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.
Worldwide, an estimated 10 million people suffer some form of traumatic brain injury (TBI) severe enough to result in either death or hospitalization each year. Nearly 20% of these TBIs occur in the United States and over 50,000 of those affected die as a result of their injury.
Characterized by a wide range of physical, psychological, and emotional impairments that range from mild memory and mood disorders to severe loss of body control and coma, TBIs are most often caused by a serious blow to the head or neck area[1].
Research has confirmed that the initial trauma resulting from the TBI is not the only factor causing damage to the brain. After sustaining an initial injury, the brain initiates a series of complex biochemical responses that significantly influence the overall severity of the damage caused as a result of the injury.
TBIs come with a tremendous cost, with direct and indirect costs estimated at over $60 billion per year in the United States alone. Additionally, there has been limited success in identifying therapeutic or pharmacological treatments that improve the long-term prognosis of moderate to severe TBI.
Considering the recent success of regenerative therapies in the treatment of a number of serious health conditions, researchers are optimistically exploring the potential benefits of using stem cells, specifically mesenchymal stem cells (MSCs), as a possible way to restore functionality to damaged neurons in and around the brain.
In this publication, Hasan et al. review numerous studies investigating the effects of the infusion of MSCs into animal models of TBIs and summarize the advances in the application of MSCs in the treatment of TBI. MSCs are multipotent stromal cells and are available for extraction from all tissue in the body.
Adding to the potential benefits offered by MSCs, they have been found to differentiate into a wide range of cell lines (not just mesenchymal cells) making them an easily accessible and potentially highly effective option for use in the regenerative treatment of TBIs.
In addition, MSCs have been observed selectively migrating and settling within injured tissue, which adds additional benefit for treatment within previously undeliverable or difficult-to-deliver sites such as the brain and the heart.
The growing evidence supporting the efficiency of using MSCs to alleviate the long-term and debilitating effects of TBI has been further bolstered by recent research highlighting the potential for the genetic modification of MSCs as a way to enhance the survival of stem and neuronal cells. Coupled with additional findings in human trials demonstrating that oxidative stress production can be manipulated by MSCs and therefore contribute to the brain’s recovery after injury, researchers are increasingly optimistic that MSC-based approaches offer significant benefits for the treatment of TBIs.
Hasan et al. also point out several concerns and potential challenges of using MSCs in the treatment of TBIs that need to be further explored and better understood before regular use in clinical settings can be approved. Among these concerns, the authors point out, is that a better understanding of the mechanisms of MSC homing in TBI-affected regions of the brain is important in order to employ them efficiently in clinical settings. Another area requiring further research is a better understanding of the respective roles of paracrine effects, transdifferentiated cells, and other factors related to tissue repair. The authors also identify a recent concern over the potential role of MSCs in the development of cancer and autoimmune diseases as a cause for further study of this potential treatment.
Despite the areas identified as in need of further research, the authors conclude that MSCs continues to demonstrate great potential in the field of regenerative medicine and specifically with respect to their use in the treatment of TBI.
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