Enhancing Bone Healing with Mesenchymal Stem Cells

Enhancing Bone Healing with Mesenchymal Stem Cells

The ability for bone to naturally repair fractures and other common injuries have been well documented.  However, research has consistently demonstrated that as they age,  bone loses its ability to heal, repair, and fend off various bone diseases. In fact, each year, in the U.S. alone, there are over 2 million fragility-associated fractures with associated healthcare costs exceeding more than $20 billion dollars.

Currently, non-stem cell bone healing therapies including estrogen and related agonists, recombinant parathyroid hormone, supplements such as vitamin D and calcium exist, but with limitations and a number of potentially serious side effects.

Considering that the incidence of fracture and the associate rate of morbidity increase with age, current research is now examining other therapeutic options for the structural and functional restoration of bone, including the viability and of tissue engineering applications such as mesenchymal stem cells (MSCs) and bioscaffolding as potential solutions for the structural and functional restoration of bone.

Stem cells are generally used therapeutically in three distinct ways, including 1.) freshly isolated stem cells transplanted directly into tissue and undergo in vivo differentiation to become a desired cell type; 2.) the stem cell can be manipulated in vitro prior to being implanted; or 3.) circulating endogenous stem cells are recruited by cytokines to facilitate cell proliferation, migration, adhesion, and differentiation.

As researchers continue to explore using MSCs as part of therapeutic bone regeneration, it is generally accepted that MSC bone marrow density and quality decrease with age.  In addition, a factor in determining the effectiveness of MSCs related to facilitating tissue repair is the ability for the stem cells to be directed to the site of injury, a process more commonly known as “homing”.  A recent study using mice has demonstrated that MSCs appear to lose their homing ability rapidly while young MSCs demonstrate better homing ability, especially when compared to old MSCs.  Considering this, future research must consider the age of both donor and recipient when determining the effectiveness of this strategy.

In addition to stem cells, bioscaffolds are also considered an essential component of the bone regeneration strategy, serving as the reservoir for multiple factors, the carrier for cells, the filler for the void space, and the template for bone regeneration.  The ideal scaffold for bone tissue engineering has been identified as:

  • Showing no local and systemic toxic effects to the host tissue
  • Supporting normal cellular activity
  • Allowing cell adhesion, proliferation, extracellular matrix deposition, and inducting new bone formation
  • Prompting the formation of blood vessels after weeks of implantation.

Considering the above, several substrates have been identified as potential bioscaffolds to support improved regeneration of bone tissue, including decellularized extracellular matrix scaffolds, synthetic scaffolds (calcium phosphate-based bioactive ceramic scaffolds; metallic scaffolds (including metal scaffolds coated with growth factors and other bioactive factors); hybrid scaffolds combining two or more materials (metal-ceramic-poly hybrid scaffolds); natural and synthetic polymeric scaffolds; and nanomaterial-based scaffolds.

As research continues to explore the possibilities of new therapeutic approaches to bone healing provided through various tissue engineering applications, the use of MSCs and bioscaffolds continue to demonstrate potential benefits.  Among the key areas requiring further study is the need to develop vascularization in engineered bone material.  Bone and bone tissue has a rich vascular supply; while the recent study has demonstrated nanomaterials as having the potential to promote vascularization (without the aid of growth factors), further research and clinical trial are required.

Reference: (2018, June 22). Bone Marrow Mesenchymal Stem Cells: Aging … – NCBI – NIH. Retrieved December 18, 2020, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733253/

Evaluating the Effectiveness of Mesenchymal Stem Cells As An Option For Stroke Therapy

Evaluating the Effectiveness of Mesenchymal Stem Cells As An Option For Stroke Therapy

Promising early research shows that when introduced into a brain injured by stroke, extracellular vesicles (EVs), also known as exosomes, a bioactive substance secreted by mesenchymal stem cells, have been associated with improved blood vessels creation, increased formation of neurons, and enhanced preservation of the neurological structure; these findings demonstrate a promising stem cell-derived stroke therapy that serves as an alternative approach to current stem cell infusion treatment options.

