Medical applications of exosomes
Exosome therapy is gaining popularity in regenerative medicine. So what exactly are exosomes? Exosomes are particles that are released but cannot be replicated. They are intrical in how cells talk to each other. One cell will have a bunch of vesicles that leave and head to another cell to deliver a “message.” These vesicles contain information in the form of chemicals, cytokines to particles of messenger RNA.
Where are Exosomes found?
Exosomes are produced from stem cells and can be found in a variety of tissues.
How are they different from Stem Cells?
Exosomes are contained in stem cells. They are messenger cells that travel to communicate with other cells to produce the needed proteins to repair damaged areas. The use of exosomes does not require donor cells to be injected in the body. Exosomes can be extracted from mesenchymal stem cells (MSCs), sterilized and then injected into the body.
Stem cell therapy injects donor cells into a specific location. These stem cells grow and divide to repair the injured area and create healthier cells overtime. Exosomes are extracted from mesenchymal stem cells and like stem cells are injected into the injured area. Exosomes get to work at communicating with the patient’s own cells and enhance communication among the cells to generate the necessary and needed cells for healing.
What Exactly is Exosome Therapy ?
Exosome products are generally used for orthopedic injuries. Much like stem cell therapy, the exosomes would be injected into the injured site. This is generally an outpatient therapy that is relatively painless.
What does Exosome Therapy Treat? (Medical applications)
Exosome therapy is used for a variety of musculoskeletal injuries, chronic pain, degenerative diseases and genetic disorders. Aging and injuries suppress your cells ability to communicate with each other. The whole purpose of exosomes is to promote communication between cells to repair damaged tissues.
Exosomes are also used to help repair the skin from effects of aging. Overtime, the dermal layer of the skin is damaged because of fragmentation in the collagen, resulting in the signs of aging and hindering the ability to heal wounds. Exosomes have been found to help the body ramp up its collagen production. Exosomes also help inhibit inflammatory cytokines. This means exosomes can help with Atopic Dermatitis, a common skin disorder.
Exosomes can also help with lyme disease. Lyme disease is a very complex disease that compromises the immune system. This can lead to the disruption of cellular health and function. Oftentimes, lyme disease patients experience difficulty with inflammation which exosomes are also known to treat.
Are Exosomes Safer than Stem Cells
While both therapies have a low risk of complications, exosome therapy does not involve a surgical procedure for harvesting cells. Stem cells’ primary job is to grow and divide new and healthy cells from the donor cells. At times these cells may rapidly multiply resulting in a tumor. Exosomes do not multiply, rather they are responsible for improving the communication among cells.
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What is Exosome Therapy?
Some of the most cutting edge treatments in regenerative medicine today are based on exosome therapy. Studies of this cellular therapy have yielded optimistic prospects, and have shown that exosomes can be used in a wide array of applications and types of treatments.
Being such a new therapy, it is important to know their chief characteristics, how they work, and the functions that they are responsible for, as well as how these details are crucial in treatment with exosomes.
What Are Exosomes?
Exosomes are small extracellular vesicles that are secreted by cells. They are responsible for intercellular communication, where they basically act as messengers carrying valuable protein signals and genetic information (DNA & RNA) between the cells.
They can spread throughout the whole body, delivering messages that tell the cells how to behave, what is happening in the nearby area, or what they should be producing. These messengers are produced by the cells in our own body naturally, and Stem Cells are the chief producers.
What Does Treatment With Exosomes Entail?
Exosomes, being mainly produced by stem cells, have been hypothesized as a treatment for the regeneration of tissue.
This was discovered during investigations in which it was observed that the repairing effect of stem cells can be replicated using only exosomes. This, in turn, opened the door to a method of regenerative medicine therapy that is completely free of stem cells.
The treatment is simple. Immediately upon applying the exosomes directly into a wound or deteriorated tissue, it will improve the communication among affected cells. These exosomes will send proteins which help cells to both regulate themselves and repair tissue.
What Can Exosome Therapy Treat?
As it is capable of regenerating many different types of tissue, exosome therapy is chiefly applied in the treatment of wounds and to diminish the effects of wear and aging on the body. Where treating wounds are concerned, exosome therapy has been proven empirically to produce two effects upon application:
A notable decrease in pain and inflammation: this is the first potential effect. This is due to exosomes being rich in immunomodulatory proteins which both facilitate and regulate the immune response of the human body. This is done through T Cells and NK Cells, which leads to reduced pain and swelling in the affected area.
