Most organs of the body recover from injury by generating new, healthy cells. Not every organ of the body has the same ability to form new cells, however. The skin is an example of an organ that has an amazing ability to regenerate. Liver and lung also have the ability to form new cells, but not as dramatically as skin. Kidney and heart have even less ability to repair and regenerate. On the opposite end of the spectrum from the skin is the brain, which has very little capacity to regenerate once it has been damaged or destroyed. All of these organ systems, especially those that are relatively unable to repair themselves, could theoretically benefit from stem cells.
Mesenchymal stem cells, also known as stromal cells, are multipotent stem cells derived from bone marrow, umbilical cord, placenta, or adipose (fat) tissue. These cells can become the cells that make up bone, cartilage, fat, heart, blood vessels, and even brain. Mesenchymal stem cells have shown a remarkable ability to help the body to produce new cells. Researchers are now realizing that the substances stem cells release may be more important than any new cells they may become. In other words, stem cells can directly become new healthy cells to a certain degree, but they can also release substances that dramatically increase the number of new, healthy cells.
Mesenchymal stromal stem cells release small packets called exosomes. These exosomes are filled with various substances that promote cell and tissue growth. Some of the most interesting and potentially useful substances are cytokines and micro RNA. Cytokines are the traffic cops of cellular repair, signaling certain events to take place while stopping others. Having the right cytokines in a particular area is critical for new tissue growth. The micro RNA released by stem cell exosomes is potentially even more exciting than cytokines. These tiny bits of RNA can directly affect how healthy and diseased cells behave. Micro RNA has a powerful ability to control the biological machinery inside of cells.
Exosomes exhibit a wide array of biological effects that promote the repair and growth of damaged and diseased organs. They promote the growth of skin cells and help wounds heal. Exosomes can reduce lung swelling and inflammation and even help the lung tissue heal itself (i.e. reduced pulmonary hypertension, decrease ventricular hypertrophy, and improve lung vascular remodeling). These small packets released by stem cells help prevent liver cells from dying (i.e. prevents apoptosis), promote liver cell regeneration, and slow down liver cirrhosis (i.e. fibrosis). Exosomes can also help protect the kidneys during acute injury and reduce the damage that occurs during a heart attack.
Several clinical trials are underway designed to allow these exciting developments to be used to treat patients. As the researchers state, “Extensive research and clinical trials are currently underway for the use of MSCs as regenerative agents in many diseases including spinal cord injury, multiple sclerosis, Alzheimer’s disease, liver cirrhosis and hepatitis, osteoarthritis, myocardial infarction, kidney disease, inflammatory bowel disease, diabetes mellitus, knee cartilage injuries, organ transplantation, and graft-versus-host disease.” We can reasonably expect that exosomes will be used to treat at least some of these conditions in the very near future.
Reference: Rani al. (2015). Mesenchymal Stem Cell-derived Extracellular Vesicles: Toward Cell-free Therapeutic Applications. Molecular Therapy. 2015 May; 23(5): 812–823.
Muscle health and strength is an important determinant of a person’s ability to function in daily life. One of the major determinants of healthy aging is how well people retain their muscle mass. The more that skeletal muscle declines, the more likely someone would not be able to care for themselves independently. Injury to muscles whether through trauma, burns, or toxins can greatly interfere with a person’s ability to perform activities of daily living. While muscle cells have a limited ability to regenerate themselves, quite often, patients never regain their former strength and level of function after serious injury.
Stem cells would seem to be ideally suited to help in this regard. Since stem cells have the potential to become muscle cells, one could imagine infusing stem cells into an area of muscle damage or injury to restore overall muscle function. While this makes sense intuitively, it may not be the case. Stem cells, for example, form new muscle cells, but they do not form cells that participate in muscle function. And yet, stem cells are able to help muscles regrow into functional skeletal muscles.
How could stem cells promote skeletal muscle regeneration without becoming functional skeletal muscle cells? The answer, as it turns out, is that stem cells produce molecules that strongly promote muscle regeneration and muscle function.
Stem cells release these molecules in tiny packets called exosomes. Exosomes are tiny spheres that “bubble out” of stem cells, in a manner of speaking. Exosomes have a cell membrane, like cells themselves, but are much smaller, and they do not have the ability to reproduce. Instead, exosomes are highly packed with proteins, DNA, messenger RNA, micro RNA, cytokines, and other factors.