With nearly 14 million people suffering strokes each year, strokes continue to be the leading cause of physical disability among adults; between 25 percent and 50 percent of stroke survivors are left with significant and debilitating disabilities.

Because mesenchymal stem cells, or MSCs, secrete extracellular vesicles thought to reduce inflammation, enhance autophagy, and promote regeneration of damaged cells, researchers evaluating potential regenerative strategies for stroke-induced neurologic deficits have identified these MSC-derived EVs as a viable option for stroke therapy. 

Although the reported beneficial effects of EV therapy has been observed in studies completed on animals, there is an increasing number of clinical studies currently being conducted on humans that suggest MSC EV stem cell therapy is a potentially safe and effective therapeutic option to improve outcomes in several various human applications. 

Specifically, this EV-mediated therapy appears to offer an off-the-shelf treatment option that is potentially effective in crossing the blood-brain-barrier (BBB) while also avoiding cell-related problems, including the formation of tumors and infarcts resulting from vascular occlusions, or blood clots, consistent with those observed in acute ischemic stroke.

While there appears to be a promising upside to MSC EV therapy for the treatment of stroke, studies are on-going to discover the optimal therapeutic treatment of stroke patients. Some areas to continue researching are the optimal time and best mode of application of EVs in stroke patients (most stroke-related recovery occurs in the first few months following the stroke).

As research continues into the effectiveness of MSC-EV therapy for stroke, early indications are that EVs derived from mesenchymal stem cells could be a viable cell-free treatment option for patients recovering from a severe stroke.

Source: (2019, March 12). Mesenchymal Stem Cell-Derived Extracellular Vesicle …. Retrieved December 4, 2020, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422999/

Exosomes from Mesenchymal Stem Cells Show to Protect Cartilage and Relieve Osteoarthritis Pain

Exosomes from Mesenchymal Stem Cells Show to Protect Cartilage and Relieve Osteoarthritis Pain

Osteoarthritis is the most common form of arthritis.  In osteoarthritis, the cartilage of the joints breaks down, bone spurs form, the synovial linings become inflamed, and the ligaments around the joint calcify. All of these pathological changes combine to cause joint pain, swelling, and stiffness. The breakdown of the joint also means that it does not function properly. The arthritic joint may “lock up,” “give out,” or simply not be able to move through its normal range of motion. Early in the disease, the pain of osteoarthritis may be brought on by movement. Later, the pain is more or less constant with severe pain flares.

Initially, the treatment for osteoarthritis is pain medications, exercise, braces, and physical therapy. Joint injections may be helpful for 4 to 6 weeks, but recent research suggests that repeated steroid injections may break down cartilage and speed up joint destruction. Unlike treatments for rheumatoid arthritis, there are no disease-modifying treatments for osteoarthritis. The disease tends to get worse over time until surgery is required. Joint replacement surgery is usually the treatment of last resort.

Since osteoarthritis is a degenerative joint disease, a reasonable approach to therapy is to try to rebuild or regenerate the joint tissues. This would not only stop the disease progression of osteoarthritis but perhaps even heal the damaged joint. For this reason, regenerative medicine, also known as stem cell therapy, is drawing the attention of many scientists who are looking for alternative therapeutic treatments for osteoarthritis.

Researchers tested the ability of mesenchymal stem cells to relieve pain and treat the damage of osteoarthritis. More specifically, they used the exosomes that the mesenchymal stem cells produce. Exosomes are tiny packets of substances like RNA and peptides that support tissue growth and repair. Exosomes contain most of the molecules that make mesenchymal stem cells helpful.

The scientists found that giving exosomes from mesenchymal stem cells to animal subjects with experimental osteoarthritis had some remarkable effects. Not only did the stem cell-derived treatment substantially reduce pain in the rats with osteoarthritis, but microscopic and molecular evidence also showed that the exosomes were able to repair cartilage in the affected joints. This is truly impressive when you consider that other treatments for osteoarthritis only reduce symptoms—they do not repair cartilage or stop the progression of the disease.

