Mesenchymal Stromal Cells are Safe and Well-Tolerated in ALS

Mesenchymal Stromal Cells are Safe and Well-Tolerated in ALS

Amyotrophic lateral sclerosis (ALS) is an incurable neurologic disorder that causes muscle weakness, and disability. In ALS, nerve cells degenerate causing muscle weakness and atrophy. ALS affects the nerve cells that connect the brain to the spinal cord (upper motor neurons), and nerve cells that connect the spinal cord to muscles (lower motor neurons). While some patients with ALS will experience paresthesias (numbness and tingling), most nerves that detect sensations remain intact until the very latest stages of the disease. Over time, people with ALS may experience cognitive problems such as mild dementia, though most stay mentally sharp. Patients with ALS may also experience Parkinson’s-like symptoms, such as tremor and slowness of movement (bradykinesia). When the nerves that control swallowing or breathing become dysfunctional, ALS can become life-threatening or lethal. Damage to these nerves and muscles could lead to aspiration pneumonia, and respiratory failure, respectively.

ALS is also known as Lou Gehrig’s disease because the famed New York Yankee publicly struggled with ALS. Perhaps people alive today are more familiar with another patient who suffered from ALS, the Nobel laureate physicist, Stephen Hawking. Dr. Hawking was well known for being confined to a wheelchair and almost completely paralyzed, requiring a specialized computer interface to communicate.

There is no specific treatment for ALS. Therapy is aimed at controlling the symptoms of the disease. For example, patients may have a breathing tube placed in their neck (tracheostomy) and be connected to a ventilator to help support breathing. Likewise, a feeding tube in the stomach can help patients receive hydration and nutrition if they cannot safely swallow food because of neck muscle weakness. Physical therapists help patients maximize the strength and function. Certain medicines can be used to help treat muscle spasms, sleep problems, pain, and depression.

Since there is no cure for ALS, and really no specific treatment for the condition, there is considerable interest in discovering effective treatments. One of the most promising potential therapies is to use stem cells to treat ALS. Since ALS is caused by the destruction and loss of motor neurons, a reasonable treatment approach is to use stem cells that can become motor neurons and promote motor neuron growth and development.

Recently, researchers conducted two clinical trials to evaluate the safety and feasibility of using bone marrow-derived mesenchymal stromal cells to treat patients with ALS. In one clinical trial, the researchers infused stem cells intravenously, while in the other they infused the stem cells into the cerebrospinal fluid around the spine (intrathecally). Patients in both trials were followed for up to 12 months after the infusion to see if the stem cells caused side effects. During the follow-up period, there were no reports of adverse events related to the treatment. Given the success of these trials, this work clears the way for future clinical trials to study the efficacy of stem cells for treating amyotrophic lateral sclerosis.

Reference: Nabavi et al. (2019). Safety, Feasibility of Intravenous and Intrathecal Injection of Autologous Bone Marrow-Derived Mesenchymal Stromal Cells in Patients with Amyotrophic Lateral Sclerosis: An Open-Label Phase I Clinical Trial. Cell Journal. 2019 Jan;20(4):592-598.

Umbilical Cord Derived Mesenchymal Stem Cells Restore Function After Stroke

Umbilical Cord Derived Mesenchymal Stem Cells Restore Function After Stroke

An ischemic stroke is a devastating event. An ischemic stroke is caused when a blood clot blocks blood flow to a portion of the brain. If the blood cannot deliver oxygen and nutrients, brain cells in the affected area die. Whatever functions that area of the brain once performed are now lost—brain cells do not regenerate the same way as other cells do.

Not surprisingly, researchers are trying to find ways to restore dead brain cells so that patients can regain function. Stem cells are one of the most promising options in this pursuit. Stem cells can reduce brain damage caused by ischemia (lack of blood flow, nutrients, and oxygen). Moreover, stem cells can help animals with stroke regain neurological function.

Scientists have wondered, however, whether mesenchymal stem cells taken from the umbilical cord can achieve the same effects. Umbilical cord tissue is plentiful and the cells taken from the umbilical cord have many incredible properties.

Dr. Zhang and researchers in his group extracted mesenchymal stem cells from umbilical cord tissue collected from humans. This umbilical cord tissue is usually thrown away after a baby is born, but researchers have been collecting this material because it is rich in mesenchymal stem cells. The researchers then created ischemic strokes in rats by blocking one of the arteries to the brain. They then used stem cells to try to block the damaging effect of stroke in these rats.

The stem cells were given to the rats intravenously. The stem cells moved from the bloodstream into the brain and collected in the area of the stroke. Some of the stem cells actually became new brain cells in the damaged area. Moreover, rats treated with stem cells had better physical functioning than animals who did not receive stem cell treatment.

