Skip to main content

Advertisement

SpringerLink
Log in

Current Trends in Regenerative Medicine: From Cell to Cell-Free Therapy

  • Published:
BioNanoScience Aims and scope Submit manuscript

Abstract

One of the most promising approaches to stimulate regeneration and angiogenesis in traumatic or ischemic tissue damage is stem cell therapy. Embryonic and fetal stem cells have the greatest potential of differentiation into different cell types; however, at the same time, they carry the highest risk of teratoma formation. Adult stem cells have the potential risk of transformation during prolonged cultivation in vitro, or as a result of genetic changes during gene-cell therapy applications. In this regard, technologies that can reduce the potential risks of cell and gene-cell therapy are of particular interest. According to the paracrine hypothesis, the beneficial effect of stem cell therapy is due to stimulation of resident cells by cell-to-cell contacts, secretion of bioactive molecules, and release of extracellular vesicles. In this review, we discuss the development of regenerative medicine from cell to cell-free therapy based on extracellular vesicles.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Mao, A. S., & Mooney, D. J. (2015). Regenerative medicine: current therapies and future directions. Proceedings of the National Academy of Sciences of the United States of America, 112, 14452–9.

    Article  Google Scholar 

  2. Calio, M. L., et al. (2014). Transplantation of bone marrow mesenchymal stem cells decreases oxidative stress, apoptosis, and hippocampal damage in brain of a spontaneous stroke model. Free Radical Biology and Medicine, 70, 141–54.

    Article  Google Scholar 

  3. Duffield, J. S., et al. (2005). Restoration of tubular epithelial cells during repair of the postischemic kidney occurs independently of bone marrow-derived stem cells. Journal of Clinical Investigation, 115, 1743–55.

    Article  Google Scholar 

  4. Biancone, L., et al. (2012). Therapeutic potential of mesenchymal stem cell-derived microvesicles. Nephrology, Dialysis, Transplantation, 27, 3037–42.

    Article  Google Scholar 

  5. Takahashi, M., et al. (2006). Cytokines produced by bone marrow cells can contribute to functional improvement of the infarcted heart by protecting cardiomyocytes from ischemic injury. American Journal of Physiology - Heart and Circulatory Physiology, 291, H886–93.

    Article  Google Scholar 

  6. Ratajczak, J., et al. (2006). Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication. Leukemia, 20, 1487–95.

    Article  Google Scholar 

  7. Choi, D. S., et al. (2015). Proteomics of extracellular vesicles: exosomes and ectosomes. Mass Spectrometry Reviews, 34, 474–90.

    Article  Google Scholar 

  8. Svennerholm, K., et al. (2016). DNA content in extracellular vesicles isolated from porcine coronary venous blood directly after myocardial ischemic preconditioning. PloS One, 11, e0159105.

    Article  Google Scholar 

  9. Jackson, L., et al. (2007). Adult mesenchymal stem cells: differentiation potential and therapeutic applications. Journal of Postgraduate Medicine, 53, 121–7.

    Article  Google Scholar 

  10. Li, C. Y., et al. (2015). Comparative analysis of human mesenchymal stem cells from bone marrow and adipose tissue under xeno-free conditions for cell therapy. Stem Cell Research & Therapy, 6, 55.

    Article  Google Scholar 

  11. Stoltz, J. F., et al. (2015). Stem cells and regenerative medicine: myth or reality of the 21th century. Stem Cells International, 2015, 734731.

    Article  Google Scholar 

  12. Mahmoudifar, N., & Doran, P. M. (2015). Mesenchymal stem cells derived from human adipose tissue. Methods in Molecular Biology, 1340, 53–64.

    Article  Google Scholar 

  13. Lopatina, T., et al. (2011). Adipose-derived stem cells stimulate regeneration of peripheral nerves: BDNF secreted by these cells promotes nerve healing and axon growth de novo. PloS One, 6, e17899.

