Secretome vs Exosome: What's the Difference?
In scientific terms, the secretome is the totality of all substances released by
stem cells to the outside. These include micro-vesicles, exosomes, proteins,
cytokines (cell messengers), hormone-like substances and so-called
immunomodulatory substances.
Based on current science, it is believed that the effect of stem cells in clinical trials conducted to date is not from the cells as such, but via the vesicles, protein molecules and other substances such as cytokines released by the cells. These substances released to the outside are called "the secretome" as an umbrella term, because the release is called secretion. Which substances of the secretome trigger the actual effects is still largely unknown.
Intercellular communication through exosomes appears to have a role in the causes of a variety of diseases, including cancer, neurodegeneration, and inflammatory diseases.
There are at least a few hundred different types of exosomes that can all do different things (R). The main challenge is that no one is absolutely clear on how to isolate specific exosomes that code for specific actions like fixing your cartilage, ligaments, tendons, muscles, or nerves.
A 12-week Prospective, Double-blind, Randomized Controlled Trial (Acta Derm Venereol 2020) concluded that the combined use of Human Adipose Tissue Stem Cell-derived Exosomes and Fractional CO2 Laser for Acne Scars would provide synergistic effects on both the efficacy and safety of atrophic acne scar treatments.
The secretome is the totality of all messenger substances released to the outside, including the micro-vesicles and exosomes, but also other important factors that are dissolved in the fluid. These include many regeneration-promoting growth factors and so-called cytokines (cell-cell messengers).
Exosomes, on the other hand, are actually only the particulate exosomes that are isolated from the whole. Isolation concentrates them, but the important solutes and micro-vesicles are lost.
Cells respond to their environment. They divide only when necessary. In a healthy body, for example, a liver cell divides only once a year to replace dead cells. The signal for a cell to divide can be the loss of neighboring cells (cut) or growth factors produced by other cells. These factors diffuse to other cells, bind to receptors on the surface, and trigger signaling cascades inside the target cell that stimulate division. Inflammation often inhibits cell division (proliferation).
Another advantage is that MSC (mesenchymal stem cells, stromal cells), which are cultivated over a longer period of time, bear the risk of cancer cells developing in the culture. If these cells are then used, they will be transferred to the patient.
When used intravenously, there can be several hundred billion exosomes in a single milliliter of product. Injected forms of the treatment use fewer, and topically applied formulas require even fewer to be effective. This is a good thing, as the higher the concentration, the more expensive the treatment. “For topical use, the concentration would be anywhere from 5–25 billion exosomes per mL,” says Dr. Peredo. “If you’re just treating the face, you use one to two mLs; if you do face, neck, and chest, then you probably use five.”
Perhaps obviously, all exosomes are derived from human sources. One common source is mesenchymal stem cells, cells that are capable of self-renewal. “Mesenchymal stem cells are [often] derived from the umbilical cords or amniotic fluid from healthy donor pregnancies,” says Dr. Cheung. They’re also taken from placenta. “Normally, the placenta is discarded,” points out Dr. Peredo. “When you take PRP from someone in their 60s and 70s, the growth factors and platelets are old. When you use exosomes, you inject something that’s very young, like placental cells from a 20-year-old.” However, Dr. Batra notes that the benefits of PRP aren’t often related to age. “Younger patients with younger platelets didn’t always have the best result,” he says. “Remember, a platelet only lives for about seven days, so your body is constantly making new platelets.”
Platelets are another common source of exosomes; platelet-derived exosomes are used by Rion, which in addition to distributing exosomes for clinical use also offers an at-home skin-care collection, ( plated ) Skin Science. These products are formulated with what the brand refers to as platelet extract. This differs from true exosomes—that’s because exosomes are from live cells. “Exosomes are very difficult to keep viable at room temperature, so the products we have either require storage in a special deep freezer and need to be defrosted before use or need to be kept refrigerated and then reconstituted before use,” explains Dr. Cheung.
Anything with true exosomes will not be very shelf stable and will have a short lifespan. Dr. Levine actually whips up exosome-infused Aquaphor for her patients, especially those who have received ablative laser treatment. “We’ve given it to people to heal after procedures, and it works really, really well,” she says. “We tell them to keep it in the refrigerator, keeping it for no more than two weeks.”
