What are stem cell exosomes?

Inside and outside stem cells are microscopic vesicles called exosomes. Exosomes were discovered in 1983, and research has progressed in the field of life sciences.
Various physiological functions and associations with pathogenesis have been suggested. In the medical field, it has already led to new diagnostic methods using bodily fluids.
In the future, there are high expectations for its use in regenerative medicine.

Mechanism of exosomes

Inside exosomes are short gene sequences called microRNAs. Direct information is written in microRNA, and it is said that this information is the effect of stem cells. A study at UC Sandiego University reported that "stem cells have similar pharmacological effects even if they are enucleated," which means that the main pharmacological action of stem cells is EVs such as exosomes. . In addition, exosomes are naturally derived from cells, are already present in large numbers in the human body, are said to have low side effects, and are being recognized for their superiority compared to cell therapy.

Flow of exosomes created at our hospital

Note: Conventionally, exosomes are almost invisible, so a laser is applied to the exosomes and reflected so that they can be seen. The magnitude of reflection depends on the particle size and angle of reflection.
In 1996, it was discovered that exosomes function to transport substances to other cells. Furthermore, in 2007, it was revealed that exosomes contain a large amount of gene transcription information (hereafter referred to as microRNA), and that exosomes function as communication tools between cells.

MSC exosome treatment

Citation: Venkat P, Chopp M, Chen J. (2018) Cell-Based and Exosome Therapy in Diabetic Stroke. Stem Cells Transl Med

In recent years, exosomes derived from mesenchymal stem cells (MSCs) have been identified as the mechanism of cell therapeutic effects of MSCs.
It has been published in many papers [1,2,3,4,5].

The advantages of stem cell therapy are that the risks in safety and efficacy are clear, the laws and regulations are in place, and the path to clinical practice is clear.
Matters related to the details and costs of treatment, etc. that are usually required for free medical care

Comparing exosomes to stem cell therapy

merit

・Exosomes themselves are isolated and purified cell-secreted components, and there is no risk that the therapeutic effect will be affected by the local conditions of the administered cells, unlike cell therapy.
・Theoretically, the possibility of embolization is low because the size is smaller than that of cells.
・Good transfer to target tissues
・Multiple administration is possible compared to cell therapy
・Exosomes are easy to quantify (number of particles)

Demerit

・Requires a larger number of cells than the number of cells required for cell administration
・Quality control and manufacturing control are not yet standardized

The Journal of Extracellular Vesicles, the journal of ISEV in 2019, defines the treatment of MSC-derived exosomes [6,7,8]. The evaluation conforms to the method presented by the Japanese Society for Regenerative Medicine.
Reference: An example of exosome manufacturing control (Japanese Society for Regenerative Medicine)

*How to prepare and treat exosomes (Japanese Society for Regenerative Medicine 2021/3/10)

(1) Clarification that it is an unapproved drug: This drug is an unapproved drug in Japan and will be prescribed at your own expense.
*Public relief systems (relief system for victims of adverse drug reactions, relief system for victims of biological product infections, etc.) are not applicable to unapproved drugs.
(2) Clarification of route of acquisition, etc.: This drug is an in-hospital preparation.
(3) Existence of domestically approved drugs with the same ingredients and efficacy: None
(4) Disclosure of information related to safety in other countries: Same as the safety of exosome therapy. No major adverse events were reported.

References

Allan D, Tieu A, Lalu M, Burger D. Mesenchymal stromal cell-derived extracellular vesicles for regenerative therapy and immune modulation: Progress and challenges toward clinical application. Stem Cells Transl Med 2020; 9(1):39-46.
Rohde E, Pachler K, Gimona M. Manufacturing and characterization of extracellular vesicles from umbilical cord-derived mesenchymal stromal cells for clinical testing. Cytotherapy 2019; 21(6):581-592.
Witwer KW, Van Balkom BWM, Bruno S, Choo A, Dominici M, Gimona M, et al. Defining mesenchymal stromal cell (MSC)-derived small extracellular vesicles for therapeutic applications. J Extracell Vesicles 2019; 8(1):1609206
Elahi FM, Farwell DG, Nolta JA, Anderson JD. Preclinical translation of exosomes derived from mesenchymal stem/stromal cells. Stem Cells 2020; 38(1):15-21.
Tsuchiya A, Takeuchi S, Watanabe T, Yoshida T, Nojiri S, Ogawa M, et al. Mesenchymal stem cell therapies for liver cirrhosis: MSCs as “conducting cells” for improvement of liver fibrosis and regeneration. Inflamm Regen 2019; 39:18 .

Lener T, Gimona M, Aigner L, Borger V, Buzas E, Camussi G, et al. Applying extracellular vesicles based therapeutics in clinical trials -an ISEV position paper. J Extracell Vesicles 2015; 4:30087.
Thery C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, Andriantsitohaina R, 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):1535750.
Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006; 8(4): 315-317

Exsm Clinical Trial for DM

NCT03106246	Circulating Extracellular Vesicles Released by Human Islets of Langerhans	McGill University Health Center CHU de Quebec-Universite Laval
NCT03660683	Effect of Saxagliptin and Dapagliflozin on Endothelial Progenitor Cell in Patients With Type 2 Diabetes Mellitus	Sabyasachi Sen\|George Washington University
NCT03250078	A Pancreatic Cancer Screening Study in High Risk Individuals Including Those With New-Onset Diabetes Mellitus	Western Connecticut Health Network
NCT02649465	SGLT2 Inhibitor Versus Sulfonylurea on Type 2 Diabetes With NAFLD	Kanazawa University Kowa Company, Ltd.
NCT02138331	Effect of Microvesicles and Exosomes Therapy on Hui-cell Mass in Type I Diabetes Mellitus (T1DM)	General Committee of Teaching Hospitals and Institutes, Egypt
NCT03027726	Prevention of Diabetes in Overweight/Obese Preadolescent Children	Basque Country University Ministerio de Competitividad, Spain
NCT03392441	Insulin Deprivation on Brain Structure and Function in Humans With Type 1 Diabetes	Mayo Clinic

Exsom Clinical Trial for Obesity

NCT03459703	Effect of Time-Restricted Feeding on Fat Loss and Cardiometabolic Risk Factors in Overweight Adults	University of Alabama at Birmingham
NCT03762629	Exercise and Diet Restriction on Cardiovascular Function in Obese Children and Adolescents	Guangzhou Sport University

What is the difference between exosomes and cell supernatant?

Exosomes are small particles of 100 nm or less extracted from the culture supernatant by high-speed centrifugation. At our hospital, he uses a Beckman Coulter Optima XE advanced centrifuge.
Nano Sight Description:https://youtu.be/TuFVmSb7NvM

A graph showing the cell diameter (horizontal axis) and the number of particles (vertical axis) obtained by measuring the exosomes and culture supernatant produced at our hospital with NanoSight. Left: exosomes,
Right: culture supernatantThe peak (steep mountain) near 100 nm is exosome,
Exosomes are detected in both cases, but there are peaks at 300 nm and 800 nm in the culture supernatant, and these are particles called MVs (Micro Vesicles) that have different functions from exosomes.By the way, stem cells are about 100 μm, which is 1000 times larger than exosomes.
have a radius.In other words, the culture supernatant contains many MVs other than exosomes, and has a composition different from that of pure exosomes.
Mesenchymal Stem Cells and Exosome Therapy:https://youtu.be/YnCQZ6DWLN4