While this work will need to be replicated in human clinical studies (and that work has already begun), this is an exciting finding for the millions of Americans who struggle with osteoarthritis.

Reference: He, L., He, T., Xing, J. et al. Bone marrow mesenchymal stem cell-derived exosomes protect cartilage damage and relieve knee osteoarthritis pain in a rat model of osteoarthritis. Stem Cell Res Ther 11, 276 (2020). https://doi.org/10.1186/s13287-020-01781-w

Stem Cell Therapy for COPD

Stem Cell Therapy for COPD

Chronic obstructive pulmonary disease (COPD) is a lung condition that makes it hard for patients to breathe. In COPD, small airways in the lungs thicken and lose their elasticity. People with COPD have shortness of breath, especially during physical activity. Patients with severe COPD may experience a more challenging quality of life. COPD patients may experience several exacerbations a year which require a stay in the hospital.

Patients with COPD typically need one or more inhalers a day. These inhalers help to open airways and, in some cases, decrease lung inflammation. Patients who also have bronchiectasis may need to take an oral antibiotic every day. During a COPD exacerbation, patients usually must receive powerful steroid treatments intravenously, routine breathing treatments, and supplemental oxygen.

People with COPD are more prone to lung infections, and so they usually receive IV antibiotics for pneumonia. Those who successfully stop smoking can help to prevent further lung damage, however, the inflammation and lung damage persists for a long time. Today, patients are seeking alternative therapies for COPD. Many are discovering regenerative medicine, also known as stem cell therapy, that may offer an incredibly promising therapy for COPD.

The lungs have a large number of naturally occurring stem cells that can restore function. For example, mice who lose half their lung capacity from experimental COPD survive, and natural stem cells within the lungs can restore their lungs to a natural state within 5 months. Unfortunately, humans with COPD cannot repair their lungs as quickly and as fully as mice can. This is why researchers are studying the use of stem cell treatment to restore lung function in patients with COPD.

Studies have shown that stem cells have the potential to help improve lung function. Stem cell treatment improved oxygen and carbon dioxide exchange, exercise tolerance, and cell injury in early studies.

One review did show that stem cell treatment is “safe and may improve patients’ condition and quality of life; however, larger-scale studies are needed to evaluate efficacy.” More research in humans is needed, but the pre-clinical (aka animal and laboratory) research in this area is quite promising.

Reference: Kokturk N, Yıldırım F, Gülhan PY, Oh YM. Stem cell therapy in chronic obstructive pulmonary disease. How far is it to the clinic?. Am J Stem Cells. 2018;7(3):56-71. Published 2018 Aug 1.

Stem Cell Science for Alzheimer’s Disease

Stem Cell Science for Alzheimer’s Disease

Alzheimer’s disease is the most common form of dementia. Among other symptoms, Alzheimer’s disease causes memory loss as nerve cells in the brain become dysfunctional and die. While the disease is known to be related to the accumulation of β-amyloid plaques and neurofibrillary tangles, how and why those things happen is still a mystery. Nonetheless, researchers have created and tested drugs to change the way the brain process β-amyloid and hyperphosphorylated tau (the substance in neurofibrillary tangles) but nothing, so far, has worked in humans. Instead, we are left with anticholinergic drugs, and memantine used to slow the progression of the disease.

These failures of drug development have forced scientists to reconsider how to treat Alzheimer’s disease. Instead of a focus on neuropathology that we cannot understand or control, why not focus on supporting nerve cells that remain or even restore the nerve cells that are lost? This is the hope of stem cell research in Alzheimer’s disease, and the focus of an extensive review article on the subject.

The review article describes the clinical possibilities of different types of stem cells:

  • Neural stem cells (NSCs)
  • Mesenchymal stem cells (MSCs)
  • Induced pluripotent stem cells (iPSCs)

Neural stem cells (NSCs)

NSCs have the magnificent ability to become any type of brain cell, be they neurons or various types of glia. NSCs would be the ideal stem cell treatment for Alzheimer’s disease except for one major problem: There are very, very few NSCs in the human brain. It is nearly impossible to harvest them in high enough numbers and, right now, we don’t have ideal ways to make them multiply and grow in a laboratory. So, while research in NSCs for the treatment of Alzheimer’s disease is well underway, they won’t be widely available any time soon. 

