The National Institute of Health estimates that nearly 250,000 people in the United States are currently living with a spinal cord injury (SCI). Most often a result of an accident, SCIs typically result in the loss of neurons and axonal damage resulting in the loss of function.
SCIs can be divided into two distinct phases, the initial physical injury and the secondary injury which typically occurs hours to days later. In most cases of SCI, damage to the axonal and tissue damage is caused by compression and/or contusion to the spinal cord. The secondary SCI injury occurs in the hours and days after the initial injury and is characterized by persistent inflammation, glial scar formation, demyelination of surrounding neurons, and death of cells. Over time, research has demonstrated that, in all aspects of secondary injury, the inflammatory response is the major cause and leads to widespread cell damage and lesion expansion.
Recent research has demonstrated that stem cells, including mesenchymal stem cells (MSCs), neural stem/progenitor, and embryonic stem cells, possess anti-inflammatory properties and promote functional recovery after SCI by inducing macrophages M1/M2 phenotype transformation.
In this review, Cheng and He discuss the general feature of macrophages in response to SCI, the phenotype, and function of macrophages in SCI, and the effects of stem cells on macrophage polarization and its role in stem cell-based therapies for SCI.
Macrophages accumulate in and around an SCI and play a very important role in neuroinflammation. Considering that recent research demonstrates the different, but important, contributions M1 and M2 macrophages make toward repairing tissue damage, this process is thought to be a promising therapeutic treatment for controlling the inflammation occurring after initial SCI.
According to this review, there are both positive and negative effects of macrophages on tissue repair and regeneration after an SCI. Interestingly, some studies show that infiltrating macrophages has harmful effects, especially in the early stages of an SCI. On the other hand, studies also indicated that macrophages have beneficial effects on tissue repair. These results included findings indicating that activated macrophages could provide a beneficial microenvironment that is good for the regeneration of sensory axons.
While the exact reason for the opposite effects of macrophages on the pathological process of SCI is not yet known, it’s thought to be because of the different phenotypes of macrophages – M1 (classical activation) and M2 (alternative activation).
Additionally, studies have demonstrated that M2 macrophages are important for efficient remyelination after CNS injury, while M1 macrophages hinder neurogenesis and inhibit neurite outgrowth and induce growth cone collapse of cortical neurons.
Considering these findings, the authors point out that polarization of macrophages to M2 is beneficial – and often preferred to M1- to facilitate the recovery after SCI. These findings have also demonstrated stem cell transplantation to hold tremendous potential for therapeutic uses in the treatment/recovery after SCI.
There is accumulating evidence indicating that the current preference of M2 macrophages compared to M1 macrophages correlates with remission of SCI in cases receiving SCI interventions including anti-inflammatory therapies and stem cells. The authors of this review conclude that while the exact process by which stem cells regulate macrophage polarization has yet to be determined, stem cells can alter macrophage polarization and promote functional recovery postinjury.
Currently, it’s estimated that over 1.3 million people in the U.S., and 10 million people around the world, are living with inflammatory bowel disease (IBD). IBD is a chronic and recurrent disease characterized by inflammation of the tissues of the digestive tract[1]. Two specific diseases included under the term IBD include Crohn’s disease (CD) and ulcerative colitis (UC).
While the exact cause of IBD has yet to be determined, research seems to suggest abnormal activation of the immune system, genetic susceptibility, and altered intestinal flora resulting from mucus barrier defects play some type of role in the pathogenesis of this disease. Currently, a complete IBD treatment or cure exists. Recent research has also demonstrated that adults with IBD are more likely to suffer from other chronic conditions, including diabetes, arthritis, lung cancer, and heart disease[2].
Clinical trials using stem cell therapy have demonstrated promising results for the potential treatment of IBD, including long-term remission in some patients.
In this review, Zhang et al. review the upcoming stem cell transplantation methods for clinical application and the results of ongoing clinical trials exploring the use of stem cell transplantation as a potential treatment for IBD.
