y, Zhang Q, Cai X, Li F, Ma Z, Xu M, Lu L. Exosomes derived from miR-181-5p-modified adipose-derived mesenchymal stem cells prevent liver fibrosis via autophagy activation. J Cell Mol Med. 2017;21:2491–502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. **n H, Katakowski M, Wang F, Qian JY, Liu XS, Ali MM, Buller B, Zhang ZG, Chopp M. MicroRNA cluster miR-17-92 cluster in exosomes enhance neuroplasticity and functional recovery after stroke in rats. Stroke. 2017;48:747–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Vrijsen KR, Maring JA, Chamuleau SA, Verhage V, Mol EA, Deddens JC, Metz CH, Lodder K, van Eeuwijk EC, van Dommelen SM, et al. Exosomes from cardiomyocyte progenitor cells and mesenchymal stem cells stimulate angiogenesis via EMMPRIN. Adv Healthc Mater. 2016;5:2555–65.

    Article  CAS  PubMed  Google Scholar 

  32. Iglesias DM, El-Kares R, Taranta A, Bellomo F, Emma F, Besouw M, Levtchenko E, Toelen J, van den Heuvel L, Chu L, et al. Stem cell microvesicles transfer cystinosin to human cystinotic cells and reduce cystine accumulation in vitro. PLoS One. 2012;7:e42840.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Shigemoto-Kuroda T, Oh JY, Kim DK, Jeong HJ, Park SY, Lee HJ, Park JW, Kim TW, An SY, Prockop DJ, Lee RH. MSC-derived extracellular vesicles attenuate immune responses in two autoimmune murine models: type 1 diabetes and uveoretinitis. Stem Cell Reports. 2017;8:1214–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Bruno S, Grange C, Deregibus MC, Calogero RA, Saviozzi S, Collino F, Morando L, Busca A, Falda M, Bussolati B, et al. Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. J Am Soc Nephrol. 2009;20:1053–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Zhu YG, Feng XM, Abbott J, Fang XH, Hao Q, Monsel A, Qu JM, Matthay MA, Lee JW. Human mesenchymal stem cell microvesicles for treatment of Escherichia coli endotoxin-induced acute lung injury in mice. Stem Cells. 2014;32:116–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Conforti A, Scarsella M, Starc N, Giorda E, Biagini S, Proia A, Carsetti R, Locatelli F, Bernardo ME. Microvescicles derived from mesenchymal stromal cells are not as effective as their cellular counterpart in the ability to modulate immune responses in vitro. Stem Cells Dev. 2014;23:2591–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Silva JD, de Castro LL, Braga CL, Oliveira GP, Trivelin SA, Barbosa-Junior CM, Morales MM, Dos Santos CC, Weiss DJ, Lopes-Pacheco M, et al. Mesenchymal stromal cells are more effective than their extracellular vesicles at reducing lung injury regardless of acute respiratory distress syndrome etiology. Stem Cells Int. 2019;2019:8262849.

    PubMed  PubMed Central  Google Scholar 

  38. Ben-David U, Mayshar Y, Benvenisty N. Large-scale analysis reveals acquisition of lineage-specific chromosomal aberrations in human adult stem cells. Cell Stem Cell. 2011;9:97–102.

    Article  CAS  PubMed  Google Scholar 

  39. Sensebe L, Tarte K, Galipeau J, Krampera M, Martin I, Phinney DG, Shi Y. Therapy MSCCotISfC: limited acquisition of chromosomal aberrations in human adult mesenchymal stromal cells. Cell Stem Cell. 2012;10:9–10 author reply 10-11.

    Article  CAS  PubMed  Google Scholar 

  40. Tarte K, Gaillard J, Lataillade JJ, Fouillard L, Becker M, Mossafa H, Tchirkov A, Rouard H, Henry C, Splingard M, et al. Clinical-grade production of human mesenchymal stromal cells: occurrence of aneuploidy without transformation. Blood. 2010;115:1549–53.

