Tel: +49 (0) 89 517 286 59 0
E-Mail: info@pelobiotech.com
Back to overview

MSCs and Extracellular Vesicle Production: A Gateway to Regenerative Medicine

From Ovi 29. February 2024 10 min
BM MSC_ourhPLmedium.jpg

Mesenchymal stem / stromal cells (MSCs) have emerged as a promising tool in regenerative medicine due to their unique properties, including self-renewal and differentiation capability.

One of the key mechanisms through which MSCs exert their therapeutic effects is via paracrine signaling, which includes the production and secretion of Extracellular Vesicle (EVs), often termed as exosomes or microvesicles that play a crucial role in intercellular communication and tissue repair. This article provides an overview of MSCs, their role in EVs production, and the potential applications of MSC-derived EVs in regenerative medicine.

In the scientific community is a very active discussion regarding the appropriate nomenclature for mesenchymal stem cells (MSCs): Some experts suggest MSCs should be more accurately termed "stromal cells" to reflect their supportive role in tissue rather than their stem cell-like qualities24-27. So here we will incorporate both names and refer to these cells mesenchymal stem/stromal cells (MSCs) throughout this article.

 

Understanding MSCs

MSCs non-hematopoietic, multipotent, adult stem / stromal cells that can be isolated from various biological sources such as bone marrow, adipose tissue, Wharton's jelly of the umbilical cord, brain, spleen, kidneys, liver, placenta, dental pulp, neurons, lungs, skin, and breast milk. MSCs have further been defined by the International Society for Cellular Therapy (ISCT) based on specific criteria outlined in a position statement from 2006. According to these criteria, MSCs must exhibit certain characteristics to be classified as such. These include the ability to adhere to plastic surfaces during in vitro culture, expression of specific surface markers such as CD105, CD73, and CD90 while lacking CD45, CD34, CD14, or CD11b, expression markers and the capacity to differentiate into osteoblasts, adipocytes, and chondrocytes under specific in vitro conditions22,23. These criteria are crucial for the identification and standardization of MSCs across various tissue sources. Importantly, the tissue source of MSCs can influence their therapeutic potential, making it essential to understand the differences between MSCs isolated from different tissues to predict their behavior and widen their clinical use1.

 

Extracellular Vesicles: Nature's Nanoscale Messengers

EVs, nanoscale membrane-bound vesicles released by various cell types, including MSCs, play a vital role in an array of cellular functions, including intercellular communication, cell differentiation, and proliferation, angiogenesis, stress response, and immune signaling. The ability to carry out these different functions is because of the complexity of EVs. These vesicles carry and transfer functional cargo like proteins, messenger RNAs, microRNAs, cytokines, lipids, cell surface receptors, enzymes and transcription factors from cells to the recipient cells. Their sizes range from 30 to 150 nanometres, originating from a specialized biogenesis pathway.

 

The composition of EVs is contingent on the donor cell type and the physiological context of production. EVs interact with recipient cells through specific adhesion molecules and can be internalized via multiple pathways, dependent on the proximity of the target cells. The nucleic acid content in EVs is particularly influential in their functional capacity. They harbour distinct markers including tetraspanins (CD9, CD63, CD81), integrins, MHC molecules, HSP70, HSP90, Alix, TSG101, and GTPases. The lipid bilayer encapsulating EVs confers stability and protection, facilitating their biological roles. MSCs release large amounts of EVs for cell-to-cell communication, maintaining a dynamic and homeostatic microenvironment for tissue repair and regeneration2,28. Furthermore, EVs have been implicated in various physiological and pathological processes, including cardiovascular diseases and neurogenesis3,29-31.

 

 

MSC-Derived EVs: Key Agents in Regenerative Medicine 

Past research has demonstrated that, despite positive effects in various settings, MSCs were barely detected in affected tissues, resulting in the hypothesis that they mainly act via their secretome rather than in a direct cellular manner15. Using the examples of an acute kidney injury model and a myocardial infarction model that MSCs were found to exert their therapeutic effects EVs33.

MSC-derived EVs have become key players in regenerative medicine, showcasing a broad range of therapeutic effects. Originating from MSCs, these EVs carry immunomodulatory, regenerative, and anti-inflammatory traits, making them highly effective in tissue repair, angiogenesis, inflammation control, and wound healing. They contribute significantly to critical cellular processes, including angiogenesis, fibrosis reduction, and remodeling of the extracellular matrix. They are particularly promising for treating a spectrum of conditions such as cardiovascular, renal, hepatic, pulmonary, and neurodegenerative diseases, and they also exhibit antimicrobial effects.