While this study was performed in rats, the implications for humans are profound. This work shows that mesenchymal stem cells taken from the umbilical cord are capable of improving function after stroke. This is exited news since it is much easier to obtain stem cells from umbilical cord tissue that it is from bone marrow (which requires an invasive procedure).

 

Reference: Zhang, Lei et al. (2017). Neural differentiation of human Wharton’s jelly-derived mesenchymal stem cells improves the recovery of neurological function after transplantation in ischemic stroke rats. Neural Regeneration Research. 2017 Jul; 12(7): 1103–1110.

Mesenchymal Stromal Cells Shown to be Safe in Multiple Sclerosis

Mesenchymal Stromal Cells Shown to be Safe in Multiple Sclerosis

Of all conditions that affect the central nervous system, Multiple Sclerosis (MS) is the most common in young adults. The severity of multiple sclerosis varies considerably and can affect almost every organ system in the body affecting eyesight, bowel function, bladder function, and sexual function. Multiple sclerosis may cause cognitive problems, depression, seizures, fatigue, and pain. Most people with multiple sclerosis will have a relapsing-remitting course, which means they will have periods of relative health punctuated by flare-ups of the condition. About one out of ten people with the condition will have primary progressive multiple sclerosis, which means once the disease occurs it almost constantly causes symptoms and progresses over time.

Multiple sclerosis appears to be an inflammatory condition that affects the covering around nerves. During acute flareups/exacerbations, physicians usually prescribe a powerful steroid medication such as methylprednisolone to combat the inflammation. Patients with multiple sclerosis generally always require some sort of treatment to help manage their immune system. No fewer than 15 immune modulating treatments have been used to treat multiple sclerosis, none of which provides a cure. As such, researchers are seeking new and innovative ways to treat this potentially debilitating condition.

Researchers at the Tisch Multiple Sclerosis Research Center of New York chose to focus their research efforts on a particular type of stem cell, namely bone marrow-derived mesenchymal stromal cells. The researchers harvested these cells from the patients themselves (autologous stem cells). Then, in their laboratory, scientists used various means to prompt the cells to become neural progenitors. A neural progenitor cell is a cell that can become any of the three main types of brain cells: neurons, astrocytes, or oligodendrocytes. Incidentally, oligodendrocytes are believed to be most affected in multiple sclerosis.

Harris and co-authors at the Tisch Center enrolled six patients with progressive multiple sclerosis. These six patients had failed to find relief from other conventional multiple sclerosis treatments. The researchers provided between 2 to 5 infusions of neural progenitor cells into the spinal fluid. The multiple sclerosis patients treated with the cells tolerated the treatment very well. No serious adverse events occurred, nor were there any safety concerns during treatment. Impressively, four of the six patients—for whom no other multiple sclerosis treatment worked—had a measurable clinical improvement after stem cell treatment.

Based on the results of this clinical study, the scientists concluded that neural progenitor cells created from autologous mesenchymal stromal cells were safe to use in patients with primary progressive multiple sclerosis. Moreover, the beneficial effect witnessed in two-thirds of treated patients suggests that these cells may be able to help patients with even the most severe and difficult-to-treat forms of multiple sclerosis. Of course, additional testing is required before this treatment becomes commonplace, but the results of this first-in-human clinical study are extremely encouraging.

 

Reference: Harris et al. (2016). Clinical safety of intrathecal administration of mesenchymal stromal cell-derived neural progenitors in multiple sclerosis. Cytotherapy. 2016 Dec;18(12):1476-1482.

Mesenchymal Stem Cells for Osteoarthritis

Mesenchymal Stem Cells for Osteoarthritis

Osteoarthritis is the most common form of arthritis. In fact, when people casually use the term “arthritis” or think of the arthritis of old-age, they are usually talking about osteoarthritis. People with arthritis experience many symptoms in and around the affected joints including pain and swelling. The affected joints may become unstable or “give out.” At the same time, people who suffer from osteoarthritis may not be able to move their joints fully or smoothly. Commonly people feel that their joints are “stiff.”

Early in osteoarthritis, the pain may just occur occasionally. Perhaps, the person feels sharp pain when moving a certain way. In later stages of osteoarthritis, the affected joints constantly ache, and moving the joint becomes intensely painful.

Nonsteroidal anti-inflammatory drugs or NSAIDs can help in some cases, but they become less effective as osteoarthritis becomes more severe. Often people with osteoarthritis must receive injections of anesthetics and steroids into the joints itself. Ultimately, patients often need orthopedic surgery to grind away diseased joint tissue or even replace the joint with the artificial one.