Repairing and Remodeling of Tissue– the second possible effect is because exosomes have the remarkable ability to instruct other cells around them to repair themselves and surrounding tissue. This brings with it long-lasting regeneration and symptom relief.
How Is This Treatment Applied?
One of the principal application routes is via injection directly into the wounded area– or the area in which one desires treatment. Exosome ampules administered in this form can count on a high concentration of exosomes, along with a smaller concentration of other cellular components like cytokines and chemokines, being delivered into the patient.
This procedure does not require any heavy set-up time, and can be realized in a clinic. Injection can be done with a fine needle to reduce any possibility of pain, and there is no recovery time required after the application.
Who Can Use Exosome Therapy?
This cell-free regenerative medicine treatment can be very beneficial for people suffering from a wide variety of illnesses. Currently, research is being conducted to discover the true reach that this treatment has– but nevertheless, marked improvement has been found in patients suffering from chronic inflammation, immune-system disorders, degenerative diseases and Lyme disease.
The deterioration that the body can suffer as a result of genetics, environmental factors, or caused by chronic diseases can be assuaged upon receiving a high dose of exosomes, which reduce inflammation and spur repairing in the tissues.
Learn More About Treatment With Exosomes
In a matter of years, the number of applications exosomes are being used for has multiplied in several different fields of interest. Currently, it is being studied for its use as a cellular therapy treatment with no cells, as well as in regenerating tissue, diagnostics, and the treatment of cancer, among other promising studies.
Insulin-producing cells grown in the lab could provide a possible cure for the age-long disease (diabetes).
Type 1 diabetes is an auto¬immune disease that wipes out insulin-producing pancreatic beta cells from the body and raises blood glucose to dangerously high levels. These high levels of Blood sugar level can be even fatal. Patients are being administered insulin and given other medications to maintain blood sugar level. To those who cannot maintain their blood sugar level, they are given beta-cell transplants but to tolerate beta cell transplants; patients have to take immunosuppressive drugs as well.
A report by a research group at Harvard University tells us that they used insulin-producing cells derived from human embryonic stem cells (ESCs) and induced pluripotent stem cells to lower blood glucose levels in mice. Nowadays, many laboratories are getting rapid progress in human stem cell technology to develop those cells that are functionally equivalent to beta-cells and the other pancreatic cell types. Other groups are developing novel biomaterials to encapsulate such cells and protect them against the immune system without the need for immunosuppressant.
Major pharmaceutical companies and life sciences venture capital firms have invested more than $100 million in each of the three most prominent biotechnological industries to bring such treatments into clinical use:
- Massachusetts–based companies Semma Therapeutics
- Sigilon Therapeutics, and ViaCyte of San Diego
Researchers of UC San Francisco have transformed human stem cells into mature insulin-producing cells for the first time, a breakthrough in the effort to develop a cure for type-1 (T1) Diabetes. Replacing these cells, which are lost in patients with T1 diabetes, has long been a dream of regenerative medicine, but until now scientists had not been able to find out how to produce cells in a lab dish that work as they do in healthy adults.
What is T1 diabetes?
T1 diabetes is an autoimmune disorder that destroys the insulin-producing beta cells of the pancreas, typically in childhood. Without insulin’s ability to regulate glucose levels in the blood, spikes in blood sugar can cause severe organ damage and eventually death. The condition can be managed by taking regular shots of insulin with meals. However, people with type 1 diabetes still often experience serious health consequences like kidney failure, heart disease and stroke. Patients facing life-threatening complications of their condition may be eligible for a pancreas transplant from a deceased donor, but these are rare, and they are supposed to wait a long time.
Researchers have just made a breakthrough that might one day make these technologies obsolete, by transforming human stem cells into functional insulin-producing cells (also known as beta cells) – at least in mice.
“We can now generate insulin-producing cells that look and act a lot like the pancreatic beta cells you and I have in our bodies,” explains one of the team, Matthias Hebrok from the University of California San Francisco (UCSF).
“This is a critical step towards our goal of creating cells that could be transplanted into patients with diabetes.”
