Skip to main content
SpringerLink
Log in

Exosomes for Regeneration, Rejuvenation, and Repair

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

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

  • 637 Accesses

Abstract

Application of regenerative medicine strategies for repair of organs/tissue negatively affected by wounding and chronic disease is an active area for product development. Such strategies often emphasize the role of stem cells as the active biological ingredient. One could argue that stem cells are necessary for such repair, but are they sufficient? Continuing efforts toward elucidating the mechanism of action of these cell therapies have focused on the role of secreted factors acting at a distance in mediating catalysis of regenerative outcomes in the absence of robust site-specific cell engraftment. A prominent component of this secreted regenerative milieu is exosomes: 40–150 nm membrane bound vesicles that mediate transfer of proteins and nucleic acids across cellular boundaries. Here, we cover recent studies highlighting how cell-based therapeutics and cosmeceutics are transitioning toward the secretome generally and exosomes specifically as a principal modulator of regenerative, rejuvenating, and reparative outcomes.

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

  • Adams SB et al (2014) Stem cell-bearing suture improves Achilles tendon healing in a rat model. Foot Ankle Int 35:293–299

    Article  Google Scholar 

  • Adzick NS, Lorenz HP (1994) Cells, matrix, growth factors and the surgeon. The biology of scarless fetal wound repair. Ann Surg 200:10–18

    Article  Google Scholar 

  • Ahmed MI et al (2014) MicroRNA-214 controls skin and hair follicle development by modulating the activity of the Wnt pathway. J Cell Biol 207:549–567

    Article  CAS  Google Scholar 

  • Akyurekli C et al (2015) A systematic review of preclinical studies on the therapeutic potential of mesenchymal stromal cell-derived microvesicles. Stem Cell Rev 11:150–160

    Article  CAS  Google Scholar 

  • Aliotta JM et al (2012) Stable cell fate changes in marrow cells induced by lung-derived microvesicles. J Extracell Vesicles. https://doi.org/10.3402/jev.v1i0.18163

    Article  CAS  Google Scholar 

  • Basu J (2014) An organ regeneration platform for industrial production of hollow neo-organs, cells and biomaterials in regenerative medicine. www.intechopen.com/books/cells-and-biomaterials-in-regenerative-medicine/an-organ-regeneration-platform-for-industrial-production-of-hollow-neo-organs

  • Basu J, Bertram T (2014) Regenerative medicine of the gastrointestinal tract. Toxicol Pathol 42:82–90

    Article  Google Scholar 

  • Basu J, Ludlow JW (2010) Platform technologies for tubular organ regeneration. Trends Biotechnol 28:526–533

    Article  CAS  Google Scholar 

  • Basu J, Ludlow JW (2011) Tissue engineering of tubular and solid organs: an industry perspective. In: Wislet-Gendebein S (ed) Advances in regenerative medicine. Intech Open, Croatia

    Google Scholar 

  • Basu J, Ludlow JW (2012a) Developmental engineering the kidney: leveraging principles of morphogenesis for renal regeneration. Birth Defects Res C Embryo Today 96:30–38

    Article  CAS  Google Scholar 

  • Basu J, Ludlow JW (2012b) Developments in tissue engineered and regenerative medicine products, a practical approach. Woodhead Publishing, Cambridge, UK

    Book  Google Scholar 

  • Basu J, Ludlow JW (2014) Cell-based therapeutic products: potency assay development and application. Regen Med 9:497–512

    Article  CAS  Google Scholar 

  • Basu J et al (2011a) Regeneration of rodent small intestine tissue following implantation of scaffolds seeded with a novel source of smooth muscle cells. Regen Med 6:721–731

    Article  CAS  Google Scholar 

  • Basu J et al (2011b) Functional evaluation of primary renal cell/biomaterial Neo-Kidney Augment prototypes for renal tissue engineering. Cell Transplant 20:1771–1790

    Article  Google Scholar 

  • Basu J et al (2012a) Regeneration of native like neo-urinary tissue from non-bladder cell sources. Tissue Eng Part A 18:1025–1034

    Article  CAS  Google Scholar 

  • Basu J et al (2012b) Extension of bladder based organ regeneration platform for tissue engineering of esophagus. Med Hypotheses 78:231–234

    Article  Google Scholar 

  • Basu J et al (2013) Tissue engineering of esophagus and small intestine in rodent injury models. Methods Mol Biol 1001:311–324

