Prof. Dr Bernd Giebel, University Medicine Essen

Within AutoCRAT, two research groups work on the EV-based therapeutic development for the modulation of osteoarthritis: Prof. Dr Bernd Giebel heads a research group within the University Medicine Essen’s Institute for Transfusion Medicine. As an expert in early human haematopoiesis and extracellular vesicles (EV) research, his group focusses on human hematopoietic stem cell biology and the therapeutic potential of mesenchymal stem/stromal cell-derived EVs. Prof. Chiara Gentili’s research team in the Department of Experimental Medicine (DIMES) at the Università degli Studi di Genova brings decades of experience with pre-clinical models for regenerative medicine and expertise in MSC and EV production for the treatment of osteoarthritis.

At the turn of the millennium, mesenchymal stromal cells (MSCs), became popular research entities in regenerative medicine. Aiming to apply allogeneic off-the-shelf MSC products for acute conditions, like myocardial infarction and ischemic stroke, researchers began studying the interaction of allogenic MSCs with components of the immune system and showed that they exert immunomodulatory functions [1, 2]. Regarding their pro-regenerative and immunomodulatory potentials, up to now, MSCs have been applied in more than a thousand clinical trials to various patient cohorts (www.clinicaltrials.gov), some confirming their therapeutic potential, others failing to show efficacy [3].

Prof. Chiara Gentili, Università degli Studi di Genova

As most systemically administered MSCs are recovered in the lungs of recipients and hardly in affected tissues, the long-lasting dogma that MSCs act in a cell replacement role became challenged. Quickly, researchers postulated that they mainly act in a paracrine cell-to-cell communication capacity [4, 5]. After confirming that MSC conditioned media exerted comparable therapeutic effects to administered cells [6-8], several groups began to search for active components in MSC conditioned media. The groups of Giovanni Camussi and Sai Kiang Lim showed in 2009 and 2010 that MSCs’ therapeutic activity was recovered in vesicle enriched culture media fractions [9, 10]. After defining microvesicles as budding from the plasma membrane and exosomes as derivatives of the endosomal compartment, and because different vesicular entities cannot yet be experimentally separated from each other, the scientific community agreed in experimental settings to the use of the term extracellular vesicles (EVs) instead of more specified terms [11, 12]. Using EVs for therapeutic purposes has many advantages over cells. For example, EV-based therapeutics are easier to handle and can be separated by filtration [13]. In recent years, the therapeutic EV field has grown exponentially. MSC-EV products, like their parental cells, modulate immune responses in animal models and have been efficaciously used to treat an otherwise treatment-resistant human with Graft-versus-Host Disease [14, 15].

Meanwhile, many groups approach the clinic intending to apply MSC-EV products to different patient cohorts including those with COVID-19 [16]. Although pre-clinical data are very encouraging and MSC-EVs, in principle, provide promising therapeutic agents for the future, several translation challenges remain. For now, production protocols are not standardized, and apparently, not all MSCs are competent in releasing therapeutically active EVs [13, 16-18]. Despite reports that MSC-EVs possess immunomodulatory, pro-regenerative, pro-angiogenic and/or anti-apoptotic properties, their precise mechanisms of action remain unclear. Collaborative research as in AutoCRAT is required to improve MSC-EV production platforms and to explore the MSC-EV’s therapeutic potential to warrant effective translation into the clinic [19, 20].

 

References:

  1. Di Nicola, M., et al., Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood, 2002. 99(10): p. 3838-43.
  2. Bartholomew, A., et al., Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Experimental hematology, 2002. 30(1): p. 42-8.
  3. Galipeau, J. and L. Sensebe, Mesenchymal Stromal Cells: Clinical Challenges and Therapeutic Opportunities. Cell Stem Cell, 2018. 22(6): p. 824-833.
  4. Caplan, A.I. and J.E. Dennis, Mesenchymal stem cells as trophic mediators. Journal of cellular biochemistry, 2006. 98(5): p. 1076-84.
  5. Caplan, A.I., Mesenchymal Stem Cells: Time to Change the Name! Stem Cells Transl Med, 2017. 6(6): p. 1445-1451.
  6. Gnecchi, M., et al., Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. The FASEB journal: official publication of the Federation of American Societies for Experimental Biology, 2006. 20(6): p. 661-9.
  7. Gnecchi, M., et al., Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nature medicine, 2005. 11(4): p. 367-8.
  8. Timmers, L., et al., Reduction of myocardial infarct size by human mesenchymal stem cell conditioned medium. Stem Cell Res, 2007. 1(2): p. 129-37.
  9. Bruno, S., et al., Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. J Am Soc Nephrol, 2009. 20(5): p. 1053-67.
  10. Lai, R.C., et al., Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res, 2010. 4(3): p. 214-22.
  11. Gould, S.J. and G. Raposo, As we wait: coping with an imperfect nomenclature for extracellular vesicles. J Extracell Vesicles, 2013. 2.
  12. Thery, C., 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(1): p. 1535750.
  13. Lener, T., et al., Applying extracellular vesicles based therapeutics in clinical trials – an ISEV position paper. J Extracell Vesicles, 2015. 4: p. 30087.
  14. Giebel, B., L. Kordelas, and V. Borger, Clinical potential of mesenchymal stem/stromal cell-derived extracellular vesicles. Stem Cell Investig, 2017. 4(10): p. 84.
  15. Börger, V., et al., Mesenchymal Stem/Stromal Cell-Derived Extracellular Vesicles and Their Potential as Novel Immunomodulatory Therapeutic Agents. Int J Mol Sci, 2017. 18(7).
  16. Börger, V., et al., ISEV and ISCT statement on EVs from MSCs and other cells: considerations for potential therapeutic agents to suppress COVID-19. Cytotherapy, 2020.
  17. Witwer, K.W., et al., Defining mesenchymal stromal cell (MSC)-derived small extracellular vesicles for therapeutic applications. J Extracell Vesicles, 2019. 8(1): p. 1609206.
  18. Reiner, A.T., et al., Concise Review: Developing Best-Practice Models for the Therapeutic Use of Extracellular Vesicles. Stem Cells Transl Med, 2017. 6(8): p. 1730-1739.
  19. Weiss, D.J., et al., Weiss Response to Sengupta et al. (DOI: 10.1089/scd.2020.0095). Stem Cells and Development, 2020. 29(24): p. 1533-1534.
  20. Lim, S.K., et al., Re: “Exosomes Derived from Bone Marrow Mesenchymal Stem Cells as Treatment for Severe COVID-19” by Sengupta et al. Stem Cells Dev, 2020.