According to the CDC, in 2019, traumatic brain injury (TBI) contributed to nearly 61,000 deaths in the United States alone. While there are several clinical treatments designed to address the neurological dysfunction after sustaining a TBI, including hyperbaric oxygen, brain stimulation, and behavioral therapy, none appear to produce satisfactory or lasting results.
In recent years, several studies have demonstrated the therapeutic potential of various stem cells, including mesenchymal stem cells (MSCs), neural stem cells (NSCs), Multipotent adult progenitor cells (MAPCs), and endothelial progenitor cells (EPCs) in the treatment of neurological impairment resulting from TBI. Specific benefits of these stem cells observed throughout these studies demonstrate that exogenous stem cells have the ability to migrate to the site of damaged brain tissue, help to repair damaged tissue, and significantly improve neurological function.
In this article, Zhou et al. review recent findings on the role, effects, deficiencies, and related mechanisms of the various stem cells being used as therapeutic agents in the treatment of TBI.
Examining numerous studies occurring between 2010-17 and exploring various TBI models and the roles of different stem cells in animal models, the author’s general summary is that the use of stem cells demonstrated some form of measurable improvement in every study reviewed. As a reference, specific observed benefits included improved integrity of the blood-brain barrier; improved neurological function, social interaction, and motor performance; enhanced neurovascular repair and recovery; and enhanced cognitive and spatial learning, information retention, and memory retrieval.
The authors point out that although there appears to be a large amount of research exploring the complexity of pathophysiology and the application of stem cell therapy for treating TBI, many problems still exist and must be addressed before the best method for TBI recovery can be determined.
Specifically, while there have been several clinical studies exploring the role of stem cells in the role of TBI treatment and recovery, and while most demonstrate promising results, the studies have almost universally been completed on mice and/or rats, contained human sample sizes that are not large enough, or failed to include a control group. As a result, Zhou et al. call for further study, including multi-center long term follow-up and randomized prospective trials that examine the safety of stem cells, route of injection, the time of injection, and the specific mechanisms as a way to identify the appropriate and effective stem-cell-based therapeutic treatment options for those suffering from various types of TBI.
Research exploring the benefits of mesenchymal stem cells (MSCs) has demonstrated tremendous potential as a regenerative therapy option for the musculoskeletal system. Research into these cell-based regenerative therapies is promising, and they must continue to provide the data necessary to show their therapeutic potential in clinical settings.
In this review, Steinert et al. review and summarize some of the promising and unique therapeutic features of adult MSCs, detail their current state of clinical application as a regenerative musculoskeletal therapy, and describe the potential for future developments in this field.
Specifically, as a part of this review, the authors share the status of 31 clinical cell therapies for musculoskeletal regeneration occurring between 1996 through 2011 and specifically covering bone defects and nonunions, avascular necrosis of the hip, cysts and benign tumors of the bone, cartilage lesions, and tendons and ligaments; results for the majority demonstrate the safety of and/or the efficacy associated with the specific method of cell-delivery being evaluated.
The field of regenerative orthopedics points to the large body of MSC clinical research indicating the successful treatment of myocardial infarction, post-stroke or spinal cord injury nerve regeneration, graft versus host disease, and a variety of other conditions as an indication that the application has tremendous potential as a regenerative therapeutic option in a wide variety of musculoskeletal indications.
Although there appears to be evidence demonstrating the paracrine and trophic functions of MSCs, research explaining the specifically demonstrated therapeutic effects is still being determined. The authors highlight that research continues to explore the reasonable therapeutic expectations associated with MSC-based treatments, an essential step required to fully understand the range of healing associated with musculoskeletal regenerative cell-based therapy.
The authors, in concluding this review, point out that the demand for MSC-based musculoskeletal regenerative therapies continues to increase. Steinert et al. call for further study into the specific combination of cell preparation, bioactive factors, and stimuli for each specific MSC therapeutic application. Once these have been demonstrated for each application and should they demonstrate better or improved outcomes compared to standard treatments, only then can they be considered for long-term clinical application.
Spinal cord injury (SCI) continues to be a significant cause of disability. In fact, it is estimated that annual SCIs account for nearly 18,000 injuries in the United States and between 250,000 and 500,000 injuries worldwide. Additionally, an estimated 294,000 people in the United States are currently living with some form of SCI, with males accounting for nearly 80% of all SCI injuries.
Despite a large number of SCIs occurring each year, therapeutic treatment options remain limited and primarily ineffective. Recently, improvements in the understanding of the promising role stem cells play in the healing process have led to significant developments in improving healing and restoring function lost as a result of Spinal Cord Injuries; specifically, the therapeutic treatment of SCIs with mesenchymal stem cells (MSCs) in animal models has demonstrated promising results.
Building off of the success observed in previous studies, Honmou Et al.’s recent study (2021) sought to further explore the safety and feasibility of intravenous infusion of MSCs is SCI patients; the study also explored the patients’ functional status after receiving IV infusion of MSC.
