Skip to main content
SpringerLink
Log in

Using Stem Cell-Derived Microvesicles in Regenerative Medicine: A New Paradigm for Cell-Based-Cell-Free Therapy

  • Chapter
  • First Online:
Stem Cell Drugs - A New Generation of Biopharmaceuticals

Part of the book series: Stem Cells in Clinical Applications ((SCCA))

  • 593 Accesses

Abstract

The current advances in the field of stem cell-based therapies have paved the way for these novel treatments to enter clinical trials. Among them, mesenchymal stem cell (MSC) based therapies have offered an important potential modality of regenerative medicine and immunotherapy. MSCs are multipotent/pluripotent fibroblast-like cells that exist in almost all tissues and have the potential to differentiate into various cell types from all three germ layers (i.e., ectoderm, mesoderm, and endoderm). The regenerative ability of MSCs might be attributed to their paracrine actions on neighboring host cells rather than a trans-differentiation into the tissue specific cells. These paracrine factors are contained in endosomal derived extracellular microvesicles (EVs), which are released at the site of injury, where they secrete large quantities of bioactive factors like proteins, mRNAs, and miRNAs with anti-inflammatory, antioxidant, trophic, antiapoptotic, and angiogenic effects. Recent findings, however, have demonstrated remarkable therapeutic effects and regenerative potential of MSC-derived EVs showing that conditioned media from stem cell cultures can produce similar efficacious effects compared to those observed for cells. In line with these findings, in a series of experiments our research teams have demonstrated that MSC-derived EVs served as trophic shuttles for enhancing sperm quality parameters and reducing complications of multiple sclerosis. As a bilipid membrane vesicle with many membrane-bound proteins and a diverse cargo, exosomes represents an ideal therapeutic agent that have the potential to home and target tissues and treat complicated diseases such as cardiovascular injuries, chemotherapy side effects, infertility, and MS. In this chapter, the latest evidence on the beneficial effects of the stem cell-derived EVs is explored to support the development of clinical grade bioproducts as new GMP-based cell-free regenerative medicines in tissue regeneration.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Ardeshiry Lajimi A, Hagh MF, Saki N, Mortaz E, Soleimani M, Rahim F (2013) Feasibility of cell therapy in multiple sclerosis: a systematic review of 83 studies. Int J Hematol Oncol Stem Cell Res 7(1):15–33

    PubMed  PubMed Central  Google Scholar 

  • Aurora AB, Olson EN (2014) Immune modulation of stem cells and regeneration. Cell Stem Cell 15(1):14–25

    Article  CAS  Google Scholar 

  • Ballios BG, van der Kooy D (2010) Biology and therapeutic potential of adult retinal stem cells. Can J Ophthalmol 45(4):342–351

    Article  Google Scholar 

  • Barkho BZ, Zhao X (2011) Adult neural stem cells: response to stroke injury and potential for therapeutic applications. Curr Stem Cell Res Ther 6(4):327–338

    Article  CAS  Google Scholar 

  • Baulch JE, Acharya MM, Allen BD, Ru N, Chmielewski NN, Martirosian V, Giedzinski E, Syage A, Park AL, Benke SN et al (2016) Cranial grafting of stem cell-derived microvesicles improves cognition and reduces neuropathology in the irradiated brain. Proc Natl Acad Sci U S A 113(17):4836–4841

    Article  CAS  Google Scholar 

  • Bi XY, Huang S, Chen JL, Wang F, Wang Y, Guo ZK (2014) [Exploration of conditions for releasing microvesicle from human bone marrow mesenchymal stem cells]. Zhongguo Shi Yan Xue Ye Xue Za Zhi 22(2):491–495

    Google Scholar 

  • Biancone L, Bruno S, Deregibus MC, Tetta C, Camussi G (2012) Therapeutic potential of mesenchymal stem cell-derived microvesicles. Nephrol Dial Transplant 27(8):3037–3042