    Article  CAS  PubMed  Google Scholar 

  41. Biswas S, Mandal G, Roy Chowdhury S, Purohit S, Payne KK, Anadon C, Gupta A, Swanson P, Yu X, Conejo-Garcia JR, Bhattacharyya A. Exosomes produced by mesenchymal stem cells drive differentiation of myeloid cells into immunosuppressive M2-polarized macrophages in breast cancer. J Immunol. 2019;203:3447–60.

    Article  CAS  PubMed  Google Scholar 

  42. Wen S, Dooner M, Papa E, Del Tatto M, Pereira M, Borgovan T, Cheng Y, Goldberg L, Liang O, Camussi G, Quesenberry P. Biodistribution of mesenchymal stem cell-derived extracellular vesicles in a radiation injury bone marrow murine model. Int J Mol Sci. 2019;20.

  43. Gholamrezanezhad A, Mirpour S, Bagheri M, Mohamadnejad M, Alimoghaddam K, Abdolahzadeh L, Saghari M, Malekzadeh R. In vivo tracking of 111In-oxine labeled mesenchymal stem cells following infusion in patients with advanced cirrhosis. Nucl Med Biol. 2011;38:961–7.

    Article  CAS  PubMed  Google Scholar 

  44. Gao X, **ong Y, Li Q, Han M, Shan D, Yang G, Zhang S, **n D, Zhao R, Wang Z, et al. Extracellular vesicle-mediated transfer of miR-21-5p from mesenchymal stromal cells to neurons alleviates early brain injury to improve cognitive function via the PTEN/Akt pathway after subarachnoid hemorrhage. Cell Death Dis. 2020;11:363.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Yu B, Kim HW, Gong M, Wang J, Millard RW, Wang Y, Ashraf M, Xu M. Exosomes secreted from GATA-4 overexpressing mesenchymal stem cells serve as a reservoir of anti-apoptotic microRNAs for cardioprotection. Int J Cardiol. 2015;182:349–60.

    Article  PubMed  Google Scholar 

  46. Domenis R, Cifu A, Quaglia S, Pistis C, Moretti M, Vicario A, Parodi PC, Fabris M, Niazi KR, Soon-Shiong P, Curcio F. Pro inflammatory stimuli enhance the immunosuppressive functions of adipose mesenchymal stem cells-derived exosomes. Sci Rep. 2018;8:13325.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Zhu LP, Tian T, Wang JY, He JN, Chen T, Pan M, Xu L, Zhang HX, Qiu XT, Li CC, et al. Hypoxia-elicited mesenchymal stem cell-derived exosomes facilitates cardiac repair through miR-125b-mediated prevention of cell death in myocardial infarction. Theranostics. 2018;8:6163–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kink JA, Forsberg MH, Reshetylo S, Besharat S, Childs CJ, Pederson JD, Gendron-Fitzpatrick A, Graham M, Bates PD, Schmuck EG, et al. Macrophages educated with exosomes from primed mesenchymal stem cells treat acute radiation syndrome by promoting hematopoietic recovery. Biol Blood Marrow Transplant. 2019;25:2124–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Haraszti RA, Miller R, Stoppato M, Sere YY, Coles A, Didiot MC, Wollacott R, Sapp E, Dubuke ML, Li X, et al. Exosomes produced from 3D cultures of MSCs by tangential flow filtration show higher yield and improved activity. Mol Ther. 2018;26:2838–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008;8:958–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Xue J, Schmidt SV, Sander J, Draffehn A, Krebs W, Quester I, De Nardo D, Gohel TD, Emde M, Schmidleithner L, et al. Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity. 2014;40:274–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Mills CD, Kincaid K, Alt JM, Heilman MJ, Hill AM. M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol. 2000;164:6166–73.