Dr. Batra explains that ( plated ) Skin Science formulas are platelet-derived exosomal products for topical use. “It’s what the exosomes release, the payload of what is in the exosomes—proteins and growth factors,” he says. “These proteins are dead. I hate to say it that way, but they still may have a biological effect or improve the appearance of fine lines and wrinkles.” (If you’re familiar with SkinMedica TNS Advanced+ Serum, which use growth factors, it’s a similar concept.)
It’s worth considering some of the common potential fears of being treated with exosomes. One such concern is that your body could reject them. That’s why, when you get PRP, it has to be sourced from your own body—if a foreign cell is incompatible with your body, your immune system will attack it. Remember though: exosomes are not cells, which is why these little messengers can be extracted from various sources and used by anyone to treat a broad range of concerns.
Another concern is the health or safety of the sourced material—what if the exosomes are pulled from someone with a serious medical condition? That shouldn’t be a worry either. “The manufacturing process essentially purifies the product,” says Dr. Batra. “I don’t worry about taking someone’s blood product—it’s sort of like vodka. When you start distilling vodka, it ends up being very pure. “You want products with detectable RNA and clinical studies, and you need to consider the tissue source,” says Dr. Cheung.
The real question with exosome safety has to do with your own health. “Exosomes are ways that the cells communicate with each other—if information is telling them to make the body do good things, that’s great,” says Dr. Levine. “But what if there’s a bad cell in your body? In someone who might be predisposed to having a disease, can this magnify it? That’s the flip side of the coin.” While there’s no data to show that exosomes do this, the FDA is saying that the knowledge just isn’t there yet—hence the aforementioned warning letter.
But plenty of experimental and well-regarded aesthetic treatments are not cleared by the FDA—including PRP. “The FDA doesn’t govern the practice of medicine, so a physician can give treatments that are considered off label,” says Dr. Batra. Currently, the FDA has approved the use of PRP only in wound care; using it for facials or hair growth is off label. It takes hundreds of millions of dollars, in-depth studies, and often, decades to achieve FDA approval. In the meantime though, providers are going to continue to treat their patients with cutting-edge exosomes—whether you’re excited to join the experiment is up to you.
It is beyond the scope of this article to describe exactly which treatment is better for which condition. Each patient should be treated like an individual and each treatment should be personalized. The choice of regenerative cells is highly individualized based on age and health of the patient and the extent of injury or degeneration.
Ultimately, nothing can substitute a thorough evaluation, history, physical examination and a diagnostic work-up. We hope that you keep these things in mind when you seek regenerative treatments anywhere.
Based on current science, it is believed that the effect of stem cells in clinical trials conducted to date is not from the cells as such, but via the vesicles, protein molecules and other substances such as cytokines released by the cells. These substances released to the outside are called "the secretome" as an umbrella term, because the release is called secretion. Which substances of the secretome trigger the actual effects is still largely unknown.
What is a Secretome?
Stem cells communicate with other cells by releasing messenger substances to the outside. The totality of all released substances is called secretome (from secretion = release to the outside). The secretome can contain exosomes, micro-vesicles, proteins, growth factors, hormones, cytokines and other substances. A scientific review article on vesicles can be found here.What is an Exosome?
An exosome is a small vesicle produced by a cell that can tell other cells what to do. Exosomes are how cells talk to each other (R). They are a part of secretome.
Put more simply, exosomes are how cells communicate. For example, we can communicate by writing small notes to each other electronically, otherwise known as email. Exosomes are a way for one cell to email another. The message may be how to behave or what’s happening in the local area. |
| Meletios Verras/Shutterstock |
Intercellular communication through exosomes appears to have a role in the causes of a variety of diseases, including cancer, neurodegeneration, and inflammatory diseases.
There are at least a few hundred different types of exosomes that can all do different things (R). The main challenge is that no one is absolutely clear on how to isolate specific exosomes that code for specific actions like fixing your cartilage, ligaments, tendons, muscles, or nerves.
