Spinal cord injury is severe neurological condition in which
the major mode of transmission between the brain and the body is disrupted.
When higher levels of the spinal cord are injured, for example, in the neck,
the injury can be immediately fatal. Those who survived spinal cord injury are
often left paralyzed and at risk for a number of comorbid conditions
such as pneumonia, depression, skin ulceration infection, urinary tract
infections, and pain.
If patients who sustain spinal cord injury can receive
medical treatment quickly, physicians may administer glucocorticoids to help
reduce swelling around the injury and preserve spinal cord function. Patients
may also undergo therapeutic
hypothermia (a.k.a. targeted temperature management, whole body cooling),
also to help reduce inflammation and prevent scar tissue from forming around
the damaged spinal cord.
After the first few days to weeks after spinal cord injury,
not much can be done to change the outcome of the disease. Patients may undergo
intensive physical, occupational, and speech therapy to help regain function,
but more often than not the neurological deficits are mostly permanent. Hence,
researchers are feverishly searching for ways to treat spinal cord injury and,
by extension, prevent or reduce paralysis and other chronic complications.
Mesenchymal stem cells are an intriguing potential therapy
for spinal cord injury. These cells can easily be obtained from many different
tissues including bone marrow and fat among others. In animals, mesenchymal stem
cells have been shown to improve changes that occur during spinal cord injury,
namely the regeneration
and strengthening of nerve cells in the spinal cord. Research
has also shown how adipose-derived stem cells are a potential option for those
with neurological conditions such as spinal cord injury.
To test this possible effect in humans, researchers collected
mesenchymal stromal (stem) cells from patients with spinal cord injury in
their upper back (i.e. thoracic spinal cord). Researchers then prepared and administered
those cells back into the cerebrospinal fluid of the same patients. Each
patient received two or three injections of approximately 1,000,000 cells per
kilogram body weight. There were no adverse effects of the treatment for up to
two years after injection. MRI imaging showed no abnormalities resulting from
stem cell infusion. While the authors write that there were too few patients to
make any firm conclusions about the efficacy of the treatment, they were
strongly encouraged by the safety of the procedure. In fact, they use these
results to begin a placebo-controlled clinical trial.
Reference
Satti et al. (2016). Autologous mesenchymal stromal cell
transplantation for spinal cord injury: A Phase I pilot study. International Society for Cellular Therapy,
18(4),518-522.
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.
Tissue injury is common to many human diseases. Cirrhosis results in damaged, fibrotic liver tissue. Idiopathic pulmonary fibrosis and related lung diseases cause damage to lung tissue. A heart attack damages heart tissue, just as a stroke damages brain tissue. In some cases, such as minor tissue injury, the damaged tissue can repair itself. Over time, however, tissue damage becomes too great and the organ itself can fail. For example, long-standing cirrhosis can cause liver failure.
One area of active research is to find ways to protect tissue from injury or, if an injury occurs, to help the tissue repair itself before the damage becomes permanent and irreversible. Indeed, tissue repair is one of the main focuses of regenerative medicine. Likewise, one of the most promising approaches in the field of regenerative medicine is stem cell therapy. Researchers are learning that when it comes to protecting against tissue injury and promoting tissue repair, exosomes harvested from stem cells are perhaps the most attractive potential therapeutic.
Why are stem cell exosomes so promising? Exosomes are small packets of molecules that stem cells release to help the cells around them grow and flourish. While one could inject stem cells as a treatment for diseases (and they certainly do work for that purpose) it may be more effective in some cases to inject exosomes directly. So instead of relying on the stem cells to produce exosomes once they are injected into the body, stem cells can create substantial amounts of exosomes in the laboratory. Exosomes with desired properties could be concentrated and safely injected in large quantities, resulting in a potentially more potent treatment for the disease.
Indeed, researchers have shown that extracellular vesicles (exosomes and their cousins, microvesicles) can be collected from stem cells and used to treat a variety of tissue injuries in laboratory animals.
Exosomes from the same type of stem cell protected the lungs and reduced lung blood pressure in mice with pulmonary hypertension.
Exosomes from endothelial progenitor cells protected the kidney from damage caused by a lack of blood flow to the organ.
