DOI:10.32604/biocell.2022.018470
| BIOCELL DOI:10.32604/biocell.2022.018470 | |
| Article |
Mesenchymal stem cell-derived exosome: The likely game-changer in stem cell research
1Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, China
2Directorate of University Health Services, University of Cape Coast, Cape Coast, Ghana
*Address correspondence to: Fei Mao, maofei2003@ujs.edu.cn; Dickson Kofi Wiredu Ocansey, dickson.ocansey@ucc.edu.gh
Received: 26 July 2021; Accepted: 26 September 2021
Abstract: Stem cell research is a promising area of transplantation and regenerative medicine with tremendous potential for improving the clinical treatment and diagnostic options across a variety of conditions and enhancing understanding of human development. Over the past few decades, mesenchymal stem cell (MSCs) studies have exponentially increased with a promising outcome. However, regardless of the huge investment and the research attention given to stem cell research, FDA approval for clinical use is still lacking. Amid the challenges confronting stem cell research as a cell-based product, there appears to be evidence of superior effect and heightened potential success in its expressed vesicles, exosomes, as cell-free products. In addition to their highly desirable intrinsic biologically unique structural, compositional, and morphological characteristics, as well as predominant physiochemical stability and biocompatibility properties, exosomes can also be altered to enhance their therapeutic capability or diagnostic imaging potential via physical, chemical, and biological modification approaches. More importantly, the powerful therapeutic potential and superior biological functions of exosomes, particularly, regarding engineered exosomes as cell-free products, and their utilization in a new generation of nanomedicine treatment, vaccination, and diagnosis platforms, brings hope of a change in the near future. This viewpoint discusses the trend of stem cell research and why stem cell-derived exosomes could be the game-changer.
Keywords: Mesenchymal stem cell; Exosome; Cell-free therapy; Regenerative medicine
The concept of stem cells emanated in the 19th century as a theoretical postulate that accounted for the ability of certain tissues including, blood and skin to self-renew for the lifetime of an organism. The discovery of stem cells as individually separate and distinct cellular entities followed many years later as a result of developed methods for their prospective isolation, in addition to rigorous bioassays designed to test their potency (Bianco et al., 2008). The currently popular concept of mesenchymal stem cells (MSCs), a term first coined by Caplan, is traced to classical experiments of bone marrow transplantation that caused de novo formation of ectopic bone and marrow (Caplan, 1991). Over the past 20 years, research on MSCs has exponentially increased (Fig. 1) due to the promising treatment outcome for a variety of human diseases including, cardiovascular diseases, blood malignancies, metabolic diseases (diabetes, obesity), bone regeneration and arthritis, neurodegenerative disease, and several inflammatory diseases, as they potently differentiate into osteoblasts, adipocytes, and chondrocytes and exhibit the potential to regenerate damaged tissues (Farahzadi et al., 2020; Fu et al., 2019). Moreover, the therapeutic potentials of MSCs are maintained and even further enhanced via modifications against the inhospitable microenvironment during culture and transplantation, resulting in improved migration, homing to target site, adhesion, survival, and reduced premature senescence (Nie et al., 2020; Ocansey et al., 2020a). There are several completed and ongoing clinical trials at different phases, involving therapeutics of MSCs across many human diseases.
However, irrespective of the huge investment and the attention given to stem cell research, approval for clinical use is still lacking. Amidst the challenges confronted by stem cell research as a cell-based product, there appears to be a gradual paradigm shift from stem cell-based research to its derived exosomes and exosomes from other sources as a cell-free product. After the discovery that exosomes are responsible for the therapeutic effects of MSCs, huge attention has been shifted towards these extracellular vesicles in regenerative medicine in the past few years (Fig. 1). Exosomes are 30 nm–150 nm size cell-derived vesicles involved in cell-to-cell communication and capable of modulating both physiological and pathological activities. The authors present their viewpoint on the superiority of MSC-derived exosomes as cell-free products and the promising potential in changing the narration on stem cell research.
Figure 1: The trend of MSC and exosome research in the past 20 years. Literature on MSCs and exosomes from the PubMed online library indicates a constant increase in research on both, with studies on exosomes increasing at a higher rate than MSCs in the past six years or more.