    Article  CAS  Google Scholar 

  • Bobis-Wozowicz S, Kmiotek K, Sekula M, Kedracka-Krok S, Kamycka E, Adamiak M, Jankowska U, Madetko-Talowska A, Sarna M, Bik-Multanowski M et al (2015) Human induced pluripotent stem cell-derived microvesicles transmit RNAs and proteins to recipient mature heart cells modulating cell fate and behavior. Stem Cells (Dayton, Ohio) 33(9):2748–2761

    Article  CAS  Google Scholar 

  • Broxmeyer HE (2011) Insights into the biology of cord blood stem/progenitor cells. Cell Prolif 44(Suppl 1):55–59

    Article  Google Scholar 

  • Bruno S, Camussi G (2013) Role of mesenchymal stem cell-derived microvesicles in tissue repair. Pediatr Nephrol (Berlin, Germany) 28(12):2249–2254

    Article  Google Scholar 

  • Bruno S, Grange C, Deregibus MC, Calogero RA, Saviozzi S, Collino F, Morando L, Busca A, Falda M, Bussolati B et al (2009) Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. J Am Soc Nephrol 20(5):1053–1067

    Article  CAS  Google Scholar 

  • Cabrera CM, Cobo F, Nieto A, Concha A (2006) Strategies for preventing immunologic rejection of transplanted human embryonic stem cells. Cytotherapy 8(5):517–518

    Article  CAS  Google Scholar 

  • Camussi G, Deregibus MC, Cantaluppi V (2013) Role of stem-cell-derived microvesicles in the paracrine action of stem cells. Biochem Soc Trans 41(1):283–287

    Article  CAS  Google Scholar 

  • Chen JY, An R, Liu ZJ, Wang JJ, Chen SZ, Hong MM, Liu JH, Xiao MY, Chen YF (2014) Therapeutic effects of mesenchymal stem cell-derived microvesicles on pulmonary arterial hypertension in rats. Acta Pharmacol Sin 35(9):1121–1128

    Article  CAS  Google Scholar 

  • Choumerianou DM, Dimitriou H, Kalmanti M (2008) Stem cells: promises versus limitations. Tissue Eng Part B Rev 14(1):53–60

    Article  CAS  Google Scholar 

  • Dorronsoro A, Robbins PD (2013) Regenerating the injured kidney with human umbilical cord mesenchymal stem cell-derived exosomes. Stem Cell Res Ther 4(2):39

    Article  Google Scholar 

  • Drommelschmidt K, Serdar M, Bendix I, Herz J, Bertling F, Prager S, Keller M, Ludwig AK, Duhan V, Radtke S et al (2017) Mesenchymal stem cell-derived extracellular vesicles ameliorate inflammation-induced preterm brain injury. Brain Behav Immun 60:220–232

    Article  CAS  Google Scholar 

  • Ebrahimi A, Rahim F (2014) Recent immunomodulatory strategies in transplantation. Immunol Investig 43(8):829–837

    Article  CAS  Google Scholar 

  • Ebrahimi A, Hosseini SA, Rahim F (2014) Immunosuppressive therapy in allograft transplantation: from novel insights and strategies to tolerance and challenges. Cent Eur J Immunol 39(3):400–409

    Article  CAS  Google Scholar 

  • Farber DB, Katsman D (2016) Embryonic stem cell-derived microvesicles: could they be used for retinal regeneration? Adv Exp Med Biol 854:563–569

    Article  CAS  Google Scholar 

  • Farsad K (2002) Exosomes: novel organelles implicated in immunomodulation and apoptosis. Yale J Biol Med 75(2):95–101

    CAS  PubMed  PubMed Central  Google Scholar 

  • Favaro E, Carpanetto A, Lamorte S, Fusco A, Caorsi C, Deregibus MC, Bruno S, Amoroso A, Giovarelli M, Porta M et al (2014) Human mesenchymal stem cell-derived microvesicles modulate T cell response to islet antigen glutamic acid decarboxylase in patients with type 1 diabetes. Diabetologia 57(8):1664–1673

