Stem Cell Exosome Therapy: Taking the Cell Out of Stem Cells

Stem Cell Exosome Therapy: Taking the Cell Out of Stem Cells

Over the past decade, scientists have learned that the molecules that mesenchymal stem cells release are every bit as important to regenerative medicine as the stem cells themselves. Stem cells release exosomes, which are tiny packets that contain countless molecules of microRNA, cytokines, and growth factors. These molecules are mainly what allows stem cells to help the body regrow and repair.

Dr. Vizoso and colleagues published a review article that describes the many benefits of the secretome, that is, stem cell exosomes and the substances they produce. They not only explain why exosomes are helpful in regenerative medicine but why stem cell exosomes bring a powerful enhancement to stem cells themselves.

Compared to exosomes, whole stem cells are rather big—one can safely inject far more exosomes than stem cells in each treatment. And, really, it seems that the stem cell exosomes are what is supplying most of the benefits.

Stem cells can be made to produce millions of exosomes. These stem cell exosomes can then be collected, stored, shipped, and infused with much less cost and aggravation than stem cells themselves. Exosomes have small molecules on their surfaces that allow them to seek out and find areas in the body where they are needed. Stem cells often need to be injected near the site of injury. Exosomes may work if simply infused into a vein.

Dr. Vizoso and coauthors make a persuasively strong argument about the potential benefits of infusing stem cell exosomes instead of stem cells themselves. They also point out the potential limitations of the process, given the current technology. For example, stem cells would need to be made “immortal” so that they can keep producing large amounts of the same sorts of exosomes over time. Fortunately, the techniques of cell immortalization have been around for at least 30 years. Thus, most of the barriers to widespread, large scale exosome use are things scientists already know how to overcome.

While there may still be benefits for direct stem cell infusions, the future of research is moving forward with stem cells and exosomes.

Reference: Vizoso, F., et al. (2017). Mesenchymal Stem Cell Secretome: Toward Cell-Free Therapeutic Strategies in Regenerative Medicine. International Journal of Molecular Sciences. 2017, 18(9), 1852.

Exosomes Protect Joints from Osteoarthritis Damage

Exosomes Protect Joints from Osteoarthritis Damage

Odds are, you or someone you know has osteoarthritis—it is that common. Osteoarthritis is a chronic inflammation and destruction of one or more joints. Osteoarthritis is the kind of arthritis most people think of when they think of “arthritis.” The disease usually causes joint pain, stiffness, and limited joint motion. Common sites of osteoarthritis are the hands, knees, feet, spine, and hips.

Unlike rheumatoid arthritis, there are few good treatments for osteoarthritis. Most people with advanced disease must take analgesics (painkillers) each day to dull the pain. Unfortunately, each painkiller comes with its own problems. Aspirin increases the risk of bleeding. NSAIDs like ibuprofen wreak havoc on the gastrointestinal system and affect the kidneys. Chronic acetaminophen can be harmful to the liver. Opioids come with the risk of dependence and addiction. The only definitive treatment for osteoarthritis is surgery, which is expensive and usually requires a long recovery period.

Mesenchymal stem cells, also known as stromal cells, have shown remarkable promise in the treatment of osteoarthritis. For example, mesenchymal stem cells taken from bone marrow or fat tissue (adipose) that are then injected into joints can protect the joint from degeneration and slow the progression of osteoarthritis. However, there are some limitations with stem cell treatment.  One issue is that only so many cells can be injected in a space at once. For these reasons, scientists have pivoted some of their focus from stem cells to the tiny packets of information stem cells release called exosomes.

Exosomes contain millions of beneficial molecules including small proteins, cytokines, RNA, microRNA, and DNA. One stem cell can release thousands of exosomes. Since the exosomes are so small, many more exosomes can be collected and injected than stem cells themselves.

Researchers recently showed that exosomes collected from mesenchymal stem cells were able to provide the same benefits against osteoarthritis in mice as bone marrow stem cells did themselves. Stem cells slowed down the clinical signs of arthritis in mice just as whole stem cells did. Exosomes also protected cartilage and other joint structures from destruction.

This research demonstrates the developing science to use exosomes to treat osteoarthritis instead of the stem cells themselves. This gives doctors (and patients) considerably more flexibility in how they approach treatment. Exosomes tend to find their way to sites of disease, meaning they may be able to be injected into a vein instead of injected in the diseased joint. In addition, patients may be able to receive a higher “dose” of exosomes when simply purified exosomes are injected. This exciting research will need to be extended to humans, but clinical trials are in the planning phase.

Reference:  Cosenza, S., Ruiz, M., Toupet, K. et al. Mesenchymal stem cells derived exosomes and microparticles protect cartilage and bone from degradation in osteoarthritis. Sci Rep 7, 16214 (2017).