Reasons for the increased focus on MSC-derived exosomes
Regardless of the progress made in stem cell research, the only stem cell-based products that are approved for use in the US by the FDA consist of blood-forming stem cells (hematopoietic progenitor cells) derived from cord blood for limited use in patients with disorders that affect the body system that is involved in the production of blood (FDA, 2019). Several investors might have reduced support for stem cell research, with sources of funds running out or already dried up as recently reported of California, a state in the US (Kaiser, 2019). Several factors contribute to the gradual changing trend toward exosomal research. Studies show that the pleiotropic effects of MSCs are not associated with their capability of differentiation, but rather the mediation of secreted soluble paracrine factors such as exosomes. Exosomes have unique structural, compositional, and morphological characteristics as well as predominant physiochemical stability and biocompatibility properties (Wu et al., 2020). These desirable intrinsic biological properties are maintained and even further enhanced through genetic modification and preconditioning modification (using drugs, growth factors, and other molecules) against the inhospitable microenvironment during culture and transplantation. The ability of MSCs to get engrafted or concentrate at the target site to promote direct damage repair is highly desirable, however, relatively few intravenously administered MSCs get to the site of injury due to “caught-up” in lung capillaries, leading to clearance; while other studies report short-lived therapeutic effects of MSCs (Guadalajara et al., 2012; Ocansey et al., 2020b). Moreover, compared with MSCs, exosomes are more convenient to store and transport.
More importantly, exosomes, as cell-free therapy, possess enhanced delivery of exogenous biological particles to the target site and directly into the cytosol, circumventing the lysosomal-endosomal pathway, and consequently elevating transfection efficiency (Wu et al., 2020). As a result of their small sizes and other camouflage strategies, exosomes are capable of evading the mononuclear phagocytic system’s clearance, leading to extended circulatory time for passive targeting of inflammatory and cancerous cells (Belhadj et al., 2020; Parada et al., 2021). In comparison to their parent cells, these extracellular vesicles are more stable and could reduce the inherent safety risks associated with the administration of cell-based therapy, including the risk of occlusion in the microvasculature, as well as possible immune recognition by the host system (Nikfarjam et al., 2020). Recent development also indicates that exosomes are speedily evolving as a potential treatment option for cancer, and potential biomarkers for both the diagnosis and prognosis of cancer and other inflammatory conditions. These special properties among others (Fig. 2) give MSC-derived exosomes enormous potentials over the parental cell therapy in regenerative medicine and cancer treatment.
Figure 2: The characteristic features of MSC-derived exosomes that highlight their potentials. Both the inherent biological properties and the ability of easy modification of exosomes makes them a better option as cell-free products than their parental cells.
The promise of MSC-derived exosomal research
The constantly expanding exploration of MSC-derived exosomes covers research in several human diseases including application in neurodegenerative conditions and nerve injury (Dong et al., 2019; Perets et al., 2019), liver diseases (Lou et al., 2017), cardiac conditions (Lai et al., 2010), inflammatory bowel disease (Ocansey et al., 2020c; Wang et al., 2020), eye diseases (Harrell et al., 2018), cartilage regeneration (Toh et al., 2017) and matrix homeostasis restoration for osteoarthritis (Zhang et al., 2019), cutaneous regeneration (Wu et al., 2018), bone regeneration (Fan et al., 2020), among others. Many research teams in the field of stem cell research, are now keenly exploring the complex array of cargoes (proteins, lipids, RNAs, and DNAs) that are differentially expressed in exosomes from a variety of sources, including MSCs. The development towards a better understanding of the molecular composition, mechanism of effects, and heterogeneity of exosomes is paving the way not only for their therapeutic application but diagnostic and prognostic implications in several diseases (Ferguson and Nguyen, 2016; Yang et al., 2019; Zamani et al., 2019). Interestingly, exosomes have been shown to not only regulate inflammation but also shape the gut microbiota, a crucial determinant of inflammatory and metabolic diseases (Teng et al., 2018). Given the critical role of the gut microbiota in health and diseases, and the involvement of exosomes in cell-to-cell communication, the discovery and subsequent optimization of the mechanism of exosome-mediated restoration of the gut microbiota would be an important breakthrough for medicine. Moreover, harnessing exosomes as therapeutic drug delivery tools and vaccinations is a promising development in translational medicine. Engineered exosomes may be used to improve targeted therapy in tissues damage repair and cancer, and may be developed as an individualized imaging diagnostic reagent, among other potential applications (Wu et al., 2020).