    Article  CAS  Google Scholar 

  • Fonsato V, Collino F, Herrera MB, Cavallari C, Deregibus MC, Cisterna B, Bruno S, Romagnoli R, Salizzoni M, Tetta C et al (2012) Human liver stem cell-derived microvesicles inhibit hepatoma growth in SCID mice by delivering antitumor microRNAs. Stem Cells (Dayton, Ohio) 30(9):1985–1998

    Article  CAS  Google Scholar 

  • Herrera MB, Fonsato V, Gatti S, Deregibus MC, Sordi A, Cantarella D, Calogero R, Bussolati B, Tetta C, Camussi G (2010) Human liver stem cell-derived microvesicles accelerate hepatic regeneration in hepatectomized rats. J Cell Mol Med 14(6b):1605–1618

    Article  CAS  Google Scholar 

  • Jaimes Y, Naaldijk Y, Wenk K, Leovsky C, Emmrich F (2017) Mesenchymal stem cell-derived microvesicles modulate lipopolysaccharides-induced inflammatory responses to microglia cells. Int J Cancer 35(3):812–823

    CAS  Google Scholar 

  • Ji Y, Ma Y, Chen X, Ji X, Gao J, Zhang L, Ye K, Qiao F, Dai Y, Wang H et al (2017) Microvesicles released from human embryonic stem cell derived-mesenchymal stem cells inhibit proliferation of leukemia cells. Oncol Rep 38(2):1013–1020

    Article  Google Scholar 

  • Kang HS, Choi SH, Kim BS, Choi JY, Park G-B, Kwon TG, Chun SY (2015) Advanced properties of urine derived stem cells compared to adipose tissue derived stem cells in terms of cell proliferation, immune modulation and multi differentiation. J Korean Med Sci 30(12):1764–1776

    Article  CAS  Google Scholar 

  • Karlsson T, Lundholm M, Widmark A, Persson E (2016) Tumor cell-derived exosomes from the prostate cancer cell line TRAMP-C1 impair osteoclast formation and differentiation. PLoS One 11(11):e0166284

    Article  Google Scholar 

  • Katsman D, Stackpole EJ, Domin DR, Farber DB (2012) Embryonic stem cell-derived microvesicles induce gene expression changes in Muller cells of the retina. PLoS One 7(11):e50417

    Article  CAS  Google Scholar 

  • Kugler J, Huhse B, Tralau T, Luch A (2017) Embryonic stem cells and the next generation of developmental toxicity testing. Expert Opin Drug Metab Toxicol 13(8):833–841

    Article  CAS  Google Scholar 

  • Lai RC, Arslan F, Lee MM, Sze NS, Choo A, Chen TS, Salto-Tellez M, Timmers L, Lee CN, El Oakley RM et al (2010) Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res 4(3):214–222

    Article  CAS  Google Scholar 

  • Li X, Liu L, Chai J (2015) [Progress of mesenchymal stem cell-derived exosomes in tissue repair]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi, 29(2):234–238

    Google Scholar 

  • Li J, Luo H, Dong X, Liu Q, Wu C, Zhang T, Hu X, Zhang Y, Song B, Li L (2017) Therapeutic effect of urine-derived stem cells for protamine/lipopolysaccharide-induced interstitial cystitis in a rat model. Stem Cell Res Ther 8(1):107

    Article  Google Scholar 

  • Lin SS, Zhu B, Guo ZK, Huang GZ (2014a) [Protective effect of bone marrow mesenchymal stem cell-derived microvesicles on glutamate injured PC12 cells]. Zhongguo Shi Yan Xue Ye Xue Za Zhi 22(4):1078–1083

    Google Scholar 

  • Lin SS, Zhu B, Guo ZK, Huang GZ, Wang Z, Chen J, Wei XJ, Li Q (2014b) Bone marrow mesenchymal stem cell-derived microvesicles protect rat pheochromocytoma PC12 cells from glutamate-induced injury via a PI3K/Akt dependent pathway. Neurochem Res 39(5):922–931

