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Mesenchymal Stem Cell Exosome Therapy
and Bioregulation
Circulating microvesicles, called exosomes, are small membrane enclosed structures that are released into the extracellular space that typically are only 30 to 100 nanometers in diameter. Exosomes are secreted by many cell types, such as B and T lymphocytes, dendritic cells, mast cells, platelets and tumor cells and are found in most bodily fluids such as blood, urine, cerebrospinal liquid, breast milk and saliva.
Exosomes are generated through invagination of the cellular membrane and then released through exocytosis. Cells can also shed portions of their membrane to generate circulating microvesicles that are typically larger and more variable in size than exosomes. Once released from the cell exosomes, can be detected in body fluids including urine and the blood. Each exosome contains proteins and RNAs that are representative of its cell of origin, including surface and cytoplasmic proteins, messenger RNA and micro RNAs. It is also known that exosomes can transfer their contents to other cells. A process that is thought to be important to several biological regulatory processes, including immune response, intercellular communication and transport, metastasis, angiogenesis and cellular survival.
In short, exosomes are extracellular vesicles and are generally hypothesized to be intercellular communication vehicles and function to transfer lipids, nucleic acids (messenger- RNAs and micro-RNAs) and proteins between cells to elicit biological responses in recipient cells. There has been an exponential increase in the number of exosome-related publications over the last several years.
Therapeutically, mesenchymal stem cell exosomes are tiny molecules of micro-RNA that are ultra-concentrated and can exert dynamic healing inside the body. Mesenchymal stem exosomes are therapeutically administered through injection. Mesenchymal stem cell exosomes injections are considered safer than other forms of stem cell therapy. They are smaller than a cell and exert all the beneficial effects of stem cell therapy but are not delayed in their bioregulation process. In other words, you do not have to wait for their effect. Also, there is no foreign DNA, there is no use of a preservative to freeze it that might cause an allergic reaction, it is sterile, and it is safe to use in more than one location. Exosomes can be injected into a joint or around a nerve, injected into the spine or CSF, applied to a facial, or even infused intravenously or intrathecally to influence neurologic or immunologic disorders that previously could not be treated with former stem cell therapies.
Beneficial uses of mesenchymal stem cell exosomes include (but are not limited to):
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chronic inflammatory and autoimmune diseases; chronic fatigue syndrome
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neurodegenerative diseases including Parkinson’s disease, multiple sclerosis, stroke, chronic demyelinating inflammatory neuropathies, etc (exosomes penetrate through the blood brain barrier)
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arthritis
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acute and chronic tendinitis and tendinosis
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muscle fatigue and muscle weakness
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coronary artery disease and congestive heart failure
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chronic hepatitis and other liver diseases
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chronic kidney diseases
This diagram demonstrates the pathway of exosome therapy in stroke and brain regeneration.
Mesenchymal Stem Cells Derived Exosomes and Osteoarthritis
Cosenza, Stella, Maxime Ruiz, Karine Toupet, Christian Jorgensen, and Danièle Noël. Mesenchymal stem cells derived exosomes and microparticles protect cartilage and bone from degradation in osteoarthritis. Scientific reports 7, no. 1 (2017): 16214.
Kato, Tomohiro, Shigeru Miyaki, Hiroyuki Ishitobi, Yoshihiro Nakamura, Tomoyuki Nakasa, Martin K. Lotz, and Mitsuo Ochi. Exosomes from IL-1β stimulated synovial fibroblasts induce osteoarthritic changes in articular chondrocytes. Arthritis research & therapy 16, no. 4 (2014): R163.
Kordelas, L., V. Rebmann, A. K. Ludwig, S. Radtke, J. Ruesing, T. R. Doeppner, M. Epple, P. A. Horn, D. W. Beelen, and B. Giebel. MSC-derived exosomes: a novel tool to treat therapy-refractory graft-versus-host disease. Leukemia 28, no. 4 (2014): 970.
Pourakbari, Ramin, Meysam Khodadadi, Ali Aghebati-Maleki, Leili Aghebati-Maleki, and Mehdi Yousefi. The potential of exosomes in the therapy of the cartilage and bone complications; emphasis on osteoarthritis. Life Sciences (2019): 116861.
Tao, Shi-Cong, Ting Yuan, Yue-Lei Zhang, Wen-Jing Yin, Shang-Chun Guo, and Chang-Qing Zhang. Exosomes derived from miR-140-5p-overexpressing human synovial mesenchymal stem cells enhance cartilage tissue regeneration and prevent osteoarthritis of the knee in a rat model. Theranostics 7, no. 1 (2017): 180.
Toh, Wei Seong, Ruenn Chai Lai, James Hoi Po Hui, and Sai Kiang Lim. MSC exosome as a cell-free MSC therapy for cartilage regeneration: implications for osteoarthritis treatment. In Seminars in cell & developmental biology, vol. 67, pp. 56-64. Academic Press, 2017.