    Article  Google Scholar 

  14. Masgutov, R. F., et al. (2016). Human adipose-derived stem cells stimulate neuroregeneration. Clinical and Experimental Medicine, 16, 451–61.

    Article  Google Scholar 

  15. Kolar, M. K., et al. (2014). The therapeutic effects of human adipose-derived stem cells in a rat cervical spinal cord injury model. Stem Cells and Development, 23, 1659–74.

    Article  Google Scholar 

  16. Kim, E. K., et al. (2011). The effect of human adipose-derived stem cells on healing of ischemic wounds in a diabetic nude mouse model. Plastic and Reconstructive Surgery, 128, 387–94.

    Article  Google Scholar 

  17. Bai, X., et al. (2010). Both cultured and freshly isolated adipose tissue-derived stem cells enhance cardiac function after acute myocardial infarction. European Heart Journal, 31, 489–501.

    Article  Google Scholar 

  18. Amariglio, N., et al. (2009). Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient. PLoS Medicine, 6, e1000029.

    Article  Google Scholar 

  19. Rosland, G. V., et al. (2009). Long-term cultures of bone marrow-derived human mesenchymal stem cells frequently undergo spontaneous malignant transformation. Cancer Research, 69, 5331–9.

    Article  Google Scholar 

  20. Kunter, U., et al. (2007). Mesenchymal stem cells prevent progressive experimental renal failure but maldifferentiate into glomerular adipocytes. Journal of the American Society of Nephrology, 18, 1754–64.

    Article  Google Scholar 

  21. Breitbach, M., et al. (2007). Potential risks of bone marrow cell transplantation into infarcted hearts. Blood, 110, 1362–9.

    Article  Google Scholar 

  22. Cherqui, S., et al. (2007). Lentiviral gene delivery of vMIP-II to transplanted endothelial cells and endothelial progenitors is proangiogenic in vivo. Molecular Therapy, 15, 1264–72.

    Article  Google Scholar 

  23. Huang, J., et al. (2010). Genetic modification of mesenchymal stem cells overexpressing CCR1 increases cell viability, migration, engraftment, and capillary density in the injured myocardium. Circulation Research, 106, 1753–62.

    Article  Google Scholar 

  24. Hacein-Bey-Abina, S., et al. (2008). Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. Journal of Clinical Investigation, 118, 3132–42.

    Article  Google Scholar 

  25. Imberti, B., et al. (2007). Insulin-like growth factor-1 sustains stem cell mediated renal repair. Journal of the American Society of Nephrology, 18, 2921–8.

    Article  Google Scholar 

  26. Togel, F., et al. (2009). VEGF is a mediator of the renoprotective effects of multipotent marrow stromal cells in acute kidney injury. Journal of Cellular and Molecular Medicine, 13, 2109–14.

    Article  Google Scholar 

  27. Eppler, S. M., et al. (2002). A target-mediated model to describe the pharmacokinetics and hemodynamic effects of recombinant human vascular endothelial growth factor in humans. Clinical Pharmacology and Therapeutics, 72, 20–32.

    Article  Google Scholar 

  28. Lee, K., Silva, E. A., Mooney, D. J. (2011). Growth factor delivery-based tissue engineering: general approaches and a review of recent developments. Journal of the Royal Society, Interface, 8, 153–70.

    Article  Google Scholar 

  29. Kawabata, K., Takakura, Y., Hashida, M. (1995). The fate of plasmid DNA after intravenous injection in mice: involvement of scavenger receptors in its hepatic uptake. Pharmaceutical Research, 12, 825–30.

    Article  Google Scholar 

  30. Puddu, P., et al. (2010). The involvement of circulating microparticles in inflammation, coagulation and cardiovascular diseases. Canadian Journal of Cardiology, 26, 140–5.