    Article  CAS  Google Scholar 

  • Basu J et al (2015) MSC sourced exosomes as therapeutic agents for wound healing and skin regeneration: from scaled production to functional regenerative outcomes in vitro and in vivo. International Society for Stem Cell Research Annual Meeting, Stockholm

    Google Scholar 

  • Batagov AO et al (2011) Identification of nucleotide patterns enriched in secreted RNAs as putative cis-acting elements targeting them to exosome nano-vesicles. BMC Genomics 12(Suppl 3):S18

    Article  CAS  Google Scholar 

  • Buck SH et al (2014) Exosomes secreted by nematode parasites transfer small RNAs to mammalian cells and modulate innate immunity. Nat Commun 5:5488

    Article  CAS  Google Scholar 

  • Buckley G et al (2012) Denervation affects regenerative responses in MRL/MpJ and repair in C57BL/6 ear wounds. J Anat 220:3–12

    Article  CAS  Google Scholar 

  • Buschow SI et al (2010) MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis. Immunol Cell Biol 88:851–856

    Article  CAS  Google Scholar 

  • Cadwell JS. Culture of placental derived cells in a hollow fiber bioreactor cartridge. http://fibercellsystems.com/documents/FibercellSystemsPlacental%20Stem%20Cell%20Culture.pdf

  • Campani V et al (2014) Development of a liposome based formulation for vitamin K1 nebulization on the skin. Int J Nanomedicine 9:1823–1832

    PubMed  PubMed Central  Google Scholar 

  • Caplan AI, Correa D (2011) The MSC: an injury drugstore. Cell Stem Cell 9:11–15

    Article  CAS  Google Scholar 

  • Chen TS et al (2011) Enabling a robust scalable manufacturing process for therapeutic exosomes through oncogenic immortalization of human ESC-derived MSCs. J Transl Med 9:47

    Article  CAS  Google Scholar 

  • Chen CC et al (2014) Regenerative hair waves in aging mice and extra-follicular modulators Follistatin, Dkk1 and Sfrp4. J Invest Dermatol 134:2086–2096

    Article  CAS  Google Scholar 

  • Dai S et al (2008) Phase I clinical trial of autologous ascites-derived exosomes combined with GM-CSF for colorectal cancer. Mol Ther 16:782–790

    Article  CAS  Google Scholar 

  • Danilchik M et al (2013) Blastocoel spanning filopodia in cleavage stage Xenopus laevis: potential roles in morphogen distribution and detection. Dev Biol 382:70–81

    Article  CAS  Google Scholar 

  • Deregibus MC et al (2007) Endothelial progenitor cell derived microvesicles activate an angiogenic program in endothelial cells by a horizontal transfer of mRNA. Blood 110:2440–2448

    Article  CAS  Google Scholar 

  • Escudier B et al (2005) Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived-exosomes: results of the first Phase I clinical trial. J Transl Med 3:10

    Article  Google Scholar 

  • Fleury A et al (2014) Extracellular vesicles as therapeutic tools in cardiovascular diseases. Front Immunol 5:370

    Article  Google Scholar 

  • Fukuoka H, Suga H (2015) Hair regeneration treatment using adipose-derived stem cell conditioned medium: follow-up with trichograms. Eplasty 15:e10

    PubMed  PubMed Central  Google Scholar 

  • Garcia-Contreras M et al (2014) Therapeutic potential of human adipose-derived stem cells (ADSCs) from cancer patients: a pilot study. PLoS One:e113288

    Article  Google Scholar 

  • Genheimer G et al (2012) Molecular characterization of the regenerative response induced by intrarenal transplantation of selected renal cells in a rodent model of chronic kidney disease. Cells Tissues Organs 196:374–384

    Article  CAS  Google Scholar 

  • Gibbings DJ et al (2009) Multivesicular bodies associate with components of miRNA effector complexes and modulate miRNA activity. Nat Cell Biol 11:1143–1149

    Article  CAS  Google Scholar 

  • Gimona M et al (2017) Manufacturing of human extracellular vesicle-based therapeutics for clinical use. Int J Mol Sci 18(6). https://doi.org/10.3390/ijms18061190

    Article  Google Scholar 

  • Godwin JW et al (2013) Macrophages are required for adult salamander limb regeneration. Proc Natl Acad Sci U S A 110:9415–9420