Specific stem cells, known as hematopoietic stem cells (HSC), have been shown to be particularly effective when used as a therapeutic treatment. HSCs are isolated from blood, bone marrow, and cord blood that migrate directly to damaged mucosal tissues. Initially used in patients with IBD because of other hematologic indications, including leukemia and non-Hodgkin’s lymphoma, the use of HSC therapy (HSCT) demonstrated improvement in intestinal lesions. Further study using HSCT showed that some patients with UC and CD demonstrated sustained clinical and endoscopic improvement. The authors point out that while these limited clinical trials have demonstrated promising results, the observed risk of relapse currently prevents HSCT from being classified as an effective treatment and calls for larger samples and longer-term efficacy observations.
Another stem cell treatment currently being evaluated for the treatment of IBD is the use of mesenchymal stem cells (MSCs). When injected intravenously, MSCs demonstrate the ability to reach the injured area of the intestine, colonize mucosa to control inflammation, improve microcirculation, and repair damaged tissues. A systematic review conducted by Lalu et al. found that the use of MSCs did not show significant side effects and was a relatively safe therapeutic treatment option.
Zhang et al. conclude that the significant advance in stem cell research made over the past twenty years has made them a promising therapeutic option for the treatment of IBD. Although a limited number of clinical trials have confirmed the efficacy of specific stem cells, specifically HSC and MSCs in IBD, the authors point out that the current treatments need to be improved and further research must be conducted in order to fully understand the complexity associated with the condition.
While this review focuses primarily on the use of HSC and MSC, Zhang et al. call for continued preclinical exploration of other cell therapy methods with the goal of improving the quality of life of IBD patients.
An estimated 100 million people in the U.S. have some form of acute or chronic liver disease. Many factors, including viral and bacterial infections, substance abuse, diabetes, and fat deposition, contribute to conditions that harm the liver.
Left untreated, these liver conditions often progress to more serious diseases that often require a liver transplant. Historically, a host of issues – including a low number of tissue donors, a high rate of tissue rejection, medicine-induced immunosuppression, and high associated medical costs – has limited access to, and the effectiveness of, liver transplantation as a viable solution.
Considering the limited options available for the successful treatment of liver disease, identifying alternative treatment options has become very important. Recently, the potential treatment of acute and chronic liver disease using regenerative medicine, also known as stem cell therapy, has garnered an increased amount of attention.
While a number of different types of stem cells have been used to treat liver disease, mesenchymal stem cells (MSCs) have been the most studied and successful in reducing the need for liver transplantation.
MSCs have been used to repair liver tissue through a number of different methods, including co-culturing with HSCs to reduce and prevent the progression of fibrosis and the proliferation of disease-causing cells through the production and secretion of specific inflammatory factors.
Treatment of liver disease with MSCs has also been shown to increase endothelial precursor cell proliferation while suppressing apoptosis in LSECs and hepatocytes, and by lowering serum transaminase enzyme levels. MSCs have also been shown to compensate for hepatocyte reduction resulting through liver-disease induced apoptosis by differentiating into hepatocyte-like cells.
Considering the observed role of MSCs in liver tissue repair and regeneration, Hazrati et al concluded that the use of MSCs induces the repair and regeneration of liver tissue through immune response modulation, differentiation into HLCs, increased proliferation and decreased apoptosis in hepatocytes, increased apoptosis and reduced function of HSCs and improve the function of LSECs.
The authors also point out that, as of publication, there were 61 active clinical trials using MSCs to treat a variety of liver-related diseases, including cirrhosis, fibrosis, and liver failure. The associated advantages of MSCs in the treatment of acute and chronic inflammatory liver disease include ease of isolation and culture, pluripotency, immunomodulatory and anti-inflammatory properties, extracellular signaling, and their ability to differentiate.