Unlike MSCs themselves, which can pose challenges related to cell viability, potential for immune rejection, and the complexity of direct use in regenerative therapies, MSC-EVs offer a safer, more stable, and potentially more effective alternative. In contrast to cell therapies, EVs are not self-replicating and they lack endogenous tumor formation potentials. EVs do not seem to sense environmental conditions, and thus, their biological activity can be predicted more reliably than that of cells. Preconditioning and engineering techniques have enhanced the efficacy of MSC-EVs, paving the way for improved outcomes in cell-free therapeutic interventions8. This evolution emphasizes the strategic advantage of utilizing MSC-EVs over direct MSC therapies, as they represent an innovative method for harnessing the full regenerative potential of mesenchymal stem cells, setting a new standard in medical treatments.

Culture and Expansion of MSCs for EVs Production 

The origin, culture, and expansion of MSCs are crucial for EVs production. The choice of expansion method significantly impacts EVs yield and quality.

The field of MSC research faces challenges due to the inherent tendency of primary MSCs to undergo senescence during culture expansion. This limitation has prompted researchers to explore the generation and characterization of immortalized MSC (iMSC) lines as a potential solution. IMSC lines, such as those created by inducing the expression of human telomerase reverse transcriptase (hTERT), have been investigated for their ability to offer a reliable and scalable source of MSCs for EVs production17. Studies have indicated that iMSC lines could serve as a consistent resource for EVs production, which is crucial for various therapeutic applications. However, it is important to note that iMSCs may exhibit functional alterations compared to primary MSCs18.

This difference in functionality raises concerns about the suitability of iMSCs for certain applications and underscores the importance of further research to understand the implications of iMSC behavior and characteristics. Moreover, the source of MSCs, whether primary, induced pluripotent stem cell (iPSC)-derived, or immortalized, can influence EVs production. While iPSC-derived MSCs have shown promise for specific applications, primary MSCs are still preferred in many cases due to their superior supportive capabilities in co-culture systems19. The choice of MSC source is a critical consideration in EVs production, as it can impact the quantity and quality of EVs generated for therapeutic purposes.

The culture media used for MSC expansion can also influence EVs production and functionality. The use of defined media has been suggested as advantageous for maintaining the desired characteristics of MSCs and their derived EVs20. Additionally, it may be necessary to add special lipid cocktails for high EVs production.

The balance between high proliferation/expansion rates and EVs production is a critical consideration. While high proliferation rates are desirable for obtaining large quantities of MSCs, it may lead to competition for resources, such as lipids, which are essential for both proliferation and EVs biogenesis21. Studies have indicated that the efficiency of EVs production may inversely correlate with the developmental maturity of the MSC donor, further highlighting the importance of donor selection for optimal EVs yield21.

Moreover, the choice of having serum in the cell culture, such as FBS, hPL, or AB serum, can introduce both variability in proliferation, and expansion. Utilizing defined media can help to overcome these batch-to-batch variabilities and ensure consistent functional EVs production20.

In conclusion, the culture and expansion of MSCs for EVs production involve various factors that influence the quantity and quality of EVs. Careful consideration of expansion methods, culture media, cell source, proliferation rates, and serum choice is essential to optimize EVs production for therapeutic applications. Special lipid cocktails may be necessary to enhance EVs production efficiency and yield, further emphasizing the importance of optimizing culture conditions for successful EVs-based therapies.

 

Isolation Techniques for MSC-Derived EVs

Isolating EVs from MSCs is a noteworthy area of research, essential for obtaining pure EVs samples for applications ranging from therapeutic use, drug delivery, regenerative medicine, and tissue engineering. Various methods such as ultracentrifugation, differential ultracentrifugation, and tangential flow filtration are employed, each with its distinct advantages and limitations4.

 

  • Ultracentrifugation: Ultracentrifugation is one of the most traditional and widely used methods for Extracellular Vesicles isolation. This technique relies on the application of extremely high centrifugal forces, typically ranging from 100,000 to 200,000g to sediment EVs from MSC culture media or other biological fluids. The process involves multiple centrifugation steps at varying speeds and durations to progressively remove cells, cell debris, and larger vesicles, culminating in the sedimentation of EVs.

 

  • Advantages:

Widely available: The equipment required for ultracentrifugation is available in most research laboratories.