    Article  Google Scholar 

  31. STURK, A. N. R. (2012). Cell derived vesicles in health and disease. Ned Tijdschr Klin Chem Labgeneesk, 37, 65–68.

    Google Scholar 

  32. Choi, D. S., et al. (2012). The protein interaction network of extracellular vesicles derived from human colorectal cancer cells. Journal of Proteome Research, 11, 1144–51.

    Article  Google Scholar 

  33. Raposo, G., & Stoorvogel, W. (2013). Extracellular vesicles: exosomes, microvesicles, and friends. Journal of Cell Biology, 200, 373–83.

    Article  Google Scholar 

  34. Simpson, R. J., et al. (2009). Exosomes: proteomic insights and diagnostic potential. Expert Review of Proteomics, 6, 267–83.

    Article  Google Scholar 

  35. Ji, H., et al. (2014). Deep sequencing of RNA from three different extracellular vesicle (EV) subtypes released from the human LIM1863 colon cancer cell line uncovers distinct miRNA-enrichment signatures. PloS One, 9, e110314.

    Article  Google Scholar 

  36. van der Pol, E., et al. (2012). Classification, functions, and clinical relevance of extracellular vesicles. Pharmacological Reviews, 64, 676–705.

    Article  Google Scholar 

  37. Akers, J. C., et al. (2013). Biogenesis of extracellular vesicles (EV): exosomes, microvesicles, retrovirus-like vesicles, and apoptotic bodies. Journal of Neuro-Oncology, 113, 1–11.

    Article  Google Scholar 

  38. Leroyer, A. S., et al. (2010). Endothelial-derived microparticles: biological conveyors at the crossroad of inflammation, thrombosis and angiogenesis. Thrombosis and Haemostasis, 104, 456–63.

    Article  Google Scholar 

  39. Mack, M., et al. (2000). Transfer of the chemokine receptor CCR5 between cells by membrane-derived microparticles: a mechanism for cellular human immunodeficiency virus 1 infection. Nature Medicine, 6, 769–75.

    Article  Google Scholar 

  40. Rozmyslowicz, T., et al. (2003). Platelet- and megakaryocyte-derived microparticles transfer CXCR4 receptor to CXCR4-null cells and make them susceptible to infection by X4-HIV. AIDS, 17, 33–42.

    Article  Google Scholar 

  41. Bruno, S., et al. (2009). Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. Journal of the American Society of Nephrology, 20, 1053–67.

    Article  Google Scholar 

  42. Lai, R. C., et al. (2010). Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Research, 4, 214–22.

    Article  Google Scholar 

  43. Arslan, F., et al. (2013). Mesenchymal stem cell-derived exosomes increase ATP levels, decrease oxidative stress and activate PI3K/Akt pathway to enhance myocardial viability and prevent adverse remodeling after myocardial ischemia/reperfusion injury. Stem Cell Research, 10, 301–12.

    Article  Google Scholar 

  44. Herrera, M. B., et al. (2010). Human liver stem cell-derived microvesicles accelerate hepatic regeneration in hepatectomized rats. Journal of Cellular and Molecular Medicine, 14, 1605–18.

    Article  Google Scholar 

  45. Xin, H., et al. (2013). Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats. Journal of Cerebral Blood Flow and Metabolism, 33, 1711–5.

    Article  Google Scholar 

  46. Vrijsen, K. R., et al. (2010). Cardiomyocyte progenitor cell-derived exosomes stimulate migration of endothelial cells. Journal of Cellular and Molecular Medicine, 14, 1064–70.

    Google Scholar 

  47. Zhang, H. C., et al. (2012). Microvesicles derived from human umbilical cord mesenchymal stem cells stimulated by hypoxia promote angiogenesis both in vitro and in vivo. Stem Cells and Development, 21, 3289–97.

    Article  Google Scholar 

  48. Lee, Y., El Andaloussi, S., Wood, M. J. (2012). Exosomes and microvesicles: extracellular vesicles for genetic information transfer and gene therapy. Human Molecular Genetics, 21, R125–34.