    Article  CAS  PubMed  Google Scholar 

  53. Curtale G, Rubino M, Locati M. MicroRNAs as molecular switches in macrophage activation. Front Immunol. 2019;10:799.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S, Gordon S, Hamilton JA, Ivashkiv LB, Lawrence T, et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity. 2014;41:14–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Muraille E, Leo O, Moser M. TH1/TH2 paradigm extended: macrophage polarization as an unappreciated pathogen-driven escape mechanism? Front Immunol. 2014;5:603.

    PubMed  PubMed Central  Google Scholar 

  56. Colin S, Chinetti-Gbaguidi G, Staels B. Macrophage phenotypes in atherosclerosis. Immunol Rev. 2014;262:153–66.

    Article  CAS  PubMed  Google Scholar 

  57. Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004;25:677–86.

    Article  CAS  PubMed  Google Scholar 

  58. Wang LX, Zhang SX, Wu HJ, Rong XL, Guo J. M2b macrophage polarization and its roles in diseases. J Leukoc Biol. 2019;106:345–58.

    Article  CAS  PubMed  Google Scholar 

  59. Toshchakov V, Jones BW, Perera PY, Thomas K, Cody MJ, Zhang S, Williams BR, Major J, Hamilton TA, Fenton MJ, Vogel SN. TLR4, but not TLR2, mediates IFN-beta-induced STAT1alpha/beta-dependent gene expression in macrophages. Nat Immunol. 2002;3:392–8.

    Article  CAS  PubMed  Google Scholar 

  60. Porta C, Rimoldi M, Raes G, Brys L, Ghezzi P, Di Liberto D, Dieli F, Ghisletti S, Natoli G, De Baetselier P, et al. Tolerance and M2 (alternative) macrophage polarization are related processes orchestrated by p50 nuclear factor kappaB. Proc Natl Acad Sci U S A. 2009;106:14978–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Lang R, Patel D, Morris JJ, Rutschman RL, Murray PJ. Sha** gene expression in activated and resting primary macrophages by IL-10. J Immunol. 2002;169:2253–63.

    Article  CAS  PubMed  Google Scholar 

  62. Takeda N, O'Dea EL, Doedens A, Kim JW, Weidemann A, Stockmann C, Asagiri M, Simon MC, Hoffmann A, Johnson RS. Differential activation and antagonistic function of HIF-{alpha} isoforms in macrophages are essential for NO homeostasis. Genes Dev. 2010;24:491–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Liao X, Sharma N, Kapadia F, Zhou G, Lu Y, Hong H, Paruchuri K, Mahabeleshwar GH, Dalmas E, Venteclef N, et al. Kruppel-like factor 4 regulates macrophage polarization. J Clin Invest. 2011;121:2736–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Mahabeleshwar GH, Kawanami D, Sharma N, Takami Y, Zhou G, Shi H, Nayak L, Jeyaraj D, Grealy R, White M, et al. The myeloid transcription factor KLF2 regulates the host response to polymicrobial infection and endotoxic shock. Immunity. 2011;34:715–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature. 1998;391:79–82.

    Article  CAS  PubMed  Google Scholar 

  66. Zhang Y, Zhang M, Zhong M, Suo Q, Lv K. Expression profiles of miRNAs in polarized macrophages. Int J Mol Med. 2013;31:797–802.

    Article  CAS  PubMed  Google Scholar 

  67. Thulin P, Wei T, Werngren O, Cheung L, Fisher RM, Grander D, Corcoran M, Ehrenborg E. MicroRNA-9 regulates the expression of peroxisome proliferator-activated receptor delta in human monocytes during the inflammatory response. Int J Mol Med. 2013;31:1003–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Ying H, Kang Y, Zhang H, Zhao D, **a J, Lu Z, Wang H, Xu F, Shi L. MiR-127 modulates macrophage polarization and promotes lung inflammation and injury by activating the JNK pathway. J Immunol. 2015;194:1239–51.

    Article  CAS  PubMed  Google Scholar 

  69. Chaudhuri AA, So AY, Sinha N, Gibson WS, Taganov KD, O'Connell RM, Baltimore D. MicroRNA-125b potentiates macrophage activation. J Immunol. 2011;187:5062–8.