    Article  CAS  Google Scholar 

  • Liu J, Kuwabara A, Kamio Y, Hu S, Park J, Hashimoto T, Lee JW (2016) Human mesenchymal stem cell-derived microvesicles prevent the rupture of intracranial aneurysm in part by suppression of mast cell activation via a PGE2-dependent mechanism. Stem Cells (Dayton, Ohio) 34(12):2943–2955

    Article  CAS  Google Scholar 

  • Lopez-Verrilli MA, Caviedes A, Cabrera A, Sandoval S, Wyneken U, Khoury M (2016) Mesenchymal stem cell-derived exosomes from different sources selectively promote neuritic outgrowth. Neuroscience 320:129–139

    Article  CAS  Google Scholar 

  • Lunn JS, Sakowski SA, Hur J, Feldman EL (2011) Stem cell technology for neurodegenerative diseases. Ann Neurol 70(3):353–361

    Article  CAS  Google Scholar 

  • Mokarizadeh A, Delirezh N, Morshedi A, Mosayebi G, Farshid AA, Mardani K (2012) Microvesicles derived from mesenchymal stem cells: potent organelles for induction of tolerogenic signaling. Immunol Lett 147(1–2):47–54

    Article  CAS  Google Scholar 

  • Mokarizadeh A, Rezvanfar MA, Dorostkar K, Abdollahi M (2013) Mesenchymal stem cell derived microvesicles: trophic shuttles for enhancement of sperm quality parameters. Reprod Toxicol (Elmsford, NY) 42:78–84

    Article  CAS  Google Scholar 

  • Monsel A, Zhu YG, Gennai S, Hao Q, Hu S, Rouby JJ, Rosenzwajg M, Matthay MA, Lee JW (2015) Therapeutic effects of human mesenchymal stem cell-derived microvesicles in severe pneumonia in mice. Am J Respir Crit Care Med 192(3):324–336

    Article  CAS  Google Scholar 

  • Monsel A, Zhu YG, Gudapati V, Lim H, Lee JW (2016) Mesenchymal stem cell derived secretome and extracellular vesicles for acute lung injury and other inflammatory lung diseases. Expert Opin Biol Ther 16(7):859–871

    Article  CAS  Google Scholar 

  • Moore C, Kosgodage U, Lange S, Inal JM (2017) The emerging role of exosome and microvesicle- (EMV-) based cancer therapeutics and immunotherapy. Int J Cancer 141(3):428–436

    Article  CAS  Google Scholar 

  • Muraro PA, Martin R, Mancardi GL, Nicholas R, Sormani MP, Saccardi R (2017) Autologous haematopoietic stem cell transplantation for treatment of multiple sclerosis. Nat Rev Neurol 13(7):391–405

    Article  CAS  Google Scholar 

  • Nargesi AA, Lerman LO, Eirin A (2017) Mesenchymal stem cell-derived extracellular vesicles for renal repair. Curr Gene Ther 17(1):29–42

    Article  CAS  Google Scholar 

  • Outka G (2009) The ethics of embryonic stem cell research and the principle of “nothing is lost”. Yale J Health Policy Law Ethics 9(Suppl):585–602

    PubMed  Google Scholar 

  • Penna V, Lipay MV, Duailibi MT, Duailibi SE (2015) The likely role of proteolytic enzymes in unwanted differentiation of stem cells in culture. Future Sci OA 1(3):Fso28

    Article  Google Scholar 

  • Podbielska M, Banik NL, Kurowska E, Hogan EL (2013) Myelin recovery in multiple sclerosis: the challenge of remyelination. Brain Sci 3(3):1282–1324