Type-1 diabetes is characterized by a loss of insulin due to the immune system destroying cells in the pancreas – hence, type 1 diabetics need to introduce their insulin manually. Although this is a pretty good system, it’s not perfect.
Making insulin-producing cells from stem cells
Diabetes can be cured through an entire pancreas transplant or the transplantation of donor cells that produce insulin, but both of these options are limited because they rely on deceased donors. Scientists had already succeeded in turning stem cells into beta cells, but those cells remained stuck at an early stage in their maturity. That meant they weren’t responsive to blood glucose and weren’t able to secrete insulin in the right way.
Scientists at the University of California San Francisco made a breakthrough in the effort to cure diabetes mellitus type 1.
For the first time, researchers transformed human stem cells into mature insulin-producing cells, which could replace those lost in patients with the autoimmune. There is currently no known way to prevent type-1 (T1) diabetes, which destroys insulin production in the pancreas, limits glucose regulation, and results in high blood sugar levels. The condition can be managed with regular shots of insulin, but people with the disease often experience serious health complications like kidney failure, heart disease, and stroke.
“We can now generate insulin-producing cells that look and act a lot like the pancreatic beta cells you and I have in our bodies,” according to Matthias Hebrok, senior author of a study published last week in the journal Nature Cell Biology.
“This is a critical step toward our goal of creating cells that could be transplanted into patients with diabetes,” Hebrok, director of the UCSF Diabetes Center, said in a statement.
Islets of Langerhans are groupings of cells that contain healthy beta cells, among others. As beta cells develop, they have to separate physically from the pancreas to form these islets.
The team artificially separated the pancreatic stem cells and regrouped them into these islet clusters. When they did this, the cells matured rapidly and become responsive to blood sugar. In fact, the islet clusters developed in ways “never before seen” in a lab. After producing these mature cells, the team transplanted them into mice. Within days, the cells were producing insulin similar to the islets in the mice. While the study has been successful in mice, it still needs to go through more rigorous testing to see if it would work for humans as well. But the research is up-and-coming. “We can now generate insulin-producing cells that look and act a lot like the pancreatic beta cells you and I have in our bodies. This is a critical step towards our goal of creating cells that could be transplanted into patients with diabetes,” He said.
“We’re finally able to move forward on several different fronts that were previously closed to us,” he added. “The possibilities seem endless.”
Basic research keeps elucidating new aspects of beta cells; there seem to be several subtypes, so the gold standard for duplicating the cells is not entirely clear. Today, however, there is “a handful of groups in the world that can generate a cell that looks like a beta cell,” says Hebrok, who currently acts as scientific advisor to Semma and Sigilon, and has previously advised ViaCyte. “Certainly, companies have convinced themselves that what they have achieved is good enough to go into patients.”
The stem cell reprogramming methods that the three companies use to prompt cell differentiation create a mixture of islet cells. Beta cells sit in pancreatic islets of Langerhans alongside other types of endocrine cells. Alpha cells, for example, churn out glucagon, a hormone that stimulates the conversion of glycogen into glucose in the liver and raises blood sugar. Although the companies agree on the positive potential of islet cell mixtures, they take different approaches to developing and differentiating their cells. Semma, which was launched in 2014 to commercialize the Harvard group’s work and counts Novartis among its backers, describes its cells as fully mature, meaning that they are wholly differentiated into beta or other cells before transplantation. “Our cells are virtually indistinguishable from the ones you would isolate from donors,” says Semma chief executive officer BastianoSanna
To get around the donor problem, researchers, including the team at UCSF has been working on nudging stem cells into becoming fully-functional pancreatic beta cells for the last few years. Still, there have been some issues in getting them all the way there.
“The cells we and others were producing were getting stuck at an immature stage where they weren’t able to respond adequately to blood glucose and secrete insulin properly,” Hebrok said.
“It has been a major bottleneck for the field.”
“We’re finally able to move forward on a number of different fronts that were previously closed to us,” Hebrok added. “The possibilities seem endless.”
Regardless of starting cell type, the companies say they are ready to churn out their cells in large numbers. Semma, for example, can make more islet cells in a month than can be isolated from donors in a year in the United States, Sanna says, and the company’s “pristine” cells should perform better than donor islets, which are battered by the aggressive techniques required for their isolation.