The authors conclude this review by summarizing the observed benefits of using MSCs, and specifically MSC-EVs to improve liver function and support the repair of damaged liver tissue. The authors also point out that while there have been numerous clinical trials using MSCs to treat liver disease, there have been no clinical trials performed on the use of MSC-EVs and call for additional research to investigate the long-term effects of treating liver disease with MSC-EVs.
Osteoporosis is a common bone disease that occurs as a result of the body’s inability to create new bone as fast as the body is losing bone. Characterized by progressively weakened bones and decreased bone density over time, osteoporosis often results in fractures of the wrist, hip, or spine.
Currently, it is estimated that 10 million Americans have osteoporosis and an additional 44 million have low bone density considered significant enough to increase the risk of developing osteoporosis. Recent studies indicate that roughly 50% of women and 25% of men over the age of 50 will break a bone as a result of osteoporosis[1].
While traditional methods of managing osteoporosis include medication, regular participation in weight-bearing exercises, and eating a healthy diet, the condition cannot be cured through these current approaches. Recently, regenerative medicine, also known as stem cell therapy, has drawn attention as a potential new approach to regenerate bone tissue and as a way to treat osteoporosis.
Specific stem cells, known as mesenchymal stem cells (MSCs), are widely considered to be the most promising of all stem cells for regenerative applications – primarily because of their anti-inflammatory, immune-privileged potential and less ethical concerns than other forms of stem cells.
In this review, Arjmand et al. consider all the currently known effects of stem cell-based therapies, including MSC-based therapy, in the treatment of osteoporosis. Several studies have confirmed the relationship between osteoporosis and a clear reduction in endogenous MSCs’ ability to proliferate, differentiate, and ultimately form new bone. Considering this, MSCs have been the most common type of stem cell investigated for the treatment of osteoporosis in both animal models and humans.
The authors point out several advantages of using MSCs in clinical models, including their accessibility and ease of harvesting, immunosuppressive outcomes, and ability to differentiate. Arjmand et al also highlight evidence that indicates MSCs to be effective in this application most likely as a result of their paracrine effects and their supporting regenerative microenvironment ability and not solely a result of their ability to differentiate. Considering these observed paracrine effects, the authors believe MSC transplantation could open a host of new opportunities for the treatment of osteoporosis.
This review concludes by calling for further studies into stem cell therapy as a potential treatment for osteoporosis specifically to understand the outcome and biodistribution of MSCs after transplantation and to further identify important bone loss signaling pathways and genes specific to each individual.
Spinal cord injury (SCI) often results in damage to the spinal cord or the nerves found within the spinal column. Currently estimated to affect over 17,000 new patients each year in the United States, with 81% of these patients being male, the most common causes of SCIs are motor vehicle accidents, falls, acts of violence, and sports/recreational activities.
Current SCI treatment methods are unable to support the regeneration of the spinal cord and often lead to permanent nerve damage that affects motor and sensory function. The nature of SCI injuries often leaves patients unable to function at pre-injury levels and results in significant impacts on issues related to physical, mental, and socioeconomic health.
As more is learned about the potential benefits of regenerative medicine in the regeneration and repair of damaged cells and tissue, mesenchymal stem cells (MSCs) have emerged as potential candidates for the therapy management of SCIs; primarily because of their ability to release bioactive factors, their antiapoptotic effects, ability to inhibit scaring, and their ability to produce angiogenic effects.
Fracaro et al.’s review provides information about the damage from primary and secondary events after SCI, traditional treatments, and results of pre-clinical and clinical trials examining the use of MSCs as an SCI-tissue regeneration strategy.
Before sustaining an SCI, a wide range of inflammatory cells – all except for microglia – are found in blood vessels and throughout the spinal cord. Upon injury, it is common to observe immediate neuronal and glial death at the site of the injury followed by the development of an inflammatory process in the vascular and medullary region; it is this secondary response that results in the deterioration of the spinal cord and a general worsening of the condition. In the weeks and months following injury, remaining neutrophils and lymphocytes are found in the intravascular region, inactivated microglia remain in white matter, and macrophages are found in gray matter.
