A correction has been applied to this article in:
Corrigendum: Editorial: MSC-derived exosomes in tissue regeneration
Xin-Ming Chen
Xiaodan Wang
Zongliu Hou- 1Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW, Australia
- 2Renal Medicine, The University of Sydney, Darlington, NSW, Australia
- 3Central Laboratory of Kunming Yan’an Hospital, Kunming Medical University, Kunming, Yunnan, China
- 4Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, China
Editorial on the Research Topic
MSC-derived exosomes in tissue regeneration
Tissue regeneration is a process of renewal, restoration and regrowth of injured or damaged organs and tissues, this repair process includes regeneration of epithelial tissue, fibrous tissue, cartilage tissue, bone tissue, blood vessels, muscle tissue, and nerve tissue, etc. To date, various biomedical technologies such as organ transplantation, tissue engineering, stem cell therapy, miRNA treatment, nanomedicine, organoids, and 3D bio-printing have been applied in the study of regenerative medicine. Among them, stem cell-based tissue regeneration in wound healing, bone disorders, liver fibrosis, kidney fibrosis, cardiovascular fibrosis and neurological disorders has been widely reported and reviewed (Iaquinta et al., 2019; Gubert et al., 2021; Liu et al., 2021; Sivandzade and Cucullo, 2021; Liu et al., 2022; Lukomskyj et al., 2022). For example, bone marrow mesenchymal stem cells (BMSCs) were reported to increase epidermal autophagy and the rate of re-epithelialization, and lead to accelerated healing in diabetic wounds (Shi et al., 2022). Human pluripotent stem cell-derived cartilaginous organoids promote scaffold-free healing of critical size long bone defects (Tam et al., 2021). Adipose-derived stem cell transplantation attenuates inflammation and promotes liver regeneration after ischemia-reperfusion and hemihepatectomy in Swine (Jiao et al., 2019). BMSCs and their conditioned medium attenuate fibrosis in an irreversible model of unilateral ureteral obstruction (da Silva et al., 2015) and adipose-derived stem cells ameliorate renal interstitial fibrosis through inhibition of EMT and inflammatory response via TGF-β1 signaling pathway (Song et al., 2017). MSCs reverse diabetic nephropathy disease via Lipoxin A4 by targeting transforming growth factor β (TGF-β)/smad pathway and proinflammatory cytokines (Bai et al., 2019). MSCs were used to enhance the functionality and therapeutic efficacy of cell-based therapy for cardiovascular disease (Yun and Lee, 2019). MSCs were used as a multimodal treatment for nervous system diseases (Badyra et al., 2020).
Although stem cells have emerged as promising sources for regenerative medicine, there are potential safety concerns, risks and disadvantages in their clinical use such as tumorigenesis, lack of availability, survival time and unknown long-term effects. MSCs are commonly used in cellular therapy trials for immunomodulation and regenerative medicine (Squillaro et al., 2016; Galipeau and Sensebe, 2018), however, one of the key mechanisms of MSC efficacy is considered to be derived from their paracrine activity. MSC-derived exosomes are enriched with therapeutic miRNAs, mRNAs, cytokines, lipids, and growth factors. It has been reported that MSC released extracellular vesicle exosomes (30–150 nm in diameter) may act as paracrine mediators between MSCs and target cells (Heldring et al., 2015; Mendt et al., 2018). MSC-derived exosomes can recapitulate the biological activity of MSCs and may serve as an alternative to whole cell therapy (Lou et al., 2017; Bagno et al., 2018). Numerous in vivo studies have demonstrated that the therapeutic benefit of MSCs is principally orchestrated by the paracrine secretion of a broad repertoire of growth factors, chemokines, and cytokines (Deng et al., 2015; Wang et al., 2015; Yao et al., 2015). Due to their natural involvement in the intercellular exchange of biomolecules, exosomes hold great potential as a novel biotherapy. The use of MSC-derived exosomes may provide considerable advantages over their counterpart live cells due to a higher safety profile, lower immunogenicity, and the inability to directly form tumors directly (Liew et al., 2017). Therefore, MSC-derived exosomes represent a novel cell-free therapy with compelling advantages over parent MSCs as there is no risk of tumor formation and lower immunogenicity (Mendt et al., 2019; Yin et al., 2019; Joo et al., 2020).