    Article  Google Scholar 

  • Rahim F, Allahmoradi H, Salari F, Shahjahani M, Fard AD, Hosseini SA, Mousakhani H (2013) Evaluation of signaling pathways involved in gamma-globin gene induction using fetal hemoglobin inducer drugs. Int J Hematol Oncol Stem Cell Res 7(3):41–46

    PubMed  PubMed Central  Google Scholar 

  • Raisi A, Azizi S, Delirezh N, Heshmatian B, Farshid AA, Amini K (2014) The mesenchymal stem cell-derived microvesicles enhance sciatic nerve regeneration in rat: a novel approach in peripheral nerve cell therapy. J Trauma Acute Care Surg 76(4):991–997

    Article  Google Scholar 

  • Ratajczak J, Miekus K, Kucia M, Zhang J, Reca R, Dvorak P, Ratajczak MZ (2006) Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery. Leukemia 20(5):847–856

    Article  CAS  Google Scholar 

  • Razmkhah F, Soleimani M, Mehrabani D, Karimi MH, Kafi-Abad SA (2015) Leukemia cell microvesicles promote survival in umbilical cord blood hematopoietic stem cells. EXCLI J 14:423–429

    PubMed  PubMed Central  Google Scholar 

  • Razmkhah F, Soleimani M, Mehrabani D, Karimi MH, Amini Kafi-Abad S, Ramzi M, Iravani Saadi M, Kakoui J (2017) Leukemia microvesicles affect healthy hematopoietic stem cells. Tumour Biol 39(2):1010428317692234

    Article  Google Scholar 

  • Riazifar M, Pone EJ, Lotvall J, Zhao W (2017) Stem cell extracellular vesicles: extended messages of regeneration. Annu Rev Pharmacol Toxicol 57:125–154

    Article  CAS  Google Scholar 

  • Saki N, Jalalifar MA, Soleimani M, Hajizamani S, Rahim F (2013) Adverse effect of high glucose concentration on stem cell therapy. Int J Hematol Oncol Stem Cell Res 7(3):34–40

    PubMed  PubMed Central  Google Scholar 

  • Sargent A, Bai L, Shano G, Karl M, Garrison E, Ranasinghe L, Planchon SM, Cohen J, Miller RH (2017) CNS disease diminishes the therapeutic functionality of bone marrow mesenchymal stem cells. Exp Neurol 295:222–232

    Article  CAS  Google Scholar 

  • Shahrabi S, Azizidoost S, Shahjahani M, Rahim F, Ahmadzadeh A, Saki N (2014) New insights in cellular and molecular aspects of BM niche in chronic myelogenous leukemia. Tumour Biol 35(11):10627–10633

    Article  CAS  Google Scholar 

  • Sideri A, Neokleous N, Brunet De La Grange P, Guerton B, Le Bousse Kerdilles MC, Uzan G, Peste-Tsilimidos C, Gluckman E (2011) An overview of the progress on double umbilical cord blood transplantation. Haematologica 96(8):1213–1220

    Article  Google Scholar 

  • Tian S, Liu Q, Gnatovskiy L, Ma PX, Wang Z (2015) Heart regeneration with embryonic cardiac progenitor cells and cardiac tissue engineering. J Stem Cell Transplant Biol 1(1):104

    PubMed  PubMed Central  Google Scholar 

  • Tweedell KS (2017) The adaptability of somatic stem cells: a review. J Stem Cells Regen Med 13(1):3–13

    PubMed  PubMed Central  Google Scholar 

  • Wang Y, Fu B, Sun X, Li D, Huang Q, Zhao W, Chen X (2015) Differentially expressed microRNAs in bone marrow mesenchymal stem cell-derived microvesicles in young and older rats and their effect on tumor growth factor-beta1-mediated epithelial-mesenchymal transition in HK2 cells. Stem Cell Res Ther 6:185

    Article  Google Scholar 

  • Wankhade UD, Shen M, Kolhe R, Fulzele S (2016) Advances in adipose-derived stem cells isolation, characterization, and application in regenerative tissue engineering. Stem Cells Int 2016:3206807