As these products, some of which have already entered clinical trials, move toward commercialization, regulatory agencies such as the US Food and Drug Administration (FDA) and the European Medicines Agency have expressed concern about the plasticity of the reprogrammed cells. All three firms subject their cells to rigorous safety testing to ensure that they don’t turn tumorigenic. Before successful trials, companies won’t know the dose of beta cells required for a functional cure, or how long such “cures” will last before needing to be boosted. There’ll be commercial challenges, too: while the companies are investing heavily to develop suitable industrial processes, all acknowledge that no organization has yet manufactured cell therapies in commercial volumes.
Nevertheless, there’s growing confidence throughout the field that these problems will be solved, and soon. “We have the islet cells now,” says Alice Tomei, a biomedical engineer at the University of Miami who directs DRI’s Islet Immuno-engineering Laboratory.
“These stem cell companies are working hard to try to get FDA clearance on the cells.”
Protecting stem cell therapies from the immune system
Whatever the type of cell being used, another major challenge is delivering cells to the patient in a package that guards against immune attack while keeping cells fully functional. Companies are pursuing two main strategies:
- Microencapsulation, where cells are immobilized individually or as small clusters, in tiny blobs of a biocompatible gel.
- Macroencapsulation, in which greater numbers of cells are put into a much larger, implantable device.
ViaCyte, which recently partnered with Johnson & Johnson, launched its first clinical trial in 2014. The trial involved a micro-encapsulation approach that packaged up the company’s partially differentiated, ESC-derived cells into a flat device called the PEC-Encapsulation. About the size of a Band-Aid, the device is implanted under the skin, where the body forms blood vessels around it. “It has a semipermeable membrane that allows the free flow of oxygen, nutrients, and glucose,” says ViaCyte’s chief executive officer, Paul Laikind. “And even proteins like insulin and glucagon can move back and forth across that membrane, but cells cannot.”
The trial showed that the device was safe, well-tolerated, and protected from the adaptive immune system—and that some cells differentiated into working islet cells. But most cells didn’t engraft effectively because a “foreign body response,” a variant of wound healing, clogged the PEC-Encap’s membrane and prevented vascularization. ViaCyte stopped the trial and partnered with W. L. Gore & Associates, the maker of Gore-Tex, to engineer a new membrane. “With this new membrane,” says Laikind, “we’re not eliminating that foreign body response, but we’re overcoming it in such a way that allows vascularization to take place.” The company expects to resume the trial in the second half of this year, provided it receives the green light from the FDA.
Semma is also developing macro¬-encapsulation methods, including a very thin device that in prototype form is about the size of a silver dollar coin. The device is “deceptively simple, but it allows us to put [in] a fully curative dose of islets,” Sanna says.
Semma is also investigating microencapsulation alternatives. At the same time, the company is advancing toward clinical trials using established transplantation techniques to administer donated cadaver cells to high-risk patients who find it particularly difficult to control their blood glucose levels. These cells are infused via the portal vein into the liver, and patients take immunosuppressive drugs to prevent rejection.
Sigilon is working on its microencapsulation technology. Launched in 2016 on the back of work by the labs of Robert Langer and Daniel Anderson at MIT, the company has created 1.5-millimeter gel-based spheres that can hold between 5,000 and 30,000 cells (Nat Med, 22:306–11, 2016). Each sphere is like a balloon, with the outside chemically modified to provide immune-protection, says Sigilon chief executive officer Rogerio Vivaldi. “The inside of the balloon is full of a gel that creates almost a kind of a matrix net where the cells reside.”
In 2018, shortly after partnering with Eli Lilly, Sigilon and collaborators published research showing that islet cells that were encapsulated in gel spheres and transplanted into macaques remained functional for four months. The company has not disclosed a time frame for a type 1 diabetes trial “but we’re moving pretty quickly,” says chief scientific officer David Moller.
To conclude, all three firms hope to extend their work to treat some of the 400 million people worldwide with type 2 diabetes, many of them eventually benefit from insulin injections. The recent endorsements from big Pharmaceutical underline the real progress in beta-cell transplants, says Aaron Kowalski, a molecular geneticist and chief executive officer at JDRF, a foundation based in New York that has funded research at ViaCyte and academic labs whose work has been tapped by Semma and Sigilon. “These companies all realize that if they don’t do it, somebody else will. It’s hard to predict exactly when, but somebody is going to make this work.”