Recently published articles in this journal have updated the progress in MSC-derived exosomes in tissue regeneration. Huang et al. have reported that engineering MSC-derived extracellular vesicles (EV) with miR-424 promoted bone repair through targeting the BMP2 cascade. The presented results showed that the engineered MSC-derived EV enhanced osteoinductive function by activating SMADl/5/8 phosphorylation and enhanced bone repair in vivo. Based on these results it was concluded that miRNA-based EV engineering could be a promising approach for regenerative medicine. Dong et al. have reported that adipose tissue-derived small EVs (sEV-AT) modulate macrophages to improve the homing of adipocyte precursors and endothelial cells in adipose tissue regeneration. In this study, sEV-AT increased macrophage infiltration significantly, which was followed by improving homing of adipocyte precursors (APs) and endothelial cells (ECs), and sEV-AT-pretreated macrophages improved the migration of APs and ECs, accompanied by the increase of chemokines (MCP-1, SDF-1, VEGF, and FGF) and the activation of NF-kB signaling pathway. As suggested, sEV-AT might regulate the secretion of chemokines via activating the NF-kB signaling pathway to improve homing of APs and ECs and facilitate adipose tissue regeneration Dong et al. Zhao et al. have summarized the therapeutic applications of modified MSC-exosomes in wound healing and skin regeneration in the review article. In this review article, Zhao et al. have comprehensively reviewed recent studies of MSC-exosomes and bioengineering modified MSC-exosomes in skin wound healing and regeneration. It was concluded that MSC-exosomes could provide an alternative option for wound healing. However, further research warrants to a largely increase in the availability of modified MSC-exosomes for future clinical applications in wound healing and skin regeneration. Another study reported by Huang et al. has demonstrated that MSC-derived exosomes ameliorate ischemia/reperfusion induced acute kidney injury in a porcine model. This study has shown that human umbilical cord mesenchymal stem cell (hUC-MSCs)-derived exosomes significantly improved renal function impairment and reduced apoptosis and necroptosis induced by Ischemia/Reperfusion-induced Acute Kidney Injury (I/R-AKI); these exosomes inhibited the expression of some pro-inflammatory cytokines/chemokines, decreased infiltration of macrophages into the injured kidneys and suppressed the phosphorylation of nuclear factor-KB. Interestingly, hUC-MSC exosomes could promote the proliferation of renal tubular cells, angiogenesis and upregulation of Klotho and BMP7 Huang et al. Based on this study, it was concluded that hUC-MSC derived exosomes may be a promising biological therapy for AKI in a clinic.
Among the various exosome-based therapies, MSC-derived exosomes have been well reported and shown the advantage and promising role in regenerative medicine due to their diverse applicability. It was well documented that MSC-derived exosomes modulate various pathophysiological processes such as cell proliferation, migration, angiogenesis, chondrogenesis, neurogenesis, anti-apoptosis, anti-scarring, anti-inflammation, and immunomodulation (Lai et al., 2015; Pashoutan Sarvar et al., 2016; Wu et al., 2018). To date, most reports about MSC-derived exosomes in tissue regenerations were from in vitro and animal studies. The clinical studies in the area are very limited. Thus, clinical trials to use MSC-derived exosomes in various tissue regenerations are essential.