Exosomes from Bone Marrow-Derived Mesenchymal Stem Cells Reduce the Effects of Traumatic Brain Injury

Exosomes from Bone Marrow-Derived Mesenchymal Stem Cells Reduce the Effects of Traumatic Brain Injury

Traumatic brain injury is a single name given to a broad variety of conditions. In every instance of traumatic brain injury, some external force causes damage to the brain. This may be mild and short-lived, such as a concussion, or severe and permanent, such as severe head trauma. The initial trauma or injury can cause a number of injuries to the skull and brain such as skull fracture, cerebral contusion (“brain bruise”), cerebral edema (“brain swelling”), or hemorrhage (“brain bleed”).

Traumatic brain injury can also cause several secondary injuries that may continue for hours or days. The secondary effects of traumatic brain injury include:

  • Electrolyte imbalances
  • Mitochondrial dysfunction
  • Inflammation
  • Ischemia (lack of blood flow to parts of the brain)
  • Brain cell destruction

These secondary traumatic brain injuries can cause long-term and even permanent neurological dysfunction.

Unfortunately, there are very few treatments for traumatic brain injury. Neurosurgeons can sometimes stop brain bleeding, stabilize skull fractures, and reduce brain swelling; however, there is little that can be done to stop the secondary effects of traumatic brain injury. Doctors have tried using steroids or hypothermia (cooling the patient) to decrease inflammation and stop further injury, but these interventions are not highly effective.

Ideally, one would give a treatment soon after a person has had a traumatic brain injury. This treatment would reduce or block the secondary effects of traumatic brain injury. Scientists are studying whether stem cell treatment can do that very thing.

Researchers recently showed that exosomes from bone marrow mesenchymal stem cells were able to reduce the secondary effects of traumatic brain injury. They humanely caused a traumatic brain injury in a group of mice. Fifteen minutes after the TBI, half the mice were given an injection of stem cells and the other half received a placebo (i.e. saltwater).

The mice that received the stem cell exosome treatment did substantially better than the mice who received a placebo. Stem cell exosome treatment substantially reduced the size of the damage to the brain compared to control. Moreover, mice that received stem cell exosome treatment did better on sensory, motor, reflex, and balance tests. In other words, stem cell exosome treatment helped mice with traumatic brain injury move better than those that did not receive stem cell exosome treatment.

The scientists went on to show that exosome treatment helped block the secondary effects of traumatic brain injury on the cellular and molecular level. In short, stem cell exosome treatment reduced inflammation in the brain from TBI.

Taken together, these results strongly suggest that treatment with exosomes from bone marrow mesenchymal stem cells soon after traumatic brain injury has the ability to protect the brain from damage. Of course, this treatment will need to be tested in humans who have had incidental TBI. Nevertheless, the basic science results are quite exciting since few neuroprotective agents, if any, can block the secondary effects of traumatic brain injury the way exosomes did in this scientific report.

Reference: Haoqi, N., et al. (2019). Exosomes Derived From Bone Mesenchymal Stem Cells Ameliorate Early Inflammatory Responses Following Traumatic Brain Injury. Frontiers in Neuroscience. 2019 Jan 24; 13:14.

The Source of Exosomes Matters

The Source of Exosomes Matters

Many clinical studies have shown the safety and benefit of exosomes. As a result, numerous companies have been bringing exosome products to market. However, not all exosomes are the same. The cell type from which the exosomes are collected makes an enormous difference in safety and results.

Scientists have recently drawn attention to the fact that cell type matters when it comes to exosomes. Virtually every cell in the human body releases small packets of substances called exosomes. The number of exosomes and the substances inside exosomes can vary considerably, depending on the type of cell. Exosomes derived from stem cells and stromal cells have received the most research attention. That is because exosomes from stem cells contain most of the substances that provide a benefit to patients from stem cells. In other words, if you receive treatment of exosomes from stem cells, you are basically getting additional benefits from the exosomes that you would have gotten from just the stem cells themselves. However, the source of the stem cell exosomes matter.

Most of the research done in this area revolves around two types of stem cells: Exosomes taken from bone marrow mesenchymal stem cells and exosomes taken from placental mesenchymal stem cells.  Bone marrow stem cells seem to have two major advantages over the placenta-derived stem cells. The first is that bone marrow stem cells have a stronger ability to modulate the immune system. The second is that bone marrow stem cells have immune privilege, which means they can avoid the body’s immune system. Specifically, placenta stem cell exosomes contain higher levels of PDL1 and HLA-G, which can make them more likely to provoke a negative immune response.

Surprisingly but reasonably, there have been of 63,000 scientific articles published on the safety and efficacy of bone marrow stem cells, but only about 1,200 on placenta stem cells.

Talk to your stem cell and exosome provider about your choices of exosomes, and make sure to ask from what cell type the exosomes are derived.

Reference: Hicok, Kevin & Vangsness, Thomas & Dordevic, Maxwell. (2020). Exosome Origins: Why the Cell Source Matters. 4. 1-4.