In this growing field of Regenerative Medicine, research is constant and building as new science evolves from stem cell studies. Researchers are closing in on the specific exosomes that may be helpful in treating human diseases caused by tissue injury.
Reference: Zhang et al. (2016). Focus on Extracellular Vesicles: Therapeutic Potential of Stem Cell-Derived Extracellular Vesicles. International Journal of Molecular Sciences. 2016 Feb; 17(2): 174.
Patients who suffer ischemic stroke have some treatment
options, but many of them require immediate intervention and so are not useful
if too much time has elapsed between the stroke and treatment. Therapies that
employ stem cells are promising alternatives because stem cells can differentiate
into brain cells and potentially help to replace tissue that has been damaged
or destroyed.
A recent study published in Stem Cells
and Development has shown for the first time that a specific type of stem
cell – called ischemia-induced multipotent stem cells – may be able to help
with such repair of brain tissue in patients who have suffered a stroke.
Specifically, the research team demonstrated the technical ability to isolate
the ischemia-induced multipotent stem cells from the brains of elderly stroke
patients.
The scientists then used protein
binding techniques to determine where in the brain these stem cells came from.
They found that the cells came from areas of the brain where brain cells had been
damaged or killed from the stroke. These cells were located near blood vessels
and expressed certain biological markers that enabled the researchers to
confirm that they qualified as stem cells. Specifically, these cells had
proliferative qualities that suggested that they could potentially be used to
re-populate damaged areas of the brain. The cells also showed the ability to
differentiate into different types of cells, a key characteristic of stem cells
used for therapeutic purposes.
This study represents a
significant step in overcoming the technical challenges associated with
isolating and classifying ischemia-induced multipotent stem cells. The next
step for researchers will be to test the potential of these cells in stroke
treatment. If researchers show that these stem cells can be used to
successfully repair damaged areas of the brain – and more importantly, restore
functions that were disrupted by the stroke – then physicians and scientists
may be able to work together to translate these findings into therapies that
are regularly used in stroke.
Reference
Tatebayashi et al. 2017. Identification of multipotent stem
cells in human brain tissue following stroke. Stem Cells and Development, 26(11), 787-797.
Spinal cord injury can be one of the most devastating
injuries. Long neurons that extend from the brain down the spinal cord are
severed and scarred. In most cases, this damage can never be repaired. If
patients survive an injury to the spinal cord, they can be permanently
paralyzed. Researchers have attempted to use high-dose steroids and surgery to
preserve the spinal cord, but these approaches are either controversial or
largely ineffective.
Ideally, one would create an environment in which nerve
cells in the spinal cord could regrow and take up their old tasks of sensation
and movement. One of the most promising approaches to do just this is stem cell
transplantation.
To test this concept, researchers used
stem cells derived from human placenta-derived mesenchymal
stem cell tissue (not embryonic stem cells) to form neural stem cells in
the laboratory. These neural stem cells have the ability to become neuron-like
cells, similar to those found in the spinal cord. The researchers then used
these stem cells to treat rats that had experimental spinal cord injury. The
results were impressive.
Rats treated with neural stem cells regained the partial
ability to use their hindlimbs within one week after treatment. By three weeks
after treatment, injured rats had regained substantial use of their hindlimbs.
The researchers confirmed that this improvement was due to neuron growth by
using various specialized tests (e.g. electrophysiology, histopathology). Rats
that did not receive stem cells did not regain substantial use of their
hindlimbs at any point in the study.
This work is particularly exciting because it shows that
stem cells can restore movement to animals who were paralyzed after spinal cord
injury. Moreover, the researchers used human stem cells derived from placenta,
which suggests that this effect could be useful in human spinal cord injury
patients (perhaps even more so than in rats). While additional work is needed,
these results offer hope to those who may one day develop severe spinal cord
injury.
Reference:
Zhi et al. (2014). Transplantation of placenta-derived
mesenchymal stem cell-induced neural stem cells to treat spinal cord injury.
Neural Regen Research, 9(24): 2197–2204.
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.
Reference
Schmitt et al. (2012). Application of Stem Cells in Orthopedics. Stem Cells International. 2012: 394962
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