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Editorial

'Cells as tools' to 'Cell-produced tools' - An evolving paradigm in Regenerative Medicine

Internal milieu or niche of biological mechanisms on how reparative solutions take shape to control a damage as well as repair the damages caused in any organ within mammalian body are not fully known.  Recent data in the evolving era of regenerative medicine in which, cells, stem cells and adult cells have been used as tools to repair, restore, rejuvenate or regenerate the lost/damaged/dysfunctional cells, tissues and organs indicate that there could be several means with which such regenerative medicine based applications work viz, fusion, differentiation, trans-differentiation and paracrine; whilst the paracrine mechanisms are numerous[1] in which several cell produced factors[2], some are seemingly known while many yet to be explored.  This phenomena might look something new, but a careful analysis of literature doesn’t say so. Embryo culture supernatant has been used clinically for improving embryo implantation rates in in vitro fertilization (IVF) procedures from 2007[3]. This procedure of injecting embryo culture supernatant (ECS) into the uterus before blastocyst transfer (BT) has been reported to improve implantation and pregnancy rates in different randomized clinical trials[3,4]. Conditioned Media (CM) obtained by culturing cells and stem cells form another avenue of cell-free regeneration. Mesenchymal stem cell-derived CM (MSC-CM) have been reported to have potential for cell-free regeneration of bone[5]. CM from adipose-derived stem cells (ADSCs) applied in pilot human clinical studies for hair regeneration[6] and human exfoliated deciduous teeth-CM has been used for bone regeneration around teeth implants in in vivo experiments[7] form some of such clinical applications using CM.

A significant advantage to use the cell-secreted factors sans cells, if considered rationally should:

  1. Avoid issues of antigenicity and immunogenicity during clinical translation[8], and
  2. Have maximum gains where paracrine effects contribute mainly to regeneration[1].

This concept of cell-free regeneration has gained further significance by the use of exosomes, which are extracellular vesicles released from cells upon fusion of the intermediate endocytic compartment, the multivesicular body (MVB), with the plasma membrane[9].  Cell-derived exosomes from different types of cells and stem cells have been reported to be useful in several regenerative medicine applications, including myocardial regeneration[10], anti-cancer therapies[11] and hind limb ischemia[12].

Amidst the existing debate and translational constraints based on regulatory approaches in different countries on whether cell based therapies should be considered as drugs or products[13], such cell-free regeneration approaches may pave way for faster translation of the technology to the bedside. Still, the nature and functions of such cell-produced tools including exosomes are likely to have several variables based on the cell source, age of the donor, in vitro environmental conditions etc., [14] which needs further research to ascertain the effects of such variability in clinical contexts.

Nevertheless, looking into cells as factories to produce solution-oriented products or components, the domain of regenerative medicine has been only gaining strength by virtue of such novel strategies in yielding exciting solutions. This is not a simple paradigm shift of cells as tools to cell-produced tools, rather an added responsibility on the shoulders of the scientific community to ensure the right kind of in vitro environments where the cells are nurtured, enable them produce the right tools for cure.

References:

  1. Masumoto H, Matsuo T, Yamamizu K, Uosaki H, Narazaki G, Katayama S, Marui A, Shimizu T, Ikeda T, Okano T, Sakata R, Yamashita JK. Pluripotent stem cell-engineered cell sheets reassembled with defined cardiovascular populations ameliorate reduction in infarct heart function through cardiomyocyte-mediated neovascularization. Stem Cells. 2012 Jun;30(6):1196-205.
  2. Gnecchi M, Zhang Z, Ni A, Dzau VJ. Paracrine mechanisms in adult stem cell signaling and therapy. Circ Res. 2008 Nov 21;103(11):1204-19.
  3. Goto S, Kadowaki T, Hashimoto H, Kokeguchi S, Shiotani M. Stimulation of endometrium embryo transfer (SEET): injection of embryo culture supernatant into  the uterine cavity before blastocyst transfer can improve implantation and pregnancy rates. Fertil Steril. 2007 Nov;88(5):1339-43.
  4. Tehraninejad ES, Tanha FD, Ghajarzadeh M, Zandieh Z, Aziminekoo E, Zanjani HR. Stimulation of the endometrium with high-grade blastocyst culture supernatant (SEHB) can improve pregnancy outcome for couples undergoing intracytoplasmic sperm injection (ICSI): a randomized clinical trial. Arch Gynecol Obstet. 2012 Apr;285(4):1167-71.
  5. Katagiri W, Osugi M, Kawai T, Ueda M. Novel cell-free regeneration of bone using stem cell-derived growth factors. Int J Oral Maxillofac Implants. 2013 Jul-Aug;28(4):1009-16.
  6. Shin H, Won CH, Chung WK, Park BS. Up-to-date Clinical Trials of Hair Regeneration using Conditioned Media of Adipose-Derived Stem Cells in Male and Female Pattern Hair Loss. Curr Stem Cell Res Ther. 2017 May 4.
  7. Omori M, Tsuchiya S, Hara K, Kuroda K, Hibi H, Okido M, Ueda M. A new application of cell-free bone regeneration: immobilizing stem cells from human exfoliated deciduous teeth-conditioned medium onto titanium implants using atmospheric pressure plasma treatment. Stem Cell Res Ther. 2015 Jun 19;6:124.
  8. Ong SG, Wu JC. Exosomes as potential alternatives to stem cell therapy in mediating cardiac regeneration. Circ Res. 2015 Jun 19;117(1):7-9.
  9. Edgar JR. Q&A: What are exosomes, exactly? BMC Biol. 2016 Jun 13;14:46.
  10. Ibrahim AG, Cheng K, Marbán E. Exosomes as critical agents of cardiac regeneration triggered by cell therapy. Stem Cell Reports. 2014 May 8;2(5):606-19.
  11. Kim MS, Haney MJ, Zhao Y, Mahajan V, Deygen I, Klyachko NL, et al. Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells. Nanomedicine. 2015;12(3):655–64.
  12. Ranghino A, Cantaluppi V, Grange C, Vitillo L, Fop F, Biancone L, et al. Endothelial progenitor cell-derived microvesicles improve neovascularization in a murine model of hindlimb ischemia. Int J Immunopathol Pharmacol (2012) 25(1):75–85.
  13. Preethy S, John S, Ganesh JS, Srinivasan T, Terunuma H, Iwasaki M, Abraham SJ.Age-old wisdom concerning cell-based therapies with added knowledge in the stem cell era: our perspectives. Stem Cells Cloning. 2013 Apr 4;6:13-8.
  14. Willms E, Johansson HJ, Mäger I, Lee Y, Blomberg KE, Sadik M, Alaarg A, Smith CI, Lehtiö J, El Andaloussi S, Wood MJ, Vader P. Cells release subpopulations of  exosomes with distinct molecular and biological properties. Sci Rep. 2016 Mar 2;6:22519.
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