Researchers are searching for ways to reverse osteoarthritis instead of just treating the symptoms. Fortunately, stem cells may offer hope. Doctors have long known that in people with osteoarthritis, the cartilage becomes thin and breaks down. Joint cartilage lubricates the joint, acts as a shock absorber, and helps the joint move smoothly. When cartilage breaks down, the joint becomes stiff, painful, and irritated. As recent research suggests, mesenchymal stem cells may rebuild and restore joint cartilage.

Two scientists, Kristjánsson and Honsawek, recently reviewed the state of the research in this field. They identified eight clinical studies that tested mesenchymal stem cells on patients with varying degrees of osteoarthritis. The clinical trials demonstrated several intriguing findings. Most notably, mesenchymal stem cells were able to promote cartilage regeneration, reduce pain, and improve joint function. The scientists also found that the more stem cells that were injected, the better the outcome. In addition, the beneficial effect of stem cells occurred whether the cells were taken from the patient (autologous stem cells) or from young, healthy donors (allogenic stem cells).

Importantly, patients with mild to moderate osteoarthritis enjoy the greatest apparent benefit from stem cell injections. This suggests that doctors and patients should consider stem cell treatment earlier in the course of osteoarthritis before joints become too damaged and likely require surgery.

Mesenchymal stem cell injection for osteoarthritis has now been tested in at least eight clinical studies including randomized clinical trials, which are the gold standard studies for evaluating treatments in medicine. Research is ongoing and still needed but these results are strongly encouraging. They may offer, for the first time, a way for patients to reverse the changes of osteoarthritis rather than simply treating the symptoms of the disease.

 

Reference: Kristjánsson et al. (2017). Mesenchymal stem cells for cartilage regeneration in osteoarthritis. World Journal of Orthopedics. 2017 Sep 18; 8(9): 674–680.

Stem Cells Plus Hyaluronic Acid Repair Joint Cartilage Defects

Stem Cells Plus Hyaluronic Acid Repair Joint Cartilage Defects

Cartilage plays several important roles in the way joints move and function. Joint cartilage provides lubrication, acts as a shock absorber, and helps the joint move smoothly. Joint cartilage is comprised of two substances chondrocytes (i.e. cartilage cells) and extracellular matrix (proteins such as hyaluronic acid, collagen, fibronectin, etc.).

Many conditions can lead to joint cartilage defects. In young people, the most common cause of the joint cartilage defect is an injury. For instance, a football player suffers a hard contact that injures the joint. Another example is a gymnast who repeatedly places substantial impact forces on the knee and other joints of the lower body, resulting in damage. In older people, the most common cause of joint cartilage defects is Osteoarthritis. Over time, the joint cartilage breaks down in the cartilage loses its ability to lubricate, absorb shock, and support the smooth movement of the joint. This leads to stiffness, pain, and “trick” joints, among other symptoms.

Orthopedic surgeons, rheumatologists, and other physicians have attempted to treat these conditions by injecting the damaged joint with one of the two main components of joint cartilage: extracellular matrix. Physicians inject hyaluronic acid (and sometimes related extracellular matrix proteins) to help replace and restore damaged joints. This approach can be helpful for some patients, but it is certainly not a cure.

Only recently, have researchers attempted to replace the other component of joint cartilage: chondrocytes. Specifically, researchers have focused their efforts on mesenchymal stem cells that have the ability to differentiate and become cartilage cells. Li and colleagues injected combinations of bone marrow-derived mesenchymal stem cells and hyaluronic acid into animals with experimental cartilage defects. They showed that hyaluronic acid injections alone modestly repaired the cartilage damage. However, when stem cells plus hyaluronic acid was injected, the joints were almost completely repaired. In other words, stem cells plus hyaluronic acid resulted in much greater improvement in joint cartilage damage than hyaluronic acid alone.

The authors of the study concluded that “bone marrow stem cells plus hyaluronic acid could be a better way to repair cartilage defects.” While additional work is needed, these results are extremely exciting for people who suffer from joint cartilage defects such as osteoarthritis. In the future, people who are candidates for hyaluronic acid injection treatments may instead receive a combination of hyaluronic acid plus stem cells and may enjoy an even greater benefit than hyaluronic acid treatment alone.

 

Reference: Li et al. (2018). Mesenchymal Stem Cells in Combination with Hyaluronic Acid for Articular Cartilage Defects. Scientific Reports. 2018; 8: 9900.

 

Autologous Mesenchymal Stem Cell Transplantation for Spinal Cord Injury

Autologous Mesenchymal Stem Cell Transplantation for Spinal Cord Injury

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.

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