Nakamura and co-researchers showed exosomes can help regenerate muscle. These researchers showed that by injecting exosomes harvested from stem cells (without any of the stem cells themselves), they could increase muscle growth and blood vessel growth. In short, these molecules accelerate the rate at which muscles regenerate.
While more research is needed, this work suggests that exosomes retrieved from mesenchymal stem cells could be used to help regrow functional muscle in patients with various forms of muscle injury.
Reference: Nakamura et al. (2015). Mesenchymal-stem-cell-derived exosomes accelerate skeletal muscle regeneration. FEBS Letters. 2015 May 8;589(11):1257-65.
Most large joints of the body contain cartilage, a substance that is softer and more flexible than bone. Because of its softness and flexibility, cartilage is well-suited to protect the bones as they move across one another. Unfortunately, this softness and flexibility also makes cartilage prone to injury and erosion. In patients with osteoarthritis, forexample, cartilage breaks down to the point that bone rubs against bone,causing pain and disability. Certain injuries can damage the cartilage (i.e.osteochondral lesion), which can essentially have the same effect.
Once the cartilage of joints has become damaged, there is
little that can be done to fix it. Patients may receive steroid injections into
the joint to reduce inflammation, and may rely on pain medications to relieve
the pain and swelling. Short of joint replacement therapy, no treatments can
reverse cartilage damage once it has occurred.
Fortunately, mesenchymal stem cells may soon be able to reverse cartilage defects that arise from osteochondral lesions and osteoarthritis. Wakitani and colleagues took samples of patients’ bone marrow, which contains mesenchymal stem cells. They then used various laboratory techniques to increase the number of stem cells in the sample. Four weekslater, the researchers then reinjected the concentrated stem cells back intothe same patient using their own source of stem cells. The Wakitani groupshowed that stem cell transplantation improved the patient’s clinical symptoms bysix months, a benefit that continued for two years on average. Samples takenfrom the patients 12 months later showed that the damaged cartilage had beenrepaired. In other work, Centeno and co-authors showed that bone marrow-derived mesenchymal stemcells could increase the volume of cartilage, reduce pain, and increase rangeof motion 24 weeks after stem cell transplantation.
Research continues to determine which stem cells are most useful, how many stem cells should be injected, how many injections need to be administered, and how should those stem cells be prepared before they are injected? Nonetheless, certain groups are making great strides in this area. In fact, the recent discovery of human skeletal stem cells promises to accelerate stem cell research into treating disorders of bone and cartilage.
Schmitt et al. (2012). Application of Stem Cells in Orthopedics. Stem Cells International. 2012: 394962
Liver failure is a serious, potentially fatal condition in which large swaths of liver cells become dysfunctional and die. Liver failure is the result of several conditions including chronic alcohol consumption, exposure to drugs that are toxic to the liver (e.g. acetaminophen), autoimmune diseases, or infections such as hepatitis C. Liver failure causes several metabolic abnormalities including dangerously low levels of sodium, potassium, and phosphate in the blood. Moreover, four in 10 people with liver failure have trouble regulating their blood glucose levels, which can cause profound hypoglycemia. Since the liver detoxifies the blood, when the liver fails, patients can experience confusion from excessive amounts of ammonia and other substances in the blood. Seizures are also possible.
Short of liver transplantation, there are very few treatments for liver failure. Most treatments focus on restoring sodium, potassium, phosphate, and glucose levels in the blood, and bringing down ammonia levels. Fortunately, experiments show that human mesenchymal stem cells may be a promising treatment for liver failure.
Researchers enrolled 43 people with acute-on-chronic liver failure caused by hepatitis B infection. In this group, 24 patients were treated with mesenchymal stem cells derived from human umbilical cord and 19 patients received a saline solution. The groups received stem cells or placebo, respectively, three times every four weeks. Patients treated with mesenchymal stem cells showed better measures of liver function than those who received placebo. Livers of the patients treated with stem cells produced much more protein, albumin, and clotting factors, and were better able to process bilirubin. Importantly, no significant side effects were observed during the trial.
Given the serious nature of liver failure and the lack of effective treatments (besides liver transplant), this research is incredibly exciting. It offers hope that through further research scientists will be able to use mesenchymal stem cells to change the outcomes of people with acute-on-chronic liver failure.