Stem cell-derived exosome is likely to change the narration of stem cell research, as it presents enormous hope of a breakthrough in therapeutic, diagnostic, prognostic, and vaccination application. However, while stem cells express large quantities of exosomes naturally, effective separation and purification, as well as optimum storage conditions of these vesicles continue to be of concern. There is a need to focus attention on the optimal isolation and purification procedures to allow the production of a well-defined set of pharmaceutical-grade exosome products as a next-generation cell-free therapy in regenerative medicine. Moreover, we still require studies on the best exosome administration route and dosage, as well as a better understanding of the mechanisms and factors that influence their biogenesis and effects.
Author Contribution: The authors confirm contribution to the paper as follows: study conception and design: DKWO, FM, XX; data collection: LZ, DWKO; analysis and interpretation of results: FM, DKWO; draft manuscript preparation: LZ, XX, DKWO. All authors reviewed and approved the final version of the manuscript.
Funding Statement: The authors received no specific funding for this study.
Conflicts of Interest: The authors declare that they have no conflicts of interest to report regarding the present study.
Belhadj Z, He B, Deng H, Song S, Zhang H et al. (2020). A combined eat me/don’t eat me strategy based on extracellular vesicles for anticancer nanomedicine. Journal of Extracellular Vesicles 9: 1806444. DOI 10.1080/20013078.2020.1806444. [Google Scholar] [CrossRef]
Bianco P, Robey PG, Simmons PJ (2008). Mesenchymal stem cells: Revisiting history, concepts, and assays. Cell Stem Cell 2: 313–319. DOI 10.1016/j.stem.2008.03.002. [Google Scholar] [CrossRef]
Caplan AI (1991). Mesenchymal stem cells. Journal of Orthopaedic Research 9: 641–650. DOI 10.1002/(ISSN)1554-527X. [Google Scholar] [CrossRef]
Dong R, Liu Y, Yang Y, Wang H, Xu Y et al. (2019). MSC-derived exosomes-based therapy for peripheral nerve injury: A novel therapeutic strategy. BioMed Research International 2019: 1–12. DOI 10.1155/2019/6458237. [Google Scholar] [CrossRef]
Fan J, Lee CS, Kim S, Chen C, Aghaloo T et al. (2020). Generation of small RNA-modulated exosome mimetics for bone regeneration. ACS Nano 14: 11973–11984. DOI 10.1021/acsnano.0c05122. [Google Scholar] [CrossRef]
Farahzadi R, Fathi E, Vietor I (2020). Mesenchymal stem cells could be considered as a candidate for further studies in cell-based therapy of alzheimer’s disease via targeting the signaling pathways. ACS Chemical Neuroscience 11: 1424–1435. DOI 10.1021/acschemneuro.0c00052. [Google Scholar] [CrossRef]
FDA (2019). FDA Warns about Stem Cell Therapies. The US FDA. [Google Scholar]
Ferguson SW, Nguyen J (2016). Exosomes as therapeutics: The implications of molecular composition and exosomal heterogeneity. Journal of Controlled Release: Official Journal of the Controlled Release Society 228: 179–190. DOI 10.1016/j.jconrel.2016.02.037. [Google Scholar] [CrossRef]
Fu X, Liu G, Halim A, Ju Y, Song G (2019). Mesenchymal stem cell migration and tissue repair. Cells 8: 784. DOI 10.3390/cells8080784. [Google Scholar] [CrossRef]
Guadalajara H, Herreros D, De-La-Quintana P, Trebol J (2012). Long-term follow-up of patients undergoing adipose-derived adult stem cell administration to treat complex perianal fistulas. International Journal of Colorectal Disease 27: 595–600. DOI 10.1007/s00384-011-1350-1. [Google Scholar] [CrossRef]
Harrell CR, Simovic Markovic B, Fellabaum C, Arsenijevic A, Djonov V et al. (2018). Therapeutic potential of mesenchymal stem cell-derived exosomes in the treatment of eye diseases. In: Cell biology and translational medicine, 2: pp. 47–57. [Google Scholar]
Kaiser J (2019). California’s stem cell research fund dries up. Science. 365: 107–108. DOI 10.1126/science.aay6799. [Google Scholar] [CrossRef]