Note: The FDA first allowed the study of botulinum toxin’s effect on health conditions more than 50 years ago. Decades later, it was studied, then approved, as a treatment for wrinkles; today, Botox is possibly the most popular aesthetic procedure worldwide. It takes significant time to understand what innovative treatments are capable of and even longer to get them regulated and approved as an actual therapy. So when the FDA issued a warning letter against exosome treatment in 2019—many aesthetic providers took it with a grain of salt.
A 12-week Prospective, Double-blind, Randomized Controlled Trial (Acta Derm Venereol 2020) concluded that the combined use of Human Adipose Tissue Stem Cell-derived Exosomes and Fractional CO2 Laser for Acne Scars would provide synergistic effects on both the efficacy and safety of atrophic acne scar treatments.
Is Secretome the Same as Exosomes?
Secretome and exosomes are sometimes used as synonyms, but they are actually different.The secretome is the totality of all messenger substances released to the outside, including the micro-vesicles and exosomes, but also other important factors that are dissolved in the fluid. These include many regeneration-promoting growth factors and so-called cytokines (cell-cell messengers).
Exosomes, on the other hand, are actually only the particulate exosomes that are isolated from the whole. Isolation concentrates them, but the important solutes and micro-vesicles are lost.
What are Micro-Vesicles?
Micro-vesicles are also lipid membrane-coated particles that can carry cargo. However, at 100 to 1,000nm in size, they are larger than exosomes and are released to the outside by pinching off (exocytosis) at the cell membrane. A scientific review article on vesicles can be found at here.What are Growth Factors?
Chemically, growth factors usually are proteins that bind to receptors on the outer surface of target cells. Many cells produce growth factors such as EGF (epidermal growth factor), PDGF (platelet-derived growth factor), NGF (neuronal growth factor), bFGF (basic fibroblast growth factor) etc. Growth factors in general are not related to Human growth hormone (HGH).Cells respond to their environment. They divide only when necessary. In a healthy body, for example, a liver cell divides only once a year to replace dead cells. The signal for a cell to divide can be the loss of neighboring cells (cut) or growth factors produced by other cells. These factors diffuse to other cells, bind to receptors on the surface, and trigger signaling cascades inside the target cell that stimulate division. Inflammation often inhibits cell division (proliferation).
What are the Advantages of Secretome?
The great advantage of the secretome is that it can be frozen. If stem cells are frozen, their properties change and this can lead to a loss of efficacy. In the case of chronic diseases, however, a continuous therapy is needed, i.e. stem cells would have to be taken again and again. In the case of secretome, one can obtain 10-20 doses from one collection and thus treat repeatedly over a period of 2 years.Another advantage is that MSC (mesenchymal stem cells, stromal cells), which are cultivated over a longer period of time, bear the risk of cancer cells developing in the culture. If these cells are then used, they will be transferred to the patient.
More Stem Cells - More Effect?
Many patients believe that a larger amount of stem cells also achieves better effects. This is correct up to a limit that is difficult to define. However, since it is not yet possible to measure "efficacy", or only in very few cases, one should be very cautious here. Many characteristics of stem cells are not well understood so far and nobody knows exactly which factors and substances define an effect. The only thing that is really known exactly is that with increasing multiplication (generations, population doublings) the efficacy potential decreases. That is, the more you multiply stem cells, the less likely they are to still be effective.What are the differences between all the exosome products available?
There are a lot of exosome brands on the market, including Kimeravive, Benev, Exocel Bio, and Rion. Hydrafacial even also announced in September 2022 that the company plans on releasing an exosome booster sometime this year. The primary differences between these manufacturers’ exosomes are the concentration (or number) of exosomes in the end product and the source of the exosomes themselves.When used intravenously, there can be several hundred billion exosomes in a single milliliter of product. Injected forms of the treatment use fewer, and topically applied formulas require even fewer to be effective. This is a good thing, as the higher the concentration, the more expensive the treatment. “For topical use, the concentration would be anywhere from 5–25 billion exosomes per mL,” says Dr. Peredo. “If you’re just treating the face, you use one to two mLs; if you do face, neck, and chest, then you probably use five.”