    Article  CAS  PubMed  Google Scholar 

  70. Arranz A, Doxaki C, Vergadi E, Martinez de la Torre Y, Vaporidi K, Lagoudaki ED, Ieronymaki E, Androulidaki A, Venihaki M, Margioris AN, et al: Akt1 and Akt2 protein kinases differentially contribute to macrophage polarization. Proc Natl Acad Sci U S A 2012, 109:9517–9522.

  71. Xu F, Kang Y, Zhang H, Piao Z, Yin H, Diao R, **a J, Shi L. Akt1-mediated regulation of macrophage polarization in a murine model of Staphylococcus aureus pulmonary infection. J Infect Dis. 2013;208:528–38.

    Article  CAS  PubMed  Google Scholar 

  72. Vergadi E, Vaporidi K, Theodorakis EE, Doxaki C, Lagoudaki E, Ieronymaki E, Alexaki VI, Helms M, Kondili E, Soennichsen B, et al. Akt2 deficiency protects from acute lung injury via alternative macrophage activation and miR-146a induction in mice. J Immunol. 2014;192:394–406.

    Article  CAS  PubMed  Google Scholar 

  73. Zhuang G, Meng C, Guo X, Cheruku PS, Shi L, Xu H, Li H, Wang G, Evans AR, Safe S, et al. A novel regulator of macrophage activation: miR-223 in obesity-associated adipose tissue inflammation. Circulation. 2012;125:2892–903.

    Article  CAS  PubMed  Google Scholar 

  74. Banerjee S, **e N, Cui H, Tan Z, Yang S, Icyuz M, Abraham E, Liu G. MicroRNA let-7c regulates macrophage polarization. J Immunol. 2013;190:6542–9.

    Article  CAS  PubMed  Google Scholar 

  75. Saha B, Bruneau JC, Kodys K, Szabo G. Alcohol-induced miR-27a regulates differentiation and M2 macrophage polarization of normal human monocytes. J Immunol. 2015;194:3079–87.

    Article  CAS  PubMed  Google Scholar 

  76. Spinosa M, Lu G, Su G, Bontha SV, Gehrau R, Salmon MD, Smith JR, Weiss ML, Mas VR, Upchurch GR, Jr., Sharma AK: Human mesenchymal stromal cell-derived extracellular vesicles attenuate aortic aneurysm formation and macrophage activation via microRNA-147. FASEB J 2018:fj201701138RR.

  77. Lv K, Li Q, Zhang L, Wang Y, Zhong Z, Zhao J, Lin X, Wang J, Zhu K, **ao C, et al. Incorporation of small extracellular vesicles in sodium alginate hydrogel as a novel therapeutic strategy for myocardial infarction. Theranostics. 2019;9:7403–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Xu R, Zhang F, Chai R, Zhou W, Hu M, Liu B, Chen X, Liu M, Xu Q, Liu N, Liu S. Exosomes derived from pro-inflammatory bone marrow-derived mesenchymal stem cells reduce inflammation and myocardial injury via mediating macrophage polarization. J Cell Mol Med. 2019;23:7617–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Sun X, Shan A, Wei Z, Xu B. Intravenous mesenchymal stem cell-derived exosomes ameliorate myocardial inflammation in the dilated cardiomyopathy. Biochem Biophys Res Commun. 2018;503:2611–8.

    Article  CAS  PubMed  Google Scholar 

  80. Zhao J, Li X, Hu J, Chen F, Qiao S, Sun X, Gao L, **e J, Xu B. Mesenchymal stromal cell-derived exosomes attenuate myocardial ischaemia-reperfusion injury through miR-182-regulated macrophage polarization. Cardiovasc Res. 2019;115:1205–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Li J, Xue H, Li T, Chu X, **n D, **ong Y, Qiu W, Gao X, Qian M, Xu J, et al. Exosomes derived from mesenchymal stem cells attenuate the progression of atherosclerosis in ApoE(-/-) mice via miR-let7 mediated infiltration and polarization of M2 macrophage. Biochem Biophys Res Commun. 2019;510:565–72.