Author contributions
X-MC: Conceptualization, Writing–original draft, Writing–review and editing. XW: Writing–review and editing. ZH: Writing–review and editing.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
Badyra, B., Sulkowski, M., Milczarek, O., and Majka, M. (2020). Mesenchymal stem cells as a multimodal treatment for nervous system diseases. Stem Cells Transl. Med. 9, 1174–1189. doi:10.1002/sctm.19-0430
Bagno, L., Hatzistergos, K. E., Balkan, W., and Hare, J. M. (2018). Mesenchymal stem cell-based therapy for cardiovascular disease: progress and challenges. Mol. Ther. 26, 1610–1623. doi:10.1016/j.ymthe.2018.05.009
Bai, Y., Wang, J., He, Z., Yang, M., Li, L., and Jiang, H. (2019). Mesenchymal stem cells reverse diabetic nephropathy disease via Lipoxin A4 by targeting transforming growth factor β (TGF-β)/smad pathway and pro-inflammatory cytokines. Med. Sci. Monit. 25, 3069–3076. doi:10.12659/MSM.914860
da Silva, A. F., Silva, K., Reis, L. A., Teixeira, V. P., and Schor, N. (2015). Bone marrow-derived mesenchymal stem cells and their conditioned medium attenuate fibrosis in an irreversible model of unilateral ureteral obstruction. Cell Transpl. 24, 2657–2666. doi:10.3727/096368915X687534
Deng, K., Lin, D. L., Hanzlicek, B., Balog, B., Penn, M. S., Kiedrowski, M. J., et al. (2015). Mesenchymal stem cells and their secretome partially restore nerve and urethral function in a dual muscle and nerve injury stress urinary incontinence model. Am. J. Physiol. Ren. Physiol. 308, F92–F100. doi:10.1152/ajprenal.00510.2014
Galipeau, J., and Sensebe, L. (2018). Mesenchymal stromal cells: clinical challenges and therapeutic opportunities. Cell Stem Cell 22, 824–833. doi:10.1016/j.stem.2018.05.004
Gubert, F., da Silva, J. S., Vasques, J. F., de Jesus Goncalves, R. G., Martins, R. S., de Sa, M. P. L., et al. (2021). Mesenchymal stem cells therapies on fibrotic heart diseases. Int. J. Mol. Sci. 22, 7447. doi:10.3390/ijms22147447
Heldring, N., Mager, I., Wood, M. J., Le Blanc, K., and Andaloussi, S. E. (2015). Therapeutic potential of multipotent mesenchymal stromal cells and their extracellular vesicles. Hum. Gene Ther. 26, 506–517. doi:10.1089/hum.2015.072
Iaquinta, M. R., Mazzoni, E., Bononi, I., Rotondo, J. C., Mazziotta, C., Montesi, M., et al. (2019). Adult stem cells for bone regeneration and repair. Front. Cell Dev. Biol. 7, 268. doi:10.3389/fcell.2019.00268
Jiao, Z., Ma, Y., Liu, X., Ge, Y., Zhang, Q., Liu, B., et al. (2019). Adipose-derived stem cell transplantation attenuates inflammation and promotes liver regeneration after ischemia-reperfusion and hemihepatectomy in swine. Stem Cells Int. 2019, 2489584. doi:10.1155/2019/2489584
Joo, H. S., Suh, J. H., Lee, H. J., Bang, E. S., and Lee, J. M. (2020). Current knowledge and future perspectives on mesenchymal stem cell-derived exosomes as a new therapeutic agent. Int. J. Mol. Sci. 21, 727. doi:10.3390/ijms21030727
Lai, R. C., Yeo, R. W., and Lim, S. K. (2015). Mesenchymal stem cell exosomes. Semin. Cell Dev. Biol. 40, 82–88. doi:10.1016/j.semcdb.2015.03.001
Liew, L. C., Katsuda, T., Gailhouste, L., Nakagama, H., and Ochiya, T. (2017). Mesenchymal stem cell-derived extracellular vesicles: a glimmer of hope in treating alzheimer's disease. Int. Immunol. 29, 11–19. doi:10.1093/intimm/dxx002
Liu, P., Mao, Y., Xie, Y., Wei, J., and Yao, J. (2022). Stem cells for treatment of liver fibrosis/cirrhosis: clinical progress and therapeutic potential. Stem Cell Res. Ther. 13, 356. doi:10.1186/s13287-022-03041-5
Liu, Y., Su, Y. Y., Yang, Q., and Zhou, T. (2021). Stem cells in the treatment of renal fibrosis: a review of preclinical and clinical studies of renal fibrosis pathogenesis. Stem Cell Res. Ther. 12, 333. doi:10.1186/s13287-021-02391-w