Scalable: It can be adapted for large-volume preparations, making it suitable for both research and clinical applications.

 

  • Limitations:

Time-consuming: The process is labor-intensive and requires several hours to complete.

Potential for contamination: Co-isolation of protein aggregates or other vesicles of similar density can occur.

Sample integrity: The high forces applied can potentially damage the EVs or alter their functional properties.

 

  • Differential Ultracentrifugation

Differential ultracentrifugation refines the basic ultracentrifugation process by employing a series of centrifugation steps at gradually increasing speeds. This method allows for more precise separation of EVs from other components based on their size and density.

 

  • Advantages:

Improved purity: By carefully adjusting the centrifugation parameters, it is possible to enhance the purity of the isolated EVs.

Versatility: It can be used in conjunction with other purification steps to further increase the yield and purity of EVs.

 

  • Limitations:

Complexity: The process requires meticulous optimization of centrifugation speeds and times for each specific sample type.

Sample loss: Each centrifugation step may lead to a loss of EVs yield.

 

  • Tangential Flow Filtration (TFF)32

Tangential flow filtration is a more modern approach that utilizes a cross-flow mechanism, where the sample fluid flows tangentially across the surface of a membrane filter. This method effectively separates EVs based on their size, allowing them to pass through the membrane while larger particles are retained.

 

  • Advantages:

Efficiency: TFF can process large volumes of samples in a relatively short amount of time.

Gentle on samples: The technique is less likely to damage EVs compared to ultracentrifugation.

Scalability and reproducibility: TFF is easily scalable and offers high reproducibility, making it suitable for clinical applications.

 

  • Limitations:

Equipment cost: The initial investment for TFF systems can be high.

Membrane maintenance: Over time, the membrane may become clogged with particles, requiring regular maintenance or replacement.

 

The choice of an EVs isolation technique depends on various factors, including the source of MSCs, the volume of the sample, the desired purity and yield of EVs, and the available resources. Each method has its trade-offs, thus a combination of techniques should be used to achieve the best results. Continuous advancements in EVs isolation technologies are expected to enhance the efficiency, yield, and purity of EVs preparations.

 

Enhancing EVs Production from MSCs

Optimizing the production of EVs from MSCs can significantly lead to more effective application possibilities by ensuring that sufficient quantities of potent, high-quality EVs are available for research and clinical therapy.

Currently, several strategies are being developed to boost EVs production:

  • Culturing with Bioactive Glass (BG) Ion Products: Culturing MSCs with BG ion product-enriched medium significantly increases Extracellular Vesicles production without altering their inherent characteristics5.

 

  • Use of Small Molecules: Identified specific small molecules capable of enhancing Extracellular Vesicles production in MSCs, with ongoing research exploring their effects on the EVs composition and regenerative capacity6.

 

  • Preconditioning and Engineering: Innovative strategies such as preconditioning MSCs and engineering EVs are being investigated to amplify the therapeutic activity of MSC-EVs7.

 

Navigating the Evolving Landscape of Engineered EVs Therapies: Opportunity and Challenges in Clinical Translation

 

The landscape of EV-based therapies growing exponentially, with over 150 clinical trials, spanning various domains such as respiratory disorders, infectious diseases, and oncology9. Notably, MSC-EVs are particularly promising, offering a compelling alternative to traditional stem cell therapies. As we have talked earlier, MSC-EVs can replicate the therapeutic impacts of their source MSCs, with added benefits like reduced size, increased stability, and more versatile administration routes10. Various companies are at the forefront of advancing the therapeutic potential of EVs through the engineering of EVs membrane proteins. These developments have led to innovative treatments, such as the creation of inhalable COVID-19 vaccines utilizing EVs derived from lung stem cells. The contributions from multiple companies have played a significant role in driving progress in this field. The exciting world of engineered Extracellular Vesicles therapy is on the brink of transforming how we approach healing, opening up a whole new world of medical possibilities11.

Despite the promise of MSC-EVs, challenges persist in translating these therapies from bench to bedside. Issues concerning safety, standardized isolation protocols, and EVs characterization require resolution12. Additionally, the heterogeneity of EVs populations, influenced by extracellular environmental factors, complicates their therapeutic application13. A deeper understanding of exosomal cargo and its disease-specific roles is imperative for the full realization of exosomal potential in clinical settings.