    Article  Google Scholar 

  49. Akyurekli, C., et al. (2015). A systematic review of preclinical studies on the therapeutic potential of mesenchymal stromal cell-derived microvesicles. Stem Cell Reviews, 11, 150–60.

    Article  Google Scholar 

  50. Kang, D., et al. (2008). Proteomic analysis of exosomes from human neural stem cells by flow field-flow fractionation and nanoflow liquid chromatography-tandem mass spectrometry. Journal of Proteome Research, 7, 3475–80.

    Article  Google Scholar 

  51. Oksvold, M. P., Neurauter, A., Pedersen, K. W. (2015). Magnetic bead-based isolation of exosomes. Methods in Molecular Biology, 1218, 465–81.

    Article  Google Scholar 

  52. Royo, F., et al. (2016). Different EV enrichment methods suitable for clinical settings yield different subpopulations of urinary extracellular vesicles from human samples. Journal of Extracellular Vesicles, 5, 29497.

    Article  Google Scholar 

  53. Ratajczak, M. Z., 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, 1166–73.

    Article  Google Scholar 

  54. Pick, H., et al. (2005). Investigating cellular signaling reactions in single attoliter vesicles. Journal of the American Chemical Society, 127, 2908–12.

    Article  Google Scholar 

  55. MacLean-Fletcher, S., & Pollard, T. D. (1980). Mechanism of action of cytochalasin B on actin. Cell, 20, 329–41.

    Article  Google Scholar 

  56. Piccin, A., Murphy, W. G., Smith, O. P. (2007). Circulating microparticles: pathophysiology and clinical implications. Blood Reviews, 21, 157–71.

    Article  Google Scholar 

  57. Lim, J. H., et al. (2014). Nanovesicle-based bioelectronic nose for the diagnosis of lung cancer from human blood. Advanced Healthcare Materials, 3, 360–6.

    Article  Google Scholar 

  58. Mao, Z., et al. (2011). Cells as factories for humanized encapsulation. Nano Letters, 11, 2152–6.

    Article  Google Scholar 

  59. Peng, L. H., et al. (2015). Cell membrane capsules for encapsulation of chemotherapeutic and cancer cell targeting in vivo. ACS Applied Materials and Interfaces, 7, 18628–37.

    Article  Google Scholar 

  60. Soekmadji, C., Russell, P. J., Nelson, C. C. (2013). Exosomes in prostate cancer: putting together the pieces of a puzzle. Cancers (Basel), 5, 1522–44.

    Article  Google Scholar 

  61. Choi, D. S., et al. (2013). Proteomics, transcriptomics and lipidomics of exosomes and ectosomes. Proteomics, 13, 1554–71.

    Article  Google Scholar 

  62. Masyuk, A. I., Masyuk, T. V., Larusso, N. F. (2013). Exosomes in the pathogenesis, diagnostics and therapeutics of liver diseases. Journal of Hepatology, 59, 621–5.

    Article  Google Scholar 

  63. Zomer, A., et al. (2010). Exosomes: fit to deliver small RNA. Communicative & Integrative Biology, 3, 447–50.

    Article  Google Scholar 

Download references

Acknowledgments

The work is performed according to the Russian Government Program of Competitive Growth of Kazan Federal University and subsidy allocated to Kazan Federal University for the state assignment in the sphere of scientific activities.

Author information

Authors and Affiliations

  1. Kazan Federal University, 18 Kremlevskaya str, Kazan, 420008, Russia

    Marina O. Gomzikova & Albert A. Rizvanov

Authors
  1. Marina O. Gomzikova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Albert A. Rizvanov
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Albert A. Rizvanov.

Ethics declarations

Conflict of Interest

The authors declare no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gomzikova, M.O., Rizvanov, A.A. Current Trends in Regenerative Medicine: From Cell to Cell-Free Therapy. BioNanoSci. 7, 240–245 (2017). https://doi.org/10.1007/s12668-016-0348-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12668-016-0348-0

Keywords

Search

Navigation