Lou, G., Chen, Z., Zheng, M., and Liu, Y. (2017). Mesenchymal stem cell-derived exosomes as a new therapeutic strategy for liver diseases. Exp. Mol. Med. 49, e346. doi:10.1038/emm.2017.63
Lukomskyj, A. O., Rao, N., Yan, L., Pye, J. S., Li, H., Wang, B., et al. (2022). Stem cell-based tissue engineering for the treatment of burn wounds: A systematic review of preclinical studies. Stem Cell Rev. Rep. 18, 1926–1955. doi:10.1007/s12015-022-10341-z
Mendt, M., Kamerkar, S., Sugimoto, H., McAndrews, K. M., Wu, C. C., Gagea, M., et al. (2018). Generation and testing of clinical-grade exosomes for pancreatic cancer. JCI Insight 3, e99263. doi:10.1172/jci.insight.99263
Mendt, M., Rezvani, K., and Shpall, E. (2019). Mesenchymal stem cell-derived exosomes for clinical use. Bone Marrow Transpl. 54, 789–792. doi:10.1038/s41409-019-0616-z
Pashoutan Sarvar, D., Shamsasenjan, K., and Akbarzadehlaleh, P. (2016). Mesenchymal stem cell-derived exosomes: new opportunity in cell-free therapy. Adv. Pharm. Bull. 6, 293–299. doi:10.15171/apb.2016.041
Shi, Y., Wang, S., Zhang, W., Zhu, Y., Fan, Z., Huang, Y., et al. (2022). Bone marrow mesenchymal stem cells facilitate diabetic wound healing through the restoration of epidermal cell autophagy via the HIF-1α/TGF-β1/SMAD pathway. Stem Cell Res. Ther. 13, 314. doi:10.1186/s13287-022-02996-9
Sivandzade, F., and Cucullo, L. (2021). Regenerative stem cell therapy for neurodegenerative diseases: an overview. Int. J. Mol. Sci. 22, 2153. doi:10.3390/ijms22042153
Song, Y., Peng, C., Lv, S., Cheng, J., Liu, S., Wen, Q., et al. (2017). Adipose-derived stem cells ameliorate renal interstitial fibrosis through inhibition of EMT and inflammatory response via TGF-β1 signaling pathway. Int. Immunopharmacol. 44, 115–122. doi:10.1016/j.intimp.2017.01.008
Squillaro, T., Peluso, G., and Galderisi, U. (2016). Clinical trials with mesenchymal stem cells: an update. Cell Transpl. 25, 829–848. doi:10.3727/096368915X689622
Tam, W. L., Freitas Mendes, L., Chen, X., Lesage, R., Van Hoven, I., Leysen, E., et al. (2021). Human pluripotent stem cell-derived cartilaginous organoids promote scaffold-free healing of critical size long bone defects. Stem Cell Res. Ther. 12, 513. doi:10.1186/s13287-021-02580-7
Wang, Z., Wang, Y., Wang, Z., Gutkind, J. S., Wang, Z., Wang, F., et al. (2015). Engineered mesenchymal stem cells with enhanced tropism and paracrine secretion of cytokines and growth factors to treat traumatic brain injury. Stem Cells 33, 456–467. doi:10.1002/stem.1878
Wu, P., Zhang, B., Shi, H., Qian, H., and 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
Yao, Y., Huang, J., Geng, Y., Qian, H., Wang, F., Liu, X., et al. (2015). Paracrine action of mesenchymal stem cells revealed by single cell gene profiling in infarcted murine hearts. PloS one 10, e0129164. doi:10.1371/journal.pone.0129164
Yin, K., Wang, S., and Zhao, R. C. (2019). Exosomes from mesenchymal stem/stromal cells: a new therapeutic paradigm. Biomark. Res. 7, 8. doi:10.1186/s40364-019-0159-x
Keywords: exosome, stem cell, tissue regeneration, tissue injury and regeneration, exosome engineering
Citation: Chen X-M, Wang X and Hou Z (2023) Editorial: MSC-derived exosomes in tissue regeneration. Front. Cell Dev. Biol. 11:1293109. doi: 10.3389/fcell.2023.1293109
Received: 12 September 2023; Accepted: 19 September 2023;
Published: 25 September 2023.
Edited and reviewed by:
Atsushi Asakura, University of Minnesota Twin Cities, United StatesCopyright © 2023 Chen, Wang and Hou. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Xin-Ming Chen, xin-ming.chen@sydney.edu.au