Mesenchymal stem cells (MSCs)

Mesenchymal stem cells can become many different types of cells and can be harvested from many places including bone marrow, umbilical cord, and adipose (fat). MSCs are very versatile, and we are improving at safely using them in various diseases, including Alzheimer’s disease. MSCs are one of the more exciting avenues of research in Alzheimer’s disease and other neurodegenerative diseases.

Induced pluripotent stem cells (iPSCs)

iPSCs are a remarkably interesting type of stem cell. They are stem cells that are created by reprogramming cells found in the skin (fibroblasts) to become other cells of interest. Researchers take fibroblasts and genetically alter them to behave like other types of stem cells or fully differentiated cells. Recent work has shown that scientists can repurpose iPSCs to become neural precursor colonies, which are a lot like NSCs described above. If one could take iPSCs from the skin and convert them into NSCs, this could truly be a treatment for Alzheimer’s disease.

Stem cell treatments provide the promising potential to help those with Alzheimer’s disease and other neurodegenerative diseases. While research is ongoing, the breakthroughs that have been recently discovered provide hope to those seeking an alternative option.

Reference: Lee, J. H., Oh, I. H., & Lim, H. K. (2016). Stem Cell Therapy: A Prospective Treatment for Alzheimer’s Disease. Psychiatry Investigation13(6), 583–589. https://doi.org/10.4306/pi.2016.13.6.583

Stem Cell Therapy for ALS: Results From an Early Phase Clinical Trial

Stem Cell Therapy for ALS: Results From an Early Phase Clinical Trial

ALS, which stands for amyotrophic lateral sclerosis, is a neurodegenerative disease that has no cure and no substantially effective treatment. Today, there are two drugs available that can slow the progression of ALS— riluzole and edaravone—but these agents may only be modestly effective. Sadly, patients with ALS get progressively worse, sometimes even with treatment. They lose to ability to move, to swallow, and to breathe. It is a devastating disease.

As with other neurodegenerative diseases, researchers are trying to treat ALS with stem cells. Stem cells have the capacity to become other types of cells such as neurons or glia. The notion is that stem cells could be used to rescue and replenish the nerve cells that are dysfunctional or destroyed in ALS. Studies are emerging that suggest that these approaches may bear fruit.

One such stem cell trial comes out of India, published by Dr. Prabhakar and colleagues. The research scientists infused autologous bone marrow-derived stem cells (autologous means the cells were retrieved from the patient and then readministered to the same patient). The scientists conducted the clinical study in ten patients with ALS who had a mean revised ALS Functional Rating Scale score of 30.2 ± 10.58. In other words, patients with this score have about a 60 to 70% chance of being alive for 9 more months.

Impressively, patients treated with autologous bone marrow-derived stem cells did not have a significant reduction in ALS Functional Rating Scale score after one year, which means their disease stayed relatively stable over this time instead of deteriorating. It took about 16.7 months for the score on this scale to drop by 4 points, which is considered a significant drop. The median survival after the procedure was 18.0 months, which is substantially more than would have been expected at the start of the study.

Taken together, these results suggest that patients with moderately severe ALS enjoyed a stabilization of their ALS symptoms for over 16 months on average. While there was no placebo control group, the stem cell-treated patients survived about twice as long as was estimated at the start of the trial.

These positive results must be confirmed in a larger, placebo-controlled trial. However, they strongly argue for further research of stem cells for the treatment of amyotrophic lateral sclerosis.

Reference: Prabhakar S, Marwaha N, Lal V, Sharma RR, Rajan R, Khandelwal N. Autologous bone marrow-derived stem cells in amyotrophic lateral sclerosis: A pilot study. Neurol India 2012;60:465-9

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