Alzheimer’s Disease Study Shows Reduction of Brain Inflammation and Improved Memory

Alzheimer’s Disease Study Shows Reduction of Brain Inflammation and Improved Memory

Alzheimer’s disease is a progressive form of dementia, which means its symptoms get worse over time. Alzheimer’s disease primarily affects memory. People with Alzheimer’s disease first have trouble recalling recent memories, but they eventually lose memories of things that occurred earlier in life. Alzheimer’s disease can also cause irritability, social disengagement, and problems performing tasks of daily living. As the disease worsens, it becomes increasingly difficult to care for people with Alzheimer’s disease and most eventually require full-time care. This article is on an Alzheimer’s Disease study that may bring hope to those seeking an alternative to help manage symptoms or halt progression.

There is no cure for Alzheimer’s disease. Treatments include cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) or memantine.  These drugs may slightly improve cognition or temporarily slow the disease, but they do little to change the overall course of the disease or truly alleviate symptoms. Since Alzheimer’s disease affects over 5 million people in the United States alone, researchers are aggressively pursuing ways to treat the cause of dementia.

The precise cause of Alzheimer’s disease is unknown; however, the brains of people with the disease have very high levels of a protein called beta-amyloid. This protein can cause inflammation, which is damaging to brain tissue and believed to contribute to Alzheimer’s disease symptoms.

In the race for a cure, researchers tested the effects of exosomes from mesenchymal stem cells in mice with experimental Alzheimer’s disease study. Without treatment, these Alzheimer’s disease mice have difficulty with various tests of memory and cognition compared to healthy mice of the same age. Astonishingly, mice treated with exosomes retrieved from mesenchymal stem cells showed remarkable improvements in tests of spatial learning, memory, and cognition (e.g. modified Morris water-maze). The exosomes reduced the levels of beta-amyloid protein and beta-amyloid plaques in regions of the brain responsible for learning and memory. The researchers found that these exosomes, taken from the human umbilical cord, contained high amounts of enzymes that break down beta-amyloid proteins. Indeed, treatment with mesenchymal stem cell-derived exosomes reduced brain inflammation (i.e., the exosomes reduced inflammatory cells and inflammatory cytokines). These results apparently indicate treatment with stem cell-derived exosomes reduced brain inflammation, reduced brain beta-amyloid, and improved learning and memory in experimental mice.

More studies will need to be performed in humans to continue research of this treatment and impact in human cases. Nevertheless, given the lack of treatments for Alzheimer’s disease, these results are quite impressive. Few treatments, if any, improve memory or reduce beta-amyloid levels and brain inflammation. At best, patients currently hope to slow the progression of the disease and ease symptoms.

Reference: Ding M. et al. (2018). Exosomes Isolated from Human Umbilical Cord Mesenchymal Stem Cells Alleviate Neuroinflammation and Reduce Amyloid-Beta Deposition by Modulating Microglial Activation in Alzheimer’s Disease. Neurochemical Research. 2018, Nov;43(11):2165-2177.

Exosomes Show Reduced Eczema Symptoms and Inflammation

Exosomes Show Reduced Eczema Symptoms and Inflammation

Atopic dermatitis, better known as eczema, is a chronic, itchy skin disease. People with eczema have chronically dry skin, often in patches, that can be intensely itchy. The patches of atopic dermatitis vary from red bumps (papules or vesicles) when they are inflamed, to dry, scaly, pink areas when they are not inflamed.  Patients with eczema itch so frequently that the skin in the lesion can thicken and harden, a process called lichenification. Even patients who manage to clear the lesions usually have a recurrence (i.e. the itchy patches come back).

Patients with eczema can try lotion and moisturizers to soften the skin and reduce itchiness, but these are only helpful temporality and only seem to work for people with mild disease. Often, topical corticosteroids are required. Steroids are applied to areas of atopic dermatitis to reduce inflammation and itchiness. In severe cases where steroids are not fully helpful, light therapy (phototherapy) may be needed. Patients may require more intense therapy for atopic dermatitis such as cyclosporine, methotrexate, azathioprine, mycophenolate mofetil, or dupilumab. These medications have their own set of side effects, so they are reserved for people with severe, chronic eczema. Certainly better, safer treatments for atopic dermatitis are needed.

To this end, researchers conducted the first of its kind study to answer whether exosomes retrieved from mesenchymal stem cells taken from human adipose tissue (i.e. fat tissue) could relieve symptoms of atopic dermatitis in laboratory mice. Mice with experimental atopic dermatitis have similar symptoms to humans with the disease; they have itchy, red lesions that cause the skin to thicken. In the research study, treatment with stem cell-derived exosomes significantly improved the clinical score in these mice. In other words, stem cell exosome treatment reduced redness, swelling, scaling, dryness, and itching. Exosome treatment also reduced objective signs of inflammation including inflammatory cytokines (TNF, IL4, etc.), inflammatory antibodies (IgE), and inflammatory cells (eosinophils).

These results indicate that treatment with stem cell-derived exosomes substantially reduced symptoms in mice with atopic dermatitis. Of course, this work needs to be replicated in humans, but this important work lays the foundation for future clinical trials.

Reference: Cho, BS. et al. (2018). Exosomes derived from human adipose tissue-derived mesenchymal stem cells alleviate atopic dermatitis. Stem Cell Research & Therapy. 2018, Jul 11;9(1):187.

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