Stem cell culture supernatant and exosomes — what they are and how far the evidence goes

Summary — Stem cell culture supernatant is the liquid left after cells are removed from the medium in which stem cells were grown. It contains proteins and growth factors secreted by the cells, along with small vesicles called exosomes. On the hypothesis that much of the effect of mesenchymal stem cells comes from these secreted substances, it is being studied as a 'cell-free therapy', but efficacy has not been confirmed in large clinical trials in people. In 2019 the U.S. Food and Drug Administration (FDA) stated that there are no approved exosome products and that serious adverse events had been reported after use of unapproved exosome products.

What are culture supernatant and exosomes?

When stem cells are grown in the laboratory, they release many substances into the surrounding medium. The liquid left after removing the cells is called 'conditioned medium' or culture supernatant, and the full set of secreted substances is sometimes called the 'secretome'. It contains proteins such as growth factors and cytokines together with 'extracellular vesicles' — tiny membrane sacs tens to hundreds of nanometres across. Exosomes are one type of extracellular vesicle and are known to carry substances such as proteins and RNA to other cells.

Why they attracted attention

When mesenchymal stem cells are given to the body, most do not survive long, yet effects such as reduced inflammation and tissue protection have sometimes been observed. Researchers therefore hypothesised that the substances cells secrete, rather than the cells themselves, may be central to the effect. A review of the clinical use of mesenchymal stromal cells also treats this secretory action as a leading candidate mechanism. Without cells, the risks of cells growing in the wrong place or blocking blood vessels may be reduced, and storage and transport may be easier — further reasons for interest.

How far has research come?

Many animal studies report reduced inflammation and tissue recovery in models of brain, heart, lung, joint and skin injury after giving mesenchymal stem cell culture supernatant or exosomes. Studies in people have begun, but most are early-stage with small numbers of patients, and many challenges remain.

• Standardisation — the types and amounts of substances present can vary greatly with culture conditions, cell source and purification method.
• Potency measurement — standards for measuring which components produce effects and how much should be given have not been established.
• Safety — contamination during manufacture, inclusion of unwanted components and immune responses with repeated dosing must be assessed.

Regulators' notices

In 2019 the U.S. FDA issued a public safety notification on exosome products, stating that no exosome products are approved to treat or prevent disease and urging consumers to be cautious, citing serious adverse events in patients who received unapproved exosome products. The International Society for Stem Cell Research (ISSCR) also warns against the sale of unproven 'stem cell-related' products.

Position in Japan's regulatory system

Japan's regenerative medicine act covers care that processes and uses 'cells', so whether cell-free culture supernatant or exosomes fall under the same procedures has been debated. In other words, it is worth knowing that such products may not have gone through the committee review and provision-plan submission that apply to care using mesenchymal stem cells themselves. Related rules continue to be discussed and revised, so the latest information should be checked in public materials from the Ministry of Health, Labour and Welfare and other agencies.

What to check when reading information

• Whether there is evidence from controlled studies in people
• What regulatory process the product has gone through (approved product or research)
• Whether it is disclosed which cells it was made from and how

Culture supernatant and exosomes are a scientifically interesting field of research, but they are currently at the stage of studies confirming efficacy and safety.

Frequently asked questions

Q. Are exosome cosmetics the same as medical exosomes?
Cosmetics labelled with 'exosomes' or 'stem cell culture medium' are products applied to the skin for cosmetic purposes; their regulation and purpose differ from medical products for treating or preventing disease. Cosmetic labelling does not imply medical effects.

Q. Are exosome injections or drips safe?
The U.S. FDA has stated that no exosome products are approved to treat disease and that serious adverse events have been reported after use of unapproved products. For products given into the body, checking manufacturing quality and regulatory process is especially important.

Q. How can I take part in research?
Ongoing clinical trials, with eligibility criteria and institutions, can be found on public registries such as ClinicalTrials.gov and Japan's jRCT. Publicly registered studies matter because their design and results can be verified from outside.

How it differs from cell therapy

Mesenchymal stem cell therapy puts living cells into the body, while culture supernatant and exosomes use only substances the cells have produced. For cell therapy, quality standards such as cell number, viability and surface markers are relatively well defined, but standards for which components culture supernatant and exosomes should contain, and in what amounts, are still being developed. So even when both are described as 'stem cell-derived', it is important to recognise that their level of evidence and regulatory management differ.

The above summarises published papers and public-agency materials. Organisation names are given to identify sources, not to introduce or recommend any medical institution or product. Please discuss the suitability and risks of any treatment with your medical team.

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