    Article  CAS  PubMed  Google Scholar 

  82. Morrison TJ, Jackson MV, Cunningham EK, Kissenpfennig A, McAuley DF, O'Kane CM, Krasnodembskaya AD. Mesenchymal stromal cells modulate macrophages in clinically relevant lung injury models by extracellular vesicle mitochondrial transfer. Am J Respir Crit Care Med. 2017;196:1275–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Li JW, Wei L, Han Z, Chen Z. Mesenchymal stromal cells-derived exosomes alleviate ischemia/reperfusion injury in mouse lung by transporting anti-apoptotic miR-21-5p. Eur J Pharmacol. 2019;852:68–76.

    Article  CAS  PubMed  Google Scholar 

  84. Wang J, Huang R, Xu Q, Zheng G, Qiu G, Ge M, Shu Q, Xu J. Mesenchymal stem cell-derived extracellular vesicles alleviate acute lung injury via transfer of miR-27a-3p. Crit Care Med. 2020.

  85. Huang R, Qin C, Wang J, Hu Y, Zheng G, Qiu G, Ge M, Tao H, Shu Q, Xu J. Differential effects of extracellular vesicles from aging and young mesenchymal stem cells in acute lung injury. Aging (Albany NY). 2019;11:7996–8014.

    Article  CAS  Google Scholar 

  86. Deng H, Wu L, Liu M, Zhu L, Chen Y, Zhou H, Shi X, Wei J, Zheng L, Hu X, et al. Bone marrow mesenchymal stem cell-derived exosomes attenuate LPS-induced ARDS by modulating macrophage polarization through inhibiting glycolysis in macrophages. Shock. 2020.

  87. Monsel A, Zhu YG, Gennai S, Hao Q, Hu S, Rouby JJ, Rosenzwajg M, Matthay MA, Lee JW. Therapeutic effects of human mesenchymal stem cell-derived microvesicles in severe pneumonia in mice. Am J Respir Crit Care Med. 2015;192:324–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Phinney DG, Di Giuseppe M, Njah J, Sala E, Shiva S, St Croix CM, Stolz DB, Watkins SC, Di YP, Leikauf GD, et al. Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs. Nat Commun. 2015;6:8472.

    Article  CAS  PubMed  Google Scholar 

  89. Mittal M, Tiruppathi C, Nepal S, Zhao YY, Grzych D, Soni D, Prockop DJ, Malik AB. TNFalpha-stimulated gene-6 (TSG6) activates macrophage phenotype transition to prevent inflammatory lung injury. Proc Natl Acad Sci U S A. 2016;113:E8151–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Chaubey S, Thueson S, Ponnalagu D, Alam MA, Gheorghe CP, Aghai Z, Singh H, Bhandari V. Early gestational mesenchymal stem cell secretome attenuates experimental bronchopulmonary dysplasia in part via exosome-associated factor TSG-6. Stem Cell Res Ther. 2018;9:173.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Lee C, Mitsialis SA, Aslam M, Vitali SH, Vergadi E, Konstantinou G, Sdrimas K, Fernandez-Gonzalez A, Kourembanas S. Exosomes mediate the cytoprotective action of mesenchymal stromal cells on hypoxia-induced pulmonary hypertension. Circulation. 2012;126:2601–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Klinger JR, Pereira M, Del Tatto M, Brodsky AS, Wu KQ, Dooner MS, Borgovan T, Wen S, Goldberg LR, Aliotta JM, et al. Mesenchymal stem cell extracellular vesicles reverse sugen/hypoxia pulmonary hypertension in rats. Am J Respir Cell Mol Biol. 2020;62:577–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Liu Y, Lou G, Li A, Zhang T, Qi J, Ye D, Zheng M, Chen Z. AMSC-derived exosomes alleviate lipopolysaccharide/d-galactosamine-induced acute liver failure by miR-17-mediated reduction of TXNIP/NLRP3 inflammasome activation in macrophages. EBioMedicine. 2018;36:140–50.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Ohara M, Ohnishi S, Hosono H, Yamamoto K, Yuyama K, Nakamura H, Fu Q, Maehara O, Suda G, Sakamoto N. Extracellular vesicles from amnion-derived mesenchymal stem cells ameliorate hepatic inflammation and fibrosis in rats. Stem Cells Int. 2018;2018:3212643.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Zhang S, Jiang L, Hu H, Wang H, Wang X, Jiang J, Ma Y, Yang J, Hou Y, **e D, Zhang Q. Pretreatment of exosomes derived from hUCMSCs with TNF-alpha ameliorates acute liver failure by inhibiting the activation of NLRP3 in macrophage. Life Sci. 2020;246:117401.