Specifically, Honmou Et al.’s phase 2 study delivered a single infusion of autologous MSCs cultured in auto-serum, to 13 SCI patients. After infusion, the study assessed the feasibility and safety of this procedure over a six-month period by using the American Spinal Injury Association Impairment Scale (ASIA) and International Standards for Neurological Function Classification of Spinal Cord (ISCSCI-92). The researchers also used the Spinal Cord Independence Measure (SCIM-III) as a way to assess the ability of daily living after receiving MSCs infusion.
Although this was a small, early, unblinded, and uncontrolled study, the researchers point out that the intravenous infusion of autologous bone marrow-derived MSCs, expanded in auto-serum, into SCI patients appeared to be safe and feasible with none of the patients exhibiting abnormal cell growth or neurological deterioration. Additionally, and similar to what’s been observed in prior studies conducted on animal models, the findings appear to support the rapid improvement of neurological function within a few days after IV infusion. The researchers also pointed out this study had several limitations, including potential observer bias and potential improvements resulting from surgical interventions.
The researchers point out that although the specific mechanism for this observed improvement in neurological status is not clear, several studies suggest that secreted neurotrophic factors from MCSs might be associated with the rapid improvements. Additional studies have also demonstrated that IV infusion of MSCs in patients with SCIs might also encourage changes in gene expression that encourage functional improvements, an observation that was consistent with the findings of this study.
In conclusion, the authors reiterate that the observed safety, feasibility, and initial indications of functional improvement after MSC infusion support the importance of additional, larger future studies designed to examine potential efficiencies in patients with SCI. Source: (2021, February 18). Intravenous Infusion of Auto Serum-expanded … – ScienceDirect.com. Retrieved March 23, 2021, from https://www.sciencedirect.com/science/article/pii/S0303846721000925#!
Osteoarthritis (OA), the most common form of arthritis, affects over 32 million people in the U.S. each year. Characterized by a progressive degeneration of cartilage resulting in pain, stiffness, and swelling in the joints, and most frequently occurring in the hands, hips, and knees, OA has no pharmacological, biological, or surgical treatment to prevent progression of the condition. The authors of this case report focus specifically on potential treatment options for OA of the knee.
With the emergence of stem cell-based therapies for a multitude of health conditions, stem cells, and specifically mesenchymal stem cells (MSCs), have demonstrated immunosuppressive activities that could prove beneficial in supporting the regeneration of cartilage tissue in and around joints in the body.
Research has demonstrated that MSCs are effective in differentiating into essential connective tissues like fat, cartilage, and bone; MSCs have also demonstrated immunomodulatory and anti-inflammatory effects, the ability to self-renew, and plasticity, making MSCs a potentially powerful treatment of OA in the knee (and other parts of the body).
This specific case study details cartilage regeneration in the knee of a 47-year-old woman diagnosed with OA when treated with bone marrow-derived MSC cells. For the course of this treatment, autologous MSCs were collected from bone marrow harvested from the iliac crest. After processing and preparing the MSCs, the sample was confirmed to be free of microbial contamination and was prepared and transplanted into the patient’s knee joint.
Periodic follow-ups with the patient revealed no local or systemic adverse events associated with the MSC transplant procedure. The authors of this case report found that the patient’s functional status of her knee, the number of stairs she could climb, reported pain on a visual analog scale, and walking distance all improved in the two months following the MSC transplant procedure.
Additionally, twelve months after the transplant, the patient demonstrated a positive change in WOMAC (3 to 2), a continued increase in the number of stairs climbed (5 increasing to 50), and visual analog (80 mm to 11 mm). The patient also demonstrated improved gelling (or the amount of time it takes for synovial fluid to thicken as a result of rest) in the knee from 8 minutes to 30 minutes; knee flexion also increased 20° (100° to 120°). Periodic MRIs taken after the transplant procedure demonstrated an extension of the repaired tissue over the subchondral bone.
Mehrabani, et al. conclude that MSC transplantation for treating OA in the knee appears to be a simple, safe, effective, and reliable treatment option that has demonstrated pain relief, improved quality of life, and significantly improved quality of cartilage without hospitalization, pharmaceuticals, or surgery.
Autoimmune diseases occur as a result of the body’s natural immune system mistakenly attacking and damaging healthy, normal cells and tissue. Currently, an estimated 60 different autoimmune diseases affect between 5 and 8 percent of the U.S. population; making it one of the largest disease burdens faced today.
Divided into two distinct categories, autoimmune diseases are typically classified as organ-specific or systemic autoimmune diseases. Systemic autoimmune diseases include systemic lupus erythematosus (SLE), rheumatoid arthritis, systemic sclerosis, and polymyositis; organ-specific autoimmune diseases include Hashimoto thyroiditis, Graves disease, type 1 insulin-dependent diabetes, and pernicious anemia.