Lai RC, Arslan F, Lee MM, Sze NSK, Choo A et al. (2010). Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Research 4: 214–222. DOI 10.1016/j.scr.2009.12.003. [Google Scholar] [CrossRef]
Lou G, Chen Z, Zheng M, Liu Y (2017). Mesenchymal stem cell-derived exosomes as a new therapeutic strategy for liver diseases. Experimental & Molecular Medicine 49: e346. DOI 10.1038/emm.2017.63. [Google Scholar] [CrossRef]
Nie WB, Zhang D, Wang LS (2020). Growth factor gene-modified mesenchymal stem cells in tissue regeneration. Drug Design, Development and Therapy 14: 1241–1256. DOI 10.2147/DDDT.S243944. [Google Scholar] [CrossRef]
Nikfarjam S, Rezaie J, Zolbanin NM, Jafari R (2020). Mesenchymal stem cell derived-exosomes: A modern approach in translational medicine. Journal of Translational Medicine 18: 3871. DOI 10.1186/s12967-020-02622-3. [Google Scholar] [CrossRef]
Ocansey DKW, Pei B, Yan Y, Qian H, Zhang X et al. (2020a). Improved therapeutics of modified mesenchymal stem cells: An update. Journal of Translational Medicine 18: 276. DOI 10.1186/s12967-020-02234-x. [Google Scholar] [CrossRef]
Ocansey DKW, Qiu W, Wang J, Yan Y, Qian H et al. (2020b). The achievements and challenges of mesenchymal stem cell-based therapy in inflammatory bowel disease and its associated colorectal cancer. Stem Cells International 2020: 1–18. DOI 10.1155/2020/7819824. [Google Scholar] [CrossRef]
Ocansey DKW, Zhang L, Wang Y, Yan Y, Qian H et al. (2020c). Exosome-mediated effects and applications in inflammatory bowel disease. Biological Reviews 95: 1287–1307. DOI 10.1111/brv.12608. [Google Scholar] [CrossRef]
Parada N, Romero-Trujillo A, Georges N, Alcayaga-Miranda F (2021). Camouflage strategies for therapeutic exosomes evasion from phagocytosis. Journal of Advanced Research 31: 61–74. DOI 10.1016/j.jare.2021.01.001. [Google Scholar] [CrossRef]
Perets N, Betzer O, Shapira R, Brenstein S, Angel A et al. (2019). Golden exosomes selectively target brain pathologies in neurodegenerative and neurodevelopmental disorders. Nano Letters 19: 3422–3431. DOI 10.1021/acs.nanolett.8b04148. [Google Scholar] [CrossRef]
Teng Y, Ren Y, Sayed M, Hu X, Lei C et al. (2018). Plant-derived exosomal microRNAs shape the gut microbiota. Cell Host & Microbe 24: 637–652.e8. DOI 10.1016/j.chom.2018.10.001. [Google Scholar] [CrossRef]
Toh WS, Lai RC, Hui JHP, Lim SK (2017). MSC exosome as a cell-free MSC therapy for cartilage regeneration: Implications for osteoarthritis treatment. Seminars in Cell & Developmental Biology 67: 56–64. DOI 10.1016/j.semcdb.2016.11.008. [Google Scholar] [CrossRef]
Wang G, Yuan J, Cai X, Xu Z, Wang J et al. (2020). HucMSC-exosomes carrying miR-326 inhibit neddylation to relieve inflammatory bowel disease in mice. Clinical and Translational Medicine 10: 8106818. DOI 10.1002/ctm2.113. [Google Scholar] [CrossRef]
Wu P, Zhang B, Ocansey DKW, Xu W, Qian H (2020). Extracellular vesicles: A bright star of nanomedicine. Biomaterials 269: 120467. DOI 10.1016/j.biomaterials.2020.120467. [Google Scholar] [CrossRef]
Wu P, Zhang B, Shi H, Qian H, Xu W (2018). MSC-exosome: A novel cell-free therapy for cutaneous regeneration. Cytotherapy 20: 291–301. DOI 10.1016/j.jcyt.2017.11.002. [Google Scholar] [CrossRef]
Yang B, Chen Y, Shi J (2019). Exosome biochemistry and advanced nanotechnology for next-generation theranostic platforms. Advanced Materials 31: 1802896. DOI 10.1002/adma.201802896. [Google Scholar] [CrossRef]
Zamani P, Fereydouni N, Butler AE, Navashenaq JG, Sahebkar A (2019). The therapeutic and diagnostic role of exosomes in cardiovascular diseases. Trends in Cardiovascular Medicine 29: 313–323. DOI 10.1016/j.tcm.2018.10.010. [Google Scholar] [CrossRef]
Zhang S, Teo KYW, Chuah SJ, Lai RC, Lim SK et al. (2019). MSC exosomes alleviate temporomandibular joint osteoarthritis by attenuating inflammation and restoring matrix homeostasis. Biomaterials 200: 35–47. DOI 10.1016/j.biomaterials.2019.02.006. [Google Scholar] [CrossRef]
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