Vonk, Lucienne A., Sanne FJ van Dooremalen, Nalan Liv, Judith Klumperman, Paul J. Coffer, Daniël BF Saris, and Magdalena J. Lorenowicz. Mesenchymal stromal/stem cell-derived extracellular vesicles promote human cartilage regeneration in vitro. Theranostics 8, no. 4 (2018): 906.
Wang, Yafei, Dongsheng Yu, Zhiming Liu, Fang Zhou, Jun Dai, Bingbing Wu, Jing Zhou et al. Exosomes from embryonic mesenchymal stem cells alleviate osteoarthritis through balancing synthesis and degradation of cartilage extracellular matrix. Stem cell research & therapy 8, no. 1 (2017): 189.
Zhang, S., W. C. Chu, R. C. Lai, S. K. Lim, J. H. P. Hui, and W. S. Toh. Exosomes derived from human embryonic mesenchymal stem cells promote osteochondral regeneration. Osteoarthritis and cartilage 24, no. 12 (2016): 2135-2140.
Zhang, Shipin, Shang Jiunn Chuah, Ruenn Chai Lai, James Hoi Po Hui, Sai Kiang Lim, and Wei Seong Toh. MSC exosomes mediate cartilage repair by enhancing proliferation, attenuating apoptosis and modulating immune reactivity. Biomaterials 156 (2018): 16-27.
Zhang, Jieyuan, Xiaolin Liu, Haiyan Li, Chunyuan Chen, Bin Hu, Xin Niu, Qing Li, Bizeng Zhao, Zongping Xie, and Yang Wang. Exosomes/tricalcium phosphate combination scaffolds can enhance bone regeneration by activating the PI3K/Akt signaling pathway. Stem cell research & therapy 7, no. 1 (2016): 136.
Mesenchymal Stem Cells Derived Exosomes and Cardiovascular Disease
Arslan, Fatih, Ruenn Chai Lai, Mirjam B. Smeets, Lars Akeroyd, Andre Choo, Eissa NE Aguor, Leo Timmers et al. Mesenchymal stem cell-derived exosomes increase ATP levels, decrease oxidative stress and activate PI3K/Akt pathway to enhance myocardial viability and prevent adverse remodeling after myocardial ischemia/reperfusion injury. Stem cell research 10, no. 3 (2013): 301-312.
Lai, Ruenn Chai, Characterization of the secretion of mesenchymal stem cells and its relevance to cardioprotection. PhD diss., 2011.
Lai, Ruenn Chai, Tian Sheng Chen, and Sai Kiang Lim. Mesenchymal stem cell exosome: a novel stem cell-based therapy for cardiovascular disease. Regenerative medicine 6, no. 4 (2011): 481-492.
Lai, Ruenn Chai, Fatih Arslan, May May Lee, Newman Siu Kwan Sze, Andre Choo, Tian Sheng Chen, Manuel Salto-Tellez et al. Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem cell research 4, no. 3 (2010): 214-222.
Mesenchymal Stem Cells Derived Exosomes and Treatment of Stroke
Chen, Kuan-Hung, Chih-Hung Chen, Christopher Glenn Wallace, Chun-Man Yuen, Gour-Shenq Kao, Yi-Ling Chen, Pei-Lin Shao et al. Intravenous administration of xenogenic adipose-derived mesenchymal stem cells (ADMSC) and ADMSC-derived exosomes markedly reduced brain infarct volume and preserved neurological function in rat after acute ischemic stroke. Oncotarget 7, no. 46 (2016): 74537.
Chen, Jieli, and Michael Chopp. Exosome therapy for stroke. Stroke 49, no. 5 (2018): 1083-1090.
Xin, Hongqi, Yi Li, Yisheng Cui, James J. Yang, Zheng Gang Zhang, and Michael Chopp. Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats. Journal of Cerebral Blood Flow & Metabolism 33, no. 11 (2013): 1711-1715.
Xin, Hongqi, Yi Li, and Michael Chopp. Exosomes/miRNAs as mediating cell-based therapy of stroke. Frontiers in cellular neuroscience 8 (2014): 377.
Zhang, Zheng Gang, and Michael Chopp. Exosomes in stroke pathogenesis and therapy. The Journal of clinical investigation 126, no. 4 (2016): 1190-1197.
Mesenchymal Stem Cells Derived Exosomes and Parkinson's Disease Therapy
Haney, Matthew J., Natalia L. Klyachko, Yuling Zhao, Richa Gupta, Evgeniya G. Plotnikova, Zhijian He, Tejash Patel et al. Exosomes as drug delivery vehicles for Parkinson's disease therapy. Journal of Controlled Release 207 (2015): 18-30.