Currently, most cases of autoimmune disease are treated with corticosteroids, cyclophosphamide, azathioprine, and/or methotrexate. While all of these medications have been demonstrated to be effective in treating autoimmune disease in some capacity, improvement is not universal; these medications have also been associated with known toxicities.
As research continues to explore the immune system and various autoimmune disorders, it appears that adult stem cells offer promise for effective, non-pharmacological treatment of autoimmune disease.
The author of this review points out that while many animal studies exploring the potential benefits of autologous and allogeneic hematopoietic stem cells (HSCT) exist, the danger associated with allogeneic bone marrow transplants has limited studying these transplants to only those subjects with severe autoimmune disorders that are not responding to other, more proven treatments.
The review also focuses on the treatment of autoimmune disease with mesenchymal stem cells (MSCs). Specifically, the author points to several in vitro studies demonstrating the immunomodulatory properties of MSCs as well as their immunosuppressive effects on MHC-mismatched lymphocyte proliferation. This form of MSC transplantation produces relatively short effects but has proven to be profoundly different from HSCT. Specifically, this procedure does not require the patient to be immunosuppressed in advance of transplantation and produces a therapeutic effect in the affected organ as a result of the homing of MSCs. Studies have demonstrated that MSC transplant has reversed multiorgan dysfunction in SLE mice and humans while also demonstrating stable 12 – 18-month disease remission. As a result, further clinical trials exploring autologous bone marrow MSC (BM-MSC) are currently ongoing.
With the difficulty and risk associated with BM-MSC transplantation, the author points out that since adipose tissue is readily available and easily obtainable, adipose tissue-derived MSC (AT-MSC) are being explored for their potential as a regenerative treatment and wound healing option. Early studies have demonstrated AT-MSC to have immunosuppressive properties that reduce experimental autoimmune encephalomyelitis (EAE), decrease spinal cord inflammation, and significantly ameliorate the severity of colitis and arthritis. In fact, there is convincing evidence indicating that AT-MSC transplant produces therapeutic results comparable to MSCs derived from bone marrow.
At the same time, gene therapy research exploring the use of stem cells as a vehicle in autoimmune disease demonstrated delivery of brain-derived neurotrophic factor (BDNF) genes in an animal model of multiple sclerosis using bone marrow stem cells and human insulin gene transfected BM-MSC therapy in murine type 1 insulin-dependent diabetes has demonstrated positive results, including decreased blood glucose level, improved secretion of human insulin in serum and liver, and delayed onset and clinical severity of EAE.
As research continues to explore the benefits of adult stem cell therapy for the treatment of autoimmune disease, and with genetic therapy showing promising treatment options, researchers are optimistic of the benefits provided through a combination of stem cell and gene therapy.
Affecting over 52 million people, or nearly 25% of the adult patients, osteoarthritis (OA) continues to be the leading cause of disability for people in the United States. Occurring as a result of the protective cartilage, or articular cartilage, that cushions the ends of the bones breaking down, OA can occur in any joint, but most often causes pain, stiffness, and swelling in the hands, feet, knees, hips, and lower back.
To date, current conventional treatments employing pharmacological treatments have been developed to temporarily address the symptoms (i.e.: relieve pain, stiffness, and swelling) of OA, but have proven ineffective in preventing the onset, progression, or long-term symptoms of the condition. While there are a number of reasons conventional OA therapies have demonstrated themselves to be ineffective, the primary reason is that they do not regenerate the cartilage required to prevent the progressive degenerative process associated with OA.
However, recent studies exploring mesenchymal stem cell-based therapy for OA have demonstrated several potential benefits, including regenerating lost cartilage, slowing cartilage degeneration, pain relief, and improved patient mobility.
Currently, there have been a number of advancements in using cellular-based therapy for OA, including techniques such as autologous chondrocyte implantation (ACI) and treatment with embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). While all of these treatments have shown promise in the regeneration of cartilage, each has its own issues which limit its effectiveness and/or availability.
Of the cellular based therapies being evaluated, none demonstrate as much promise, with so few drawbacks, as treatment of OA-related cartridge degeneration with mesenchymal stem cells (MSCs). Sourced from a variety of tissue, including adipose, bone marrow, and synovium, MSC have demonstrated to be progenitor cells with the ability to differentiate into cartilage. Because of this, coupled with the low-level of risk and ease of production, MSCs are considered to be a realistic option, holding the best potential treatment of OA.
While each requires further study, a number of studies, both animal and human, exploring the effectiveness of MSCs gathered from adipose tissue, bone marrow, and synovium have all demonstrated varying degrees of success related to regeneration of cartilage lost as a result of OA progression.
As a result of the benefits resulting from previous studies examining the role of MSCs as a cell-based treatment for treating OA-induced cartilage degeneration and because of the effectiveness and high cost associated with current pharmacological-based treatments, the authors of this review call for further clinical study into more innovative and effective modalities to demonstrate the efficacy, safety, and benefits of MSCs in treating patients with OA.
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