    Article  CAS  Google Scholar 

  • Gould SJ, Raposo G (2013) As we wait: coping with an imperfect nomenclature for extracellular vesicles. J Extracell Vesicles 2. https://doi.org/10.3402/jev.v2i0.20389

    Article  Google Scholar 

  • Greco V et al (2001) Argosomes: a potential vehicle for the spread of morphogens through epithelia. Cell 5:633–645

    Article  Google Scholar 

  • Gupta A, Pulliam L (2014) Exosomes as mediators of neuroinflammation. J Neuroinflammation 11:68

    Article  Google Scholar 

  • Guthrie K et al (2013) Potency evaluation of tissue engineered and regenerative medicine products. Trends Biotechnol 31:505–514

    Article  CAS  Google Scholar 

  • Harn HJ et al (2013) Rejuvenation of aged pig facial skin by transplanting allogeneic granulocyte colony stimulating factor induced peripheral blood stem cells from a young pig. Cell Transplant 22:755–765

    Article  Google Scholar 

  • Hu L et al (2016) Exosomes derived from human adipose mensenchymal stem cells accelerates cutaneous wound healing via optimizing the characteristics of fibroblasts. Sci Rep 6:32993

    Article  CAS  Google Scholar 

  • Ibrahim AG et al (2014) Exosomes as critical agents of cardiac regeneration triggered by cell therapy. Stem Cell Rep 2:606–619

    Article  CAS  Google Scholar 

  • Irion U, St Johnston D (2007) bicoid RNA localization requires specific binding of an endosomal sorting complex. Nature 445:554–558

    Article  CAS  Google Scholar 

  • Jeong D et al (2014) Nanovesicles engineered from ES cells for enhanced cell proliferation. Biomaterials 35:9302–9310

    Article  CAS  Google Scholar 

  • Jo W et al (2014) Large-scale generation of cell-derived nanovesicles. Nanoscale 6:12056–12064

    Article  CAS  Google Scholar 

  • Johnstone RM (1992) The Jeanne Manery-Fisher Memorial Lecture 1991. Maturation of reticulocytes: formation of exosomes as a mechanism for shedding membrane proteins. Biochem Cell Biol 70:179–190

    Article  CAS  Google Scholar 

  • Johnstone RM et al (1987) Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J Biol Chem 262:9412–9420

    CAS  Google Scholar 

  • Justewicz DM et al (2012) Characterization of the human smooth muscle cell secretome for regenerative medicine. Tissue Eng Part C Methods 18:797–816

    Article  CAS  Google Scholar 

  • Kilpinen L et al (2013) Extracellular membrane vesicles from umbilical cord blood derived MSC protect against ischemic acute kidney injury, a feature that is lost after inflammatory conditioning. J Extracell Vesicles. https://doi.org/10.3402/jev.v2i0.21927

    Article  Google Scholar 

  • Kim WS et al (2009) Antiwrinkle effect of adipose-derived stem cell: activation of dermal fibroblast by secretory factors. J Dermatol Sci 53:96–102

    Article  CAS  Google Scholar 

  • Kooijmans SA et al (2012) Exosome mimetics: a novel class of drug delivery systems. Int J Nanomedicine 7:1525–1541

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lamichhane TN et al (2015) Emerging roles for extracellular vesicles in tissue engineering and regenerative medicine. Tissue Eng B Rev 21:45–54

    Article  CAS  Google Scholar 

  • Lane RE et al (2015) Analysis of exosome purification methods using a model liposome system and tunable-resistive pulse sensing. Sci Rep 5:7639

    Article  Google Scholar 

  • Lee C et al (2012) Exosomes mediate the cytoprotective action of mesenchymal stromal cells on hypoxia induced pulmonary hypertension. Circulation 126:2601–2611

    Article  CAS  Google Scholar 

  • Lee HJ et al (2014) Efficacy of microneedling plus human stem cell conditioned medium for skin rejuvenation: a randomized, controlled, blinded split face study. Ann Dermatol 26:584–591

    Article  Google Scholar 

  • Lener T et al (2015 Dec 31) Applying extracellular vesicles based therapeutics in clinical trials - an ISEV position paper. J Extracell Vesicles 4:30087