    Article  CAS  PubMed  Google Scholar 

  96. Lu FB, Chen DZ, Chen L, Hu ED, Wu JL, Li H, Gong YW, Lin Z, Wang XD, Li J, et al. Attenuation of experimental autoimmune hepatitis in mice with bone mesenchymal stem cell-derived exosomes carrying MicroRNA-223-3p. Mol Cells. 2019;42:906–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Cao L, Xu H, Wang G, Liu M, Tian D, Yuan Z. Extracellular vesicles derived from bone marrow mesenchymal stem cells attenuate dextran sodium sulfate-induced ulcerative colitis by promoting M2 macrophage polarization. Int Immunopharmacol. 2019;72:264–74.

    Article  CAS  PubMed  Google Scholar 

  98. An JH, Li Q, Ryu MO, Nam AR, Bhang DH, Jung YC, Song WJ, Youn HY. TSG-6 in extracellular vesicles from canine mesenchymal stem/stromal is a major factor in relieving DSS-induced colitis. PLoS One. 2020;15:e0220756.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Eirin A, Zhu XY, Puranik AS, Tang H, McGurren KA, van Wijnen AJ, Lerman A, Lerman LO. Mesenchymal stem cell-derived extracellular vesicles attenuate kidney inflammation. Kidney Int. 2017;92:114–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Song T, Eirin A, Zhu X, Zhao Y, Krier JD, Tang H, Jordan KL, Woollard JR, Taner T, Lerman A, Lerman LO. Mesenchymal stem cell-derived extracellular vesicles induce regulatory T cells to ameliorate chronic kidney injury. Hypertension. 2020;75:1223–32.

    Article  CAS  PubMed  Google Scholar 

  101. Shen B, Liu J, Zhang F, Wang Y, Qin Y, Zhou Z, Qiu J, Fan Y. CCR2 positive exosome released by mesenchymal stem cells suppresses macrophage functions and alleviates ischemia/reperfusion-induced renal injury. Stem Cells Int. 2016;2016:1240301.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Liu W, Rong Y, Wang J, Zhou Z, Ge X, Ji C, Jiang D, Gong F, Li L, Chen J, et al. Exosome-shuttled miR-216a-5p from hypoxic preconditioned mesenchymal stem cells repair traumatic spinal cord injury by shifting microglial M1/M2 polarization. J Neuroinflammation. 2020;17:47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Sun G, Li G, Li D, Huang W, Zhang R, Zhang H, Duan Y. Wang B: hucMSC derived exosomes promote functional recovery in spinal cord injury mice via attenuating inflammation. Mater Sci Eng C Mater Biol Appl. 2018;89:194–204.

    Article  CAS  PubMed  Google Scholar 

  104. Li Y, Yang YY, Ren JL, Xu F, Chen FM, Li A. Exosomes secreted by stem cells from human exfoliated deciduous teeth contribute to functional recovery after traumatic brain injury by shifting microglia M1/M2 polarization in rats. Stem Cell Res Ther. 2017;8:198.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Go V, Bowley BGE, Pessina MA, Zhang ZG, Chopp M, Finklestein SP, Rosene DL, Medalla M, Buller B, Moore TL. Extracellular vesicles from mesenchymal stem cells reduce microglial-mediated neuroinflammation after cortical injury in aged Rhesus monkeys. Geroscience. 2020;42:1–17.