Kojima, Ryosuke, Daniel Bojar, Giorgio Rizzi, Ghislaine Charpin-El Hamri, Marie Daoud El-Baba, Pratik Saxena, Simon Ausländer, Kelly R. Tan, and Martin Fussenegger. Designer exosomes produced by implanted cells intracerebrally deliver therapeutic cargo for Parkinson’s disease treatment. Nature communications 9, no. 1 (2018): 1305.
Vilaça-Faria, Helena, António J. Salgado, and Fábio G. Teixeira. Mesenchymal Stem Cells-derived Exosomes: A New Possible Therapeutic Strategy for Parkinson’s Disease? Cells 8, no. 2 (2019): 118.
Mesenchymal Stem Cells Derived Exosomes and Kidney Repair
Gatti, Stefano, Stefania Bruno, Maria Chiara Deregibus, Andrea Sordi, Vincenzo Cantaluppi, Ciro Tetta, and Giovanni Camussi. Microvesicles derived from human adult mesenchymal stem cells protect against ischaemia–reperfusion-induced acute and chronic kidney injury. Nephrology Dialysis Transplantation 26, no. 5 (2011): 1474-1483.
Van Balkom, Bas WM, Trairak Pisitkun, Marianne C. Verhaar, and Mark A. Knepper. Exosomes and the kidney: prospects for diagnosis and therapy of renal diseases. Kidney international 80, no. 11 (2011): 1138-1145.
Mesenchymal Stem Cells Derived Exosomes and Neurological Repair
Xin, Hongqi, Yi Li, Ben Buller, Mark Katakowski, Yi Zhang, Xinli Wang, Xia Shang, Zheng Gang Zhang, and Michael Chopp. Exosome‐mediated transfer of miR‐133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth. Stem cells 30, no. 7 (2012): 1556-1564.
Mesenchymal Stem Cells Derived Exosomes and Cancer
Boelens, Mirjam C., Tony J. Wu, Barzin Y. Nabet, Bihui Xu, Yu Qiu, Taewon Yoon, Diana J. Azzam et al. Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways. Cell 159, no. 3 (2014): 499-513.
Bruno, Stefania, Federica Collino, Maria Chiara Deregibus, Cristina Grange, Ciro Tetta, and Giovanni Camussi. Microvesicles derived from human bone marrow mesenchymal stem cells inhibit tumor growth. Stem cells and development 22, no. 5 (2012): 758-771.
Katakowski, Mark, Ben Buller, Xuguang Zheng, Yong Lu, Thomas Rogers, Oyinkansola Osobamiro, Wayne Shu, Feng Jiang, and Michael Chopp. Exosomes from marrow stromal cells expressing miR-146b inhibit glioma growth. Cancer letters 335, no. 1 (2013): 201-204.
Lee, Jong-Kuen, Sae-Ra Park, Bong-Kwang Jung, Yoon-Kyung Jeon, Yeong-Shin Lee, Min-Kyoung Kim, Yong-Goo Kim, Ji-Young Jang, and Chul-Woo Kim. Exosomes derived from mesenchymal stem cells suppress angiogenesis by down-regulating VEGF expression in breast cancer cells. PloS one 8, no. 12 (2013): e84256.
Wang, Jinheng, Yongjiang Zheng, and Meng Zhao. Exosome-based cancer therapy: implication for targeting cancer stem cells. Frontiers in pharmacology 7 (2017): 533.
Mesenchymal Stem Cells Derived Exosomes and Autoimmune Disease
Kim, Seon-Hee, Eric R. Lechman, Nicole Bianco, Rajasree Menon, Annahita Keravala, Joan Nash, Zhibao Mi, Simon C. Watkins, Andrea Gambotto, and Paul D. Robbins. Exosomes derived from IL-10-treated dendritic cells can suppress inflammation and collagen-induced arthritis. The Journal of Immunology 174, no. 10 (2005): 6440-6448.
Maumus, Marie, Christian Jorgensen, and Danièle Noël. Mesenchymal stem cells in regenerative medicine applied to rheumatic diseases: role of secretome and exosomes. Biochimie 95, no. 12 (2013): 2229-2234.
Perez-Hernandez, Javier, Josep Redon, and Raquel Cortes. Extracellular vesicles as therapeutic agents in systemic lupus erythematosus. International journal of molecular sciences 18, no. 4 (2017): 717.
Mesenchymal Stem Cells Derived Exosomes and Drug Delivery
Yang, Tianzhi, Paige Martin, Brittany Fogarty, Alison Brown, Kayla Schurman, Roger Phipps, Viravuth P. Yin, Paul Lockman, and Shuhua Bai. Exosome delivered anticancer drugs across the blood-brain barrier for brain cancer therapy in Danio rerio (zebrafish). Pharmaceutical research 32, no. 6 (2015): 2003-2014.