    Article  Google Scholar 

  • Li M et al (2015) Mesenchymal stem cell-conditioned medium improves the proliferation and migration of keratinocytes in a diabetes-like microenvironment. Int J Low Extrem Wounds 14:73

    Article  CAS  Google Scholar 

  • Liegeouis S et al (2006) The V0-ATPase mediates apical secretion of exosomes containing Hedgehog-related proteins in Caenorhabditis elegans. J Cell Biol 173:949–961

    Article  Google Scholar 

  • Lim CP et al (2006) Stat3 contributes to keloid pathogenesis via promoting collagen production, cell proliferation, and migration. Oncogene 25:5416–5425

    Article  CAS  Google Scholar 

  • Liu JJ et al (2013) Preparation and characterization of cosmeceutical liposomes loaded with avobenzone and arbutin. J Cosmet Sci 64:9–17

    CAS  PubMed  Google Scholar 

  • Lötvall J et al (2014 Dec 22) Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles. J Extracell Vesicles 3:26913

    Article  Google Scholar 

  • Machova Urdzikova L et al (2014) Human multipotent mesenchymal stem cells improve healing after collagenase tendon injury in the rat. Biomed Eng Online 13:42

    Article  Google Scholar 

  • Madsen JT, Andersen KE (2010) Microvesicle formulations used in topical drugs and cosmetics affect product efficiency, performance and allergenicity. Dermatitis 21:243–247

    CAS  PubMed  Google Scholar 

  • Maguire G (2013) Stem cell therapy without the cells. Commun Integr Biol 6:e26631

    Article  Google Scholar 

  • Marcus ME, Leonard JN (2013) FedExosomes: engineering therapeutic biological nanoparticles that truly deliver. Pharmaceuticals 6:659–680

    Article  CAS  Google Scholar 

  • Melo SA et al (2014) Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. Cancer Cell 26:707–721

    Article  CAS  Google Scholar 

  • Morse MA et al (2005) A Phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer. Clin Cancer Res 11:3017–3024

    Article  CAS  Google Scholar 

  • Mu X et al (2013) Regeneration of soft tissues is promoted by MMP1 treatment after digit amputation in mice. PLoS One 8:e59105

    Article  CAS  Google Scholar 

  • Pan BT et al (1985) Electron microscopic evidence for externalization of the transferrin receptor in vesicular form in sheep reticulocytes. J Cell Biol 101:942–948

    Article  CAS  Google Scholar 

  • Quesenberry PJ et al (2014) Cellular phenotype and extracellular vesicles: basic and clinical considerations. Stem Cells Dev 23:1429–1436

    Article  CAS  Google Scholar 

  • Rahimpour Y, Hamishehkar H (2012) Liposomes in cosmeceutics. Expert Opin Drug Deliv 9:443–455

    Article  CAS  Google Scholar 

  • Ranghino A et al (2015) Extracellular vesicles in the urine: markers and mediators of tissue damage and regeneration. Clin Kidney J 8:23–30

    Article  CAS  Google Scholar 

  • Rashed H et al (2017) Exosomes: from garbage bins to promising therapeutic targets. Int J Mol Sci 18(3). pii: E538

    Google Scholar 

  • Ratajczak MZ et al (2012) Pivotal role of paracrine effects in stem cell therapies in regenerative medicine: can we translate stem cell-secreted paracrine factors and microvesicles into better therapeutic strategies? Leukemia 26:1166–1173

    Article  CAS  Google Scholar 

  • Roy S, Gatien S (2008) Regeneration in axolotls: a model to aim for! Exp Gerontol 43:968–973

    Article  CAS  Google Scholar 

  • Sahoo S et al (2011) Exosomes from human CD34+ stem cells mediate their proangiogenic paracrine activity. Circ Res 109:724–728

    Article  CAS  Google Scholar 

  • Sen CK et al (2009) Human skin wounds: a major and snowballing threat to public health and the economy. Wound Repair Regen 17:763

    Article  Google Scholar 

  • Seo KY et al (2013) Skin rejuvenation by microneedle fractional radiofrequency and a human stem cell conditioned medium in Asian skin: a randomized controlled investigator blinded split face study. J Cosmet Laser Ther 15:25–33

    Article  Google Scholar 

  • Shim JH et al (2013) Human dermal stem/progenitor cell-derived conditioned medium ameliorates ultraviolet a induced damage of normal human dermal fibroblasts. PLoS One 8:e67604

