What are stem cell exosomes?

Stem cells contain tiny vesicles called "exosomes" both inside and outside the cell. Discovered in 1983, exosomes have been studied extensively in the life sciences,
suggesting their involvement in various physiological functions and disease development. In the medical field, they have already led to new diagnostic methods using bodily fluids, and
there are high hopes for their future 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: Exosomes are virtually invisible, so lasers are shone onto them to reflect the light and make them visible during imaging. The magnitude of the reflection depends on the particle size and the angle of reflection.
In 1996, it was discovered that exosomes have the function of transporting substances to other cells. Furthermore, in 2007, it was revealed that exosomes contain a large amount of gene replication information (hereinafter referred to as microRNA), and that exosomes function as a communication tool 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

exosomes derived from mesenchymal stem cells (MSCs) are important in the mechanisms of MSC-mediated cell therapy
numerous studies have shown that

The advantages of stem cell therapy include the clear understanding of the risks associated with safety and efficacy, well-established legal regulations, and a clear path to clinical trials. (
Regarding matters concerning the content and costs of treatments typically required under private medical care.)

Comparing exosomes to stem cell therapy

merit

Exosomes themselves are isolated and purified components of cell secretions, so there is no risk of the therapeutic effect being affected by the local condition of the administered cells, as is the case with cell therapy.
They are smaller in size than cells, so the possibility of embolism is theoretically low
. They have good distribution to target tissues
. Multiple administrations are possible compared to cell therapy
. Exosomes are easy to quantify (number of particles).

Demerit

- A much larger number of cells are required than the number of cells needed for cell administration.
- Quality control and manufacturing control are not yet standardized.

The 2019 Journal of Extracellular Vesicles, the official journal of ISEV, defines therapies involving MSC-derived exosomes [6,7,8]. However, the specifications and characterization of MSC exosomes used for therapeutic purposes at our hospital adhere to the methods presented by the Japanese Society for Regenerative Medicine.
See: An Example of Exosome Manufacturing Management (Japanese Society for Regenerative Medicine)

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

(1) Disclosure of the fact that it is an unapproved drug: This drug is an unapproved drug in Japan and is prescribed on a self-pay basis.
*Public relief systems (Pharmaceutical Adverse Reaction Relief System and Biological Product Infection Relief System) do not apply to unapproved drugs.
(2) Disclosure of the source of supply, etc.: This drug is prepared in-house.
(3) Existence of domestically approved drugs with the same ingredients and efficacy: None
(4) Disclosure of information on safety, etc. in other countries: The safety is the same as that of exosome therapy. No major adverse events have been 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 tiny particles less than 100 nm in size, extracted by further high-speed centrifugation of the culture supernatant. Our hospital uses a Beckman Coulter Optima XE high-speed centrifuge.
Explanation of Nano Sight:https://youtu.be/TuFVmSb7NvM

This graph shows cell diameter (horizontal axis) and particle count (vertical axis) of exosomes and culture supernatant produced at our hospital, measured with NanoSight. Left: Exosomes,
Right: Culture supernatantThe peak around 100 nm (a steep curve) represents exosomes
Exosomes are detected in both, but the culture supernatant also has peaks at 300 nm and 800 nm, which are MVs (Micro Vesicles), particles with different functions from exosomes.Incidentally, stem cells are about 100 μm in diameter,
with a radius 1000 times larger than that of exosomes.In other words, it was found that the culture supernatant contains many MVs other than exosomes, and its composition is different from that of pure exosomes.
Mesenchymal Stem Cells and Exosome Therapy:https://youtu.be/YnCQZ6DWLN4