    Article  CAS  PubMed  Google Scholar 

  106. Lankford KL, Arroyo EJ, Nazimek K, Bryniarski K, Askenase PW, Kocsis JD. Intravenously delivered mesenchymal stem cell-derived exosomes target M2-type macrophages in the injured spinal cord. PLoS One. 2018;13:e0190358.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Yang HC, Zhang M, Wu R, Zheng HQ, Zhang LY, Luo J, Li LL, Hu XQ. C-C chemokine receptor type 2-overexpressing exosomes alleviated experimental post-stroke cognitive impairment by enhancing microglia/macrophage M2 polarization. World J Stem Cells. 2020;12:152–67.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Shi Z, Wang Q, Jiang D. Extracellular vesicles from bone marrow-derived multipotent mesenchymal stromal cells regulate inflammation and enhance tendon healing. J Transl Med. 2019;17:211.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Shen H, Yoneda S, Abu-Amer Y, Guilak F, Gelberman RH. Stem cell-derived extracellular vesicles attenuate the early inflammatory response after tendon injury and repair. J Orthop Res. 2020;38:117–27.

    Article  CAS  PubMed  Google Scholar 

  110. Henao Agudelo JS, Braga TT, Amano MT, Cenedeze MA, Cavinato RA, Peixoto-Santos AR, Muscara MN, Teixeira SA, Cruz MC, Castoldi A, et al. Mesenchymal stromal cell-derived microvesicles regulate an internal pro-inflammatory program in activated macrophages. Front Immunol. 2017;8:881.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Song Y, Dou H, Li X, Zhao X, Li Y, Liu D, Ji J, Liu F, Ding L, Ni Y, Hou Y. Exosomal miR-146a contributes to the enhanced therapeutic efficacy of interleukin-1beta-primed mesenchymal stem cells against Sepsis. Stem Cells. 2017;35:1208–21.

    Article  CAS  PubMed  Google Scholar 

  112. Ti D, Hao H, Tong C, Liu J, Dong L, Zheng J, Zhao Y, Liu H, Fu X, Han W. LPS-preconditioned mesenchymal stromal cells modify macrophage polarization for resolution of chronic inflammation via exosome-shuttled let-7b. J Transl Med. 2015;13:308.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Lo Sicco C, Reverberi D, Balbi C, Ulivi V, Principi E, Pascucci L, Becherini P, Bosco MC, Varesio L, Franzin C, et al. Mesenchymal stem cell-derived extracellular vesicles as mediators of anti-inflammatory effects: endorsement of macrophage polarization. Stem Cells Transl Med. 2017;6:1018–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported by the National Natural Science Foundation of China (81671956, 81701944, 81772122), the Zhejiang Provincial Program for the Cultivation of High-level Innovative Health Talents (2016-6), and Health Commission of Zhejiang Province (grant No. 2020KY335).

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  1. The Children’s Hospital of Zhejiang University School of Medicine and National Clinical Research Center for Child Health, 3333 Binsheng Road, Hangzhou, 310051, Zhejiang, China

    Jiangmei Wang, Jie **a, Ruoqiong Huang, Yaoqin Hu, Jiajie Fan, Qiang Shu & Jianguo Xu

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  3. Ruoqiong Huang
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JW, QS, and J Xu contributed to the concept of the review. JW, J **a, RH, YH, JF, QS, and J Xu were responsible for reference selection and writing of the manuscript. JW, QS, and J Xu contributed to critical review of the manuscript. All authors read and approved the final manuscript.

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Wang, J., **a, J., Huang, R. et al. Mesenchymal stem cell-derived extracellular vesicles alter disease outcomes via endorsement of macrophage polarization. Stem Cell Res Ther 11, 424 (2020). https://doi.org/10.1186/s13287-020-01937-8

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