    Article  CAS  Google Scholar 

  • Tanaka EM, Reddien PW (2011) The cellular basis for animal regeneration. Dev Cell 21:172–185

    Article  CAS  Google Scholar 

  • Tanaka Y et al (2005) FGF-induced vesicular release of Sonic hedgehog and retinoic acid in leftward nodal flow is critical for left-right determination. Nature 435:172–177

    Article  CAS  Google Scholar 

  • Tetta C et al (2012) The role of micro-vesicles derived from mesenchymal stem cells in tissue regeneration; a dream for tendon repair? Muscles Ligaments Tendons J 2:212–221

    PubMed  PubMed Central  Google Scholar 

  • Valadi H et al (2007) Exosome mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9:654–659

    Article  CAS  Google Scholar 

  • van Koppen A et al (2012) Human embryonic mesenchymal stem cell-derived conditioned medium rescues kidney function in rats with established chronic kidney disease. PLoS One 7:e38746

    Article  Google Scholar 

  • Vyas N et al (2014) Vertebrate Hedgehog is secreted on two types of extracellular vesicles with different signaling properties. Sci Rep 4:7357

    Article  CAS  Google Scholar 

  • Wang CY et al (2012) Mesenchymal stem cell-conditioned medium facilitates angiogenesis and fracture healing in diabetic rats. J Tissue Eng Regen Med 6:559

    Article  CAS  Google Scholar 

  • Wang J et al (2017) Exosomes: a novel strategy for treatment and prevention of diseases. Front Pharmacol 8:300

    Article  Google Scholar 

  • Wessels NK (1977) Tissue interactions and development. Benjamin Cummings, Menlo Park, CA

    Google Scholar 

  • Xin H et al (2013) Systematic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats. J Cereb Blood Flow Metab 33:1711–1715

    Article  CAS  Google Scholar 

  • Yu B et al (2014) Exosomes derived from mesenchymal stem cells. Int J Mol Sci 15:4142–4157

    Article  CAS  Google Scholar 

  • Zhang HG, Grizzle WE (2014) Exosomes: a novel pathway of local and distant intercellular communication that facilitates the growth and metastasis of neoplastic lesions. Am J Pathol 184:28–41

    Article  CAS  Google Scholar 

  • Zhang B et al (2014) HucMSC-exosome mediated -Wnt4 signaling is required for cutaneous wound healing. Stem Cells. https://doi.org/10.1002/stem.1771

    Article  CAS  Google Scholar 

  • Zhang J et al (2015a) Exosomes released from human induced pluripotent stem cells derived MSCs facilitate cutaneous wound healing by promoting collagen synthesis and angiogenesis. J Transl Med 13:49

    Article  Google Scholar 

  • Zhang Y et al (2015b) Effect of exosomes derived from multipluripotent mesenchymal stromal cells on functional recovery and neurovascular plasticity in rats after traumatic brain injury. J Neurosurg 122:856–867

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Twin City Bio, LLC, Winston-Salem, NC, USA

    Joydeep Basu

  2. Zen-Bio, Inc., Research Triangle Park, NC, USA

    John W. Ludlow

Authors
  1. Joydeep Basu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John W. Ludlow
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Joydeep Basu .

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

Glossary

Allogeneic

Cells or cell-sourced materials derived from a donor source genetically dissimilar to the intended recipient are said to be allogeneic. Such biologics are typically immune-privileged.

Cosmeceutical

Topically applied cosmetic products with biologically active ingredients purporting to have medical or drug-like benefits.

Exosome

40–100 nm membrane bound vesicles that mediate transfer of proteins and nucleic acids across cellular boundaries.

Keloid

Scar tissue formed at site of healed skin injury composed of either type III (early phase) or type I (late phase) collagen.

Potency

Defined by FDA as the specific ability or capacity of the product, as indicated by appropriate laboratory tests or by adequately controlled clinical data obtained through the administration of the product in the manner intended, to effect a given result. Potency is an important quality control criteria for all cell-based biologics, see Basu and Ludlow (2014) and Guthrie et al. (2013) for detailed discussion of potency assays and metrics for regenerative medicine and tissue engineered products.

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

Basu, J., Ludlow, J.W. (2018). Exosomes for Regeneration, Rejuvenation, and Repair. 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_4

Download citation

Publish with us

Policies and ethics

Search

Navigation