Traditional SCI treatments have demonstrated an inability to completely regenerate nervous tissue. Most of these traditional treatment methods attempt to reduce side effects and protect injured nerve tissue. Commonly used SCI treatments frequently include decompression surgery to relieve pressure and reduce hypoxia and ischemia; intravenous application of methylprednisolone sodium succinate (MPSS) to inhibit lipid peroxidation; neuroprotective agents to reduce cell dysfunction and death; and electrostimulation as a way to inhibit inflammation and reduce secondary injuries.
Despite the different techniques mentioned above, cell-based therapy is the only promising treatment aimed at regeneration. Stromal cells, and specifically MSCs, have demonstrated the potential for self-regeneration, differentiation, and immunomodulation. Although research has yet to determine exactly how MSCs promote functional recovery after SCI, they are widely thought to work through secreting different factors and biomolecules. MSCs have also demonstrated the ability to reduce inflammation, which is a very common secondary event occurring after SCI trauma.
The authors conclude this review by pointing out that a better understanding of the regenerative effects of stromal cells in the nervous system is required in order for the future development of cell-based therapies for patients with SCI.
Currently, it’s estimated that over 40% of adults over the age of 40 have at least one degenerative disc in their vertebrae; by age 80, the percentage afflicted with this condition is estimated to be over 80%. Characterized by erosion of the rubber-like discs between each vertebra of the spine, degenerative disc degeneration often results in chronic and debilitating back and neck pain. The condition is commonly accompanied by prolonged numbness in the arms and legs and pain that tends to radiate downward through the lower back and buttocks.
Adding to the seriousness of degenerative disc disease is the fact that chronic back pain continues to be a significant public health issue and among the leading causes of lost days of work and one of the most widely reported symptoms contributing to a diminished quality of life. In fact, a study conducted by the University of Maryland Medical Center found that the total cost of back pain (when factoring in medical costs, lost days of work, and the condition’s impact on wages) amounts to a staggering $560 to $635 billion annually.
Historically, chronic cases of degenerative disc disease required surgery. Unfortunately, surgical treatment of this condition not only demonstrated an inability to completely correct the conditions but also produced additional biomechanical problems and accelerated degeneration of nearby discs and portions of the spine.
Considering this, researchers began to investigate the potential use of autologous and allogeneic mesenchymal stem cells (MSCs) as options for treating degenerative disc disease.
In this review, Noriega et al. provide follow-up findings as a result of their long-term randomized controlled trial using allogeneic bone marrow-derived MSCs. As part of this trial, participants in the treatment group received an intradiscal injection of healthy allogeneic bone marrow MSCs while those in the control group received sham infiltration in the paravertebral musculature.
Outcomes of this trial were followed and recorded for one year after injection and subsequently followed up on 3.5 years afterward as part of this review.
As part of the original study and in addition to confirming the feasibility and safety of degenerative disc treatment with injection of MSCs, Noriega et al. found that patients treated with MSCs demonstrated rapid and significant improvements in algo functional indices when compared to those in the control group.
Examining outcomes nearly 3.5 years after original interventions, the authors reported no serious adverse effects of the investigation for either the treatment or control group. Findings also indicated that the improvements in both pain relief and disability improvement continued to increase in those receiving MSC injections while control patients did not show any significant healing after 3.5 years of receiving the intervention.
Of particular interest, the authors noted that patients treated with MSCs showed two distinct patterns – one subpopulation that showed a significant response to this treatment (responders) and another subpopulation that demonstrated no significant difference from patients in the control group (non-responders).
Noriega et al. also reported that observed structural changes in those receiving MSC injections occurring after year one of treatment were maintained over the period of 3.5 years while those in the control group continued to show a decrease in grading used to measure results of the trial.
The authors conclude that these long-term outcomes support the use of MSCs as a valid alternative for managing degenerative disc disease. Findings indicate that MSC injection as a treatment for degenerative disc disease provides effective and durable pain relief and objective improvements in disc degeneration.
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