Lastly, the scale-up of MSC-EVs production for clinical applications encounters significant difficulties, primarily due to the substantial volume required to treat a single patient. Traditional volume reduction methods, such as ultracentrifugation, are notably inefficient for this scale, with the maximum processing volume per run capped at under 500 mL, starkly inadequate for the quantities needed for EV-based therapeutics. This limitation highlights a critical bottleneck in the transition from laboratory-scale research to clinical applications. Key challenges include maintaining the purity and functionality of EVs, ensuring consistent quality across batches, source of EVs, isolation methods, and biodistribution, which are crucial for the successful translation of MSC-EVs into clinical use.

In summary, the synergy between MSCs and EVs is illuminating new frontiers in regenerative medicine. As we unravel the complexities of MSC-EVs, we edge closer to a new epoch of therapeutic interventions that are safer, more efficacious, and transformative. These diminutive vesicles, emerging from the intricacies of cellular communication, hold the potential to redefine medical treatments, offering renewed hope for patients worldwide.

 

References

  1. Cuesta-Gomez, N., Graham, G. J., & Campbell, J. (2021). Chemokines and their receptors: predictors of the therapeutic potential of mesenchymal stromal cells. Journal of Translational Medicine, 19(1). https://doi.org/10.1186/s12967-021-02822-5
  2. Ti, D., Hao, H., Tong, C., Liu, J., Dong, L., Zheng, J., … & Han, W. (2015). Lps-preconditioned mesenchymal stromal cells modify macrophage polarization for resolution of chronic inflammation via exosome-shuttled let-7b. Journal of Translational Medicine, 13(1). https://doi.org/10.1186/s12967-015-0642-6
  3. Tian, J., Popal, M. S., Zhao, Y., Liu, Y., Chen, K., & Liu, Y. (2019). Interplay between exosomes and autophagy in cardiovascular diseases: novel promising target for diagnostic and therapeutic application. Aging and Disease, 10(6), 1302. https://doi.org/10.14336/ad.2018.1020
  4. Helwa I, Cai J, Drewry MD, Zimmerman A, Dinkins MB, Khaled ML, Seremwe M, Dismuke WM, Bieberich E, Stamer WD, Hamrick MW, Liu Y. A Comparative Study of Serum Exosome Isolation Using Differential Ultracentrifugation and Three Commercial Reagents. PLoS One. 2017 Jan 23;12(1): e0170628. doi: 10.1371/journal.pone.0170628.
  5. Zhi Wu, Dan He, Haiyan Li. Bioglass enhances the production of exosomes and improves their capability of promoting vascularization. Bioactive materials (2021) doi: 10.1016/j.bioactmat.2020.09.011.
  6. Wang J, Bonacquisti EE, Brown AD, Nguyen J. Boosting the Biogenesis and Secretion of Mesenchymal Stem Cell-Derived Exosomes. Cells. 2020 Mar 9;9(3):660. doi: 10.3390/cells9030660.
  7. Chen S, Sun F, Qian H, Xu W, Jiang J. Preconditioning and Engineering Strategies for Improving the Efficacy of Mesenchymal Stem Cell-Derived Exosomes in Cell-Free Therapy. Stem Cells Int. 2022 May 14; 2022:1779346. doi: 10.1155/2022/1779346.
  8. Lee, J., Park, B., Kim, J., Choo, Y. W., Kim, H. Y., Yoon, J., … & Kim, B. S. (2020). Nanovesicles derived from iron oxide nanoparticles–incorporated mesenchymal stem cells for cardiac repair. Science Advances, 6(18). https://doi.org/10.1126/sciadv.aaz0952
  9. Mendt, M. C., Rezvani, K., & Shpall, E. J. (2019). Mesenchymal stem cell-derived exosomes for clinical use. Bone Marrow Transplantation, 54(S2), 789-792. https://doi.org/10.1038/s41409-019-0616-z