    Article  Google Scholar 

  • Wen S, Dooner M, Cheng Y, Papa E, Del Tatto M, Pereira M, Deng Y, Goldberg L, Aliotta J, Chatterjee D et al (2016) Mesenchymal stromal cell-derived extracellular vesicles rescue radiation damage to murine marrow hematopoietic cells. Leukemia 30(11):2221–2231

    Article  CAS  Google Scholar 

  • Xie H, Wang Z, Zhang L, Lei Q, Zhao A, Wang H, Li Q, Chen Z, Zhang W (2016a) Development of an angiogenesis-promoting microvesicle-alginate-polycaprolactone composite graft for bone tissue engineering applications. PeerJ 4:e2040

    Article  Google Scholar 

  • Xie H, Sun L, Zhang L, Liu T, Chen L, Zhao A, Lei Q, Gao F, Zou P, Li Q et al (2016b) Mesenchymal stem cell-derived microvesicles support ex vivo expansion of cord blood-derived CD34(+) Cells. Stem Cells Int 2016:6493241

    PubMed  PubMed Central  Google Scholar 

  • Xie L, Mao M, Zhou L, Jiang B (2016c) Spheroid mesenchymal stem cells and mesenchymal stem cell-derived microvesicles: two potential therapeutic strategies. Stem Cells Dev 25(3):203–213

    Article  CAS  Google Scholar 

  • Yang B, Qiu Y, Zhou N, Ouyang H, Ding J, Cheng B, Sun J (2017) Application of stem cells in oral disease therapy: progresses and perspectives. Front Physiol 8:197

    PubMed  PubMed Central  Google Scholar 

  • Yin H, Jiang H (2015) [Application prospect of stem cell-derived microvesicles in regeneration of injured tissues]. Sheng Wu Yi Xue Gong Cheng Xue Za Zhi 32(3):688–692

    Google Scholar 

  • Yin G, Hu G, Wan R, Yu G, Cang X, Xiong J, Ni J, Hu Y, Xing M, Fan Y et al (2016) Role of microvesicles from bone marrow mesenchymal stem cells in acute pancreatitis. Pancreas 45(9):1282–1293

    Article  Google Scholar 

  • Yu B, Zhang X, Li X (2014) Exosomes derived from mesenchymal stem cells. Int J Mol Sci 15(3):4142–4157

    Article  CAS  Google Scholar 

  • Zhu X, You Y, Li Q, Zeng C, Fu F, Guo A, Zhang H, Zou P, Zhong Z, Wang H et al (2014) BCR-ABL1-positive microvesicles transform normal hematopoietic transplants through genomic instability: implications for donor cell leukemia. Leukemia 28(8):1666–1675

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Toxicology and Diseases, Pharmaceutical Sciences Research Center (PSRC), Tehran University of Medical Sciences (TUMS), Tehran, Iran

    Mohammad Amin Rezvanfar & Mohammad Abdollahi

  2. Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences (TUMS), Tehran, Iran

    Mohammad Abdollahi

  3. Health Research Institute, Research Center of Thalassemia and Hemoglobinopathies, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Fakher Rahim

Authors
  1. Mohammad Amin Rezvanfar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mohammad Abdollahi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fakher Rahim
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Laboratory of Stem Cell Research & Application, University of Science, Vietnam National University, Ho Chi Minh, Vietnam

    Phuc Van Pham

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Rezvanfar, M.A., Abdollahi, M., Rahim, F. (2018). Using Stem Cell-Derived Microvesicles in Regenerative Medicine: A New Paradigm for Cell-Based-Cell-Free Therapy. In: Pham, P. (eds) Stem Cell Drugs - A New Generation of Biopharmaceuticals. Stem Cells in Clinical Applications. Springer, Cham. https://doi.org/10.1007/978-3-319-99328-7_1

Download citation

Publish with us

Policies and ethics

Search

Navigation