Perhaps obviously, all exosomes are derived from human sources. One common source is mesenchymal stem cells, cells that are capable of self-renewal. “Mesenchymal stem cells are [often] derived from the umbilical cords or amniotic fluid from healthy donor pregnancies,” says Dr. Cheung. They’re also taken from placenta. “Normally, the placenta is discarded,” points out Dr. Peredo. “When you take PRP from someone in their 60s and 70s, the growth factors and platelets are old. When you use exosomes, you inject something that’s very young, like placental cells from a 20-year-old.” However, Dr. Batra notes that the benefits of PRP aren’t often related to age. “Younger patients with younger platelets didn’t always have the best result,” he says. “Remember, a platelet only lives for about seven days, so your body is constantly making new platelets.”
Platelets are another common source of exosomes; platelet-derived exosomes are used by Rion, which in addition to distributing exosomes for clinical use also offers an at-home skin-care collection, ( plated ) Skin Science. These products are formulated with what the brand refers to as platelet extract. This differs from true exosomes—that’s because exosomes are from live cells. “Exosomes are very difficult to keep viable at room temperature, so the products we have either require storage in a special deep freezer and need to be defrosted before use or need to be kept refrigerated and then reconstituted before use,” explains Dr. Cheung.
Anything with true exosomes will not be very shelf stable and will have a short lifespan. Dr. Levine actually whips up exosome-infused Aquaphor for her patients, especially those who have received ablative laser treatment. “We’ve given it to people to heal after procedures, and it works really, really well,” she says. “We tell them to keep it in the refrigerator, keeping it for no more than two weeks.”
Dr. Batra explains that ( plated ) Skin Science formulas are platelet-derived exosomal products for topical use. “It’s what the exosomes release, the payload of what is in the exosomes—proteins and growth factors,” he says. “These proteins are dead. I hate to say it that way, but they still may have a biological effect or improve the appearance of fine lines and wrinkles.” (If you’re familiar with SkinMedica TNS Advanced+ Serum, which use growth factors, it’s a similar concept.)
Are exosomes safe?
The short answer is yes, with the longer answer being that the scientific community isn’t so sure yet, due to limited information. “The real workhorse in regenerative medicine is exosomes,” says Dr. Batra. “They can affect intercellular communication in a really special way. I think it’s very promising. There’s tremendous excitement in the hair world and dermatology.”It’s worth considering some of the common potential fears of being treated with exosomes. One such concern is that your body could reject them. That’s why, when you get PRP, it has to be sourced from your own body—if a foreign cell is incompatible with your body, your immune system will attack it. Remember though: exosomes are not cells, which is why these little messengers can be extracted from various sources and used by anyone to treat a broad range of concerns.
Another concern is the health or safety of the sourced material—what if the exosomes are pulled from someone with a serious medical condition? That shouldn’t be a worry either. “The manufacturing process essentially purifies the product,” says Dr. Batra. “I don’t worry about taking someone’s blood product—it’s sort of like vodka. When you start distilling vodka, it ends up being very pure. “You want products with detectable RNA and clinical studies, and you need to consider the tissue source,” says Dr. Cheung.
The real question with exosome safety has to do with your own health. “Exosomes are ways that the cells communicate with each other—if information is telling them to make the body do good things, that’s great,” says Dr. Levine. “But what if there’s a bad cell in your body? In someone who might be predisposed to having a disease, can this magnify it? That’s the flip side of the coin.” While there’s no data to show that exosomes do this, the FDA is saying that the knowledge just isn’t there yet—hence the aforementioned warning letter.
But plenty of experimental and well-regarded aesthetic treatments are not cleared by the FDA—including PRP. “The FDA doesn’t govern the practice of medicine, so a physician can give treatments that are considered off label,” says Dr. Batra. Currently, the FDA has approved the use of PRP only in wound care; using it for facials or hair growth is off label. It takes hundreds of millions of dollars, in-depth studies, and often, decades to achieve FDA approval. In the meantime though, providers are going to continue to treat their patients with cutting-edge exosomes—whether you’re excited to join the experiment is up to you.
Take Home Messages
Ultimately, nothing can substitute a thorough evaluation, history, physical examination and a diagnostic work-up. We hope that you keep these things in mind when you seek regenerative treatments anywhere.
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