  10. Levy, O., Kuai, R., Siren, E. M. J., Bhere, D., Milton, Y., Nissar, N., … & Karp, J. M. (2020). Shattering barriers toward clinically meaningful MSCs therapies. Science Advances, 6(30). https://doi.org/10.1126/sciadv.aba6884
  11. Yin, K., Wang, S., & Zhao, R. C. (2019). Exosomes from mesenchymal stem/stromal cells: a new therapeutic paradigm. Biomarker Research, 7(1). https://doi.org/10.1186/s40364-019-0159-x
  12. Lee, B., Kang, I. H., & Yu, K. (2021). Therapeutic features and updated clinical trials of mesenchymal stem cell (MSCs)-derived exosomes. Journal of Clinical Medicine, 10(4), 711. https://doi.org/10.3390/jcm10040711
  13. Ahmadi, M. and Rezaie, J. (2020). Ageing and mesenchymal stem cells derived exosomes: molecular insight and challenges. Cell Biochemistry and Function, 39(1), 60-66. https://doi.org/10.1002/cbf.3602
  14. Xu, H., Chen, L., Zhou, S., Li, Y., & Xiang, C. (2020). Multifunctional role of micrornas in mesenchymal stem cell-derived exosomes in treatment of diseases. World Journal of Stem Cells, 12(11), 1276-1294. https://doi.org/10.4252/wjsc.v12.i11.1276
  15. Arnold I. Caplan, Diego Correa, The MSC: An Injury Drugstore. Volume 9, Issue 1, 8 July 2011, Pages 11-15. https://doi.org/10.1016/j.stem.2011.06.008
  16. 2023. “Sources and Potential Applications of Mesenchymal Stromal Cells” https://www.biorender.com/.
  17. Burk, J., Holland, H., Lauermann, A., May, T., Siedlaczek, P., Charwat, V., … & Kasper, C. (2019). Generation and characterization of a functional human adipose‐derived multipotent mesenchymal stromal cell line. Biotechnology and Bioengineering, 116(6), 1417-1426. https://doi.org/10.1002/bit.26950
  18. Piñeiro-Ramil, M., Sanjurjo-Rodríguez, C., Rodríguez-Fernández, S., Castro-Viñuelas, R., Hermida-Gómez, T., Blanco, F., … & Díaz-Prado, S. (2021). Generation of mesenchymal cell lines derived from aged donors. International Journal of Molecular Sciences, 22(19), 10667. https://doi.org/10.3390/ijms221910667
  19. Vasko, T., Frobel, J., Lubberich, R., Goecke, T., & Wagner, W. (2016). Ipsc-derived mesenchymal stromal cells are less supportive than primary mscs for co-culture of hematopoietic progenitor cells. Journal of Hematology & Oncology, 9(1). https://doi.org/10.1186/s13045-016-0273-2
  20. Wang, J., Bonacquisti, E., Brown, A., & Nguyen, J. (2020). Boosting the biogenesis and secretion of mesenchymal stem cell-derived exosomes. Cells, 9(3), 660. https://doi.org/10.3390/cells9030660
  21. Chen, T., Yeo, R., Arslan, F., Yin, Y., Tan, S., Lai, R., … & Lim, S. (2013). Efficiency of exosome production correlates inversely with the developmental maturity of msc donor. Journal of Stem Cell Research & Therapy, 3(3). https://doi.org/10.4172/2157-7633.1000145
  22. Dominici, M., Blanc, K. L., Mueller, I., Slaper‐Cortenbach, I., Marini, F. C., Krause, D. S., … & Horwitz, E. M. (2006). Minimal criteria for defining multipotent mesenchymal stromal cells. the international society for cellular therapy position statement. Cytotherapy, 8(4), 315-317. https://doi.org/10.1080/14653240600855905
  23. Murray, I. R., Chahla, J., Safran, M. R., Krych, A. J., Saris, D. B., Caplan, A. I., … & Nakamura, N. (2019). International expert consensus on a cell therapy communication tool: doses. Journal of Bone and Joint Surgery, 101(10), 904-911. https://doi.org/10.2106/jbjs.18.00915
  24. Caplan AI. Mesenchymal Stem Cells: Time to Change the Name! Stem Cells Transl Med. 2017 Jun;6(6):1445-1451. doi: 10.1002/sctm.17-0051. Epub 2017 Apr 28. PMID: 28452204; PMCID: PMC5689741.
  25. Lindner U, Kramer J, Rohwedel J, Schlenke P. Mesenchymal Stem or Stromal Cells: Toward a Better Understanding of Their Biology? Transfus Med Hemother. 2010 Apr;37(2):75-83. doi: 10.1159/000290897. Epub 2010 Mar 15. PMID: 20737049; PMCID: PMC2914415.
  26. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop Dj, Horwitz E. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315-7. doi: 10.1080/14653240600855905. PMID: 16923606.
  27. Elahi FM, Farwell DG, Nolta JA, Anderson JD. Preclinical translation of exosomes derived from mesenchymal stem/stromal cells. Stem Cells. 2020 Jan;38(1):15-21. doi: 10.1002/stem.3061. Epub 2019 Oct 1. PMID: 31381842; PMCID: PMC7004029.
  28. Yáñez-Mó M, Siljander PR, Andreu Z, Zavec AB, Borràs FE, Buzas EI, Buzas K, Casal E, Cappello F, Carvalho J, Colás E, Cordeiro-da Silva A, Fais S, Falcon-Perez JM, Ghobrial IM, Giebel B, Gimona M, Graner M, Gursel I, Gursel M, Heegaard NH, Hendrix A, Kierulf P, Kokubun K, Kosanovic M, Kralj-Iglic V, Krämer-Albers EM, Laitinen S, Lässer C, Lener T, Ligeti E, Linē A, Lipps G, Llorente A, Lötvall J, Manček-Keber M, Marcilla A, Mittelbrunn M, Nazarenko I, Nolte-'t Hoen EN, Nyman TA, O'Driscoll L, Olivan M, Oliveira C, Pállinger É, Del Portillo HA, Reventós J, Rigau M, Rohde E, Sammar M, Sánchez-Madrid F, Santarém N, Schallmoser K, Ostenfeld MS, Stoorvogel W, Stukelj R, Van der Grein SG, Vasconcelos MH, Wauben MH, De Wever O. Biological properties of extracellular vesicles and their physiological functions. J Extracell Vesicles. 2015 May 14;4:27066. doi: 10.3402/jev.v4.27066. PMID: 25979354; PMCID: PMC4433489.
  29. Lener T, Gimona M, Aigner L, Börger V, Buzas E, Camussi G, Chaput N, Chatterjee D, Court FA, Del Portillo HA, O'Driscoll L, Fais S, Falcon-Perez JM, Felderhoff-Mueser U, Fraile L, Gho YS, Görgens A, Gupta RC, Hendrix A, Hermann DM, Hill AF, Hochberg F, Horn PA, de Kleijn D, Kordelas L, Kramer BW, Krämer-Albers EM, Laner-Plamberger S, Laitinen S, Leonardi T, Lorenowicz MJ, Lim SK, Lötvall J, Maguire CA, Marcilla A, Nazarenko I, Ochiya T, Patel T, Pedersen S, Pocsfalvi G, Pluchino S, Quesenberry P, Reischl IG, Rivera FJ, Sanzenbacher R, Schallmoser K, Slaper-Cortenbach I, Strunk D, Tonn T, Vader P, van Balkom BW, Wauben M, Andaloussi SE, Théry C, Rohde E, Giebel B. Applying extracellular vesicles based therapeutics in clinical trials - an ISEV position paper. J Extracell Vesicles. 2015 Dec 31;4:30087. doi: 10.3402/jev.v4.30087. PMID: 26725829; PMCID: PMC4698466.
  30. Agnes T. Reiner, Kenneth W. Witwer, Bas W.M. van Balkom, Joel de Beer, Chaya Brodie, Randolph L. Corteling, Susanne Gabrielsson, Mario Gimona, Ahmed G. Ibrahim, Dominique de Kleijn, Charles P. Lai, Jan Lötvall, Hernando A. del Portillo, Ilona G. Reischl, Milad Riazifar, Carlos Salomon, Hidetoshi Tahara, Wei Seong Toh, Marca H.M. Wauben, Vicky K. Yang, Yijun Yang, Ronne Wee Yeh Yeo, Hang Yin, Bernd Giebel, Eva Rohde, Sai Kiang Lim, Concise Review: Developing Best-Practice Models for the Therapeutic Use of Extracellular Vesicles, Stem Cells Translational Medicine, Volume 6, Issue 8, August 2017, Pages 1730–1739, https://doi.org/10.1002/sctm.17-0055
  31. Dirk M. Hermann, Thorsten R. Doeppner, and Bernd Giebel, "Extracellular Vesicles as Diagnostic Tool in Transient Ischemic Attack and Ischemic Stroke," Stroke, vol. 52, no. 9, pp. 3348–3350, Aug. 2021. https://doi.org/10.1161/STROKEAHA.121.036150
  32. Börger, V., Dittrich, R., Staubach, S., Zumegen, S., Horn, P., & Giebel, B. (2019). Tangential flow filtration, a potential method for the scaled preparation of extracellular vesicles. Cytotherapy, 21(5), S89. https://doi.org/10.1016/j.jcyt.2019.03.431&#8203
Back to overview
E-Mail schreiben Jetzt anrufen