Ankylosing spondylitis (AS) is a progressive, inflammatory rheumatoid disease that, over time, can result in chronic spinal arthritis and can cause the vertebrae to fuse together. Affecting an estimated 300,000 people in the U.S., AS causes the spine to become less flexible and can result in a hunched posture.
There is no current treatment for AS and current drug therapy options are focused on reducing inflammation, stiffness, and back pain. While current treatments assist in reducing inflammation, many patients with AS continue to experience unresponsive or painful side effects from these drugs.
In the search for a cure for AS, stem cells – and specifically, mesenchymal stem cells (MSCs) have emerged as a potentially promising treatment option. Specifically, researchers believe the immunomodulatory and regenerative properties demonstrated by MSCs could reduce inflammatory responses and help tissue repair through cell-to-cell contact and secretion of soluble factors.
In this review, Abdolmohammadi et al. describe immunopathogenesis and current treatment restrictions of AS and discuss the recent findings of clinical trials involving MSC therapy in AS.
The safety and therapeutic potency of MSC therapy have been shown in many types of research. While there are currently a number of in-process clinical trials exploring MSC transplantation in related disorders, the transplantation of MSCs is a therapeutic option for AS patients who cannot tolerate the anti-inflammatory drugs.
Previous studies have demonstrated MSC infusion in AS patients to be a safe and beneficial choice with no severe side effects and is effective in decreasing related clinical symptoms and severity of the disease. There are also a number of clinical trials for curing AS patients currently in progress. These trials include phase 1 exploring the application of human umbilical cord-derived MSCs (hUC-MSCs) and IV infusion of MSCs plus NSAIDs in AS patients, phase 2 of a clinical trial evaluating human bone marrow-derived MSCs application in AS patients, and clinical trial phase I/II for the safety of MSC transplantation in patients with AS.
Although there have been notable achievements in the treatment of AS using NSAIDs, glucocorticoids, and other drugs, a therapeutic option without side effects has yet to be discovered. MSCs offer a favorable treatment option for the treatment of immune-mediated disorders, including AS.
While findings of previous studies demonstrate that MSC injection might be beneficial in alleviating AS signs and symptoms, the authors point out that further study is required to determine several important features of MSC therapy, including cell origin, dosage, administration route, and the most ideal stage of disease for intervention, before it can be accepted as a clinical option for treating AS.
Articular cartilage primarily consists of chondrocytes and extracellular matrix and has an essential role in the process of joint movement, including lubrication, shock absorption, and conduction. However, over time, damage to the articular cartilage caused by acute or repetitive trauma or disease of the joints – including osteoarthritis – often results in pain, lack of mobility, and reduced quality of life for an estimated 500 million people worldwide.
Current treatments to address articular cartilage defects include physiotherapy, medication, intra-articular injection, and intra-articular irrigation; none of these treatments are able to regenerate the new cartilage needed to correct the issue.
In recent years, mesenchymal stem cells (MSCs) have been found to be potential solutions for a number of diseases, including OA, specifically because of their ability to differentiate and produce a variety of cells. MSCs have also been found to be safe for use in humans and have demonstrated the ability to improve clinical symptoms such as pain, disability, and physical function.
Additionally, hyaluronic acid (HA) has demonstrated itself to be an important component of the synovial fluid by protecting joint cartilage by providing lubrication and acting as a shock absorber. However, in the presence of OA, HA concentration decreases and results in increased aggravation and joint damage to cartilage. Like MSCs, clinical studies have also demonstrated HA’s ability to relieve pain in patients with OA.
Specifically, 24 healthy canines were operated on to induce cartilage defect model before being randomly divided into 3 groups; each of these groups received a different treatment: bone marrow mesenchymal stem cells (MBSCs) plus HA, HA alone, or saline. After 28 weeks, Li et al. found that the canines treated with BMSCs plus HA (BMSC-HA) showed significant improvement in cartilage defects compared to those receiving just HA or just saline.
The authors also found that while BMSCs-HA demonstrated the most significant improvement in cartilage defect, treatment with HA alone also demonstrated improvements when compared to those receiving saline alone.
Li et al. also identified a number of important limitations of this study, including the limited level of cells and proteins; the repair of cartilage defects in this study was a dynamic process that limited the study to the terminal point of repair; and that this was a preliminary and non-blinded study, which could have affected the evaluation of ICRS macroscopic and histological score. Considering this, the authors call for further blinded and basic experiments as a way to further improve understanding.
As a result of this study, Li et al. concluded that both BMSCs-HA and HA alone could significantly promote new cartilage formation, with BMSCs-HA demonstrating a better way to repair cartilage defects in a canine model.
Systemic Lupus Erythematosus (SLE) is an autoimmune disease that causes inflammation to affect many different body systems including the joints, skin, kidneys, blood cells, brain, heart, and lungs.
Affecting over 5 million people worldwide, and associated with a wide range of symptoms, SLE is difficult to diagnose. Currently, there is no treatment to prevent or cure lupus and current therapeutic treatment options are only designed to treat and minimize the symptoms of the disease.
Considering their strong protective and immunomodulatory abilities, mesenchymal stem cells (MSCs) have been recognized as a potential treatment for various autoimmune diseases and inflammatory disorders, including SLE.
In this research article, Zhou et al. conducted a meta-analysis with the goal of assessing if MSCs are able to become a new treatment for SLE with good efficacy and safety.
Specifically, using predetermined criteria, the authors conducted a bibliographical search and statistical analysis to assess the efficacy and safety of MSCs for SLE. This search and analysis resulted in 10 studies comprising of 8 prospective or retrospective case series, including 231 SLE patients, and four randomized control trials (RCTs) with 47 patients with SLE in the case group and 37 patients with SLE in the control group, that fulfilled the inclusion criteria for this meta-analysis.
The authors found that all of the studies included as part of the meta-analysis of RCT and self-controlled studies with the exception of one indicated that MSC treatment of SLE can achieve better efficacy. Specific results of the RCT meta-analysis supporting this conclusion included lower proteinuria, increased serum albumin, and increased serum C3 at 3 months, lower SLEDAI values at 3 months and 6 months, and a lower rate of adverse events in the MSC group when compared to the control group.
Similar results were observed and reported from the meta-analysis of self-controlled studies. These results included MSC treatment significantly reducing proteinuria and the value of SLEDAI at 1 month, 2 months, 3 months, 4 months, 6 months, and 12 months. Further supporting evidence reported included improved values of SCR, BUN, C3, and C4.
While the results of this meta-analysis were overwhelmingly supportive of MSCs as a potential treatment option for SLE, the authors also noticed several limitations associated with their findings. These limitations included the small sample sizes of the included studies and the inconsistency of the severity of the patient’s disease.
Although more studies with larger sample sizes should be conducted to confirm these findings, Zhou et at. concluded that MSCs might be a good treatment agent for SLE in the clinic.
Biomedical applications of mesenchymal stem cells (MSCs) in the field of regenerative medicine continue to evolve. Coupled with the rapid development of molecular biology and transplantation techniques, MSC applications have become a central focus of research surrounding regenerative medicine.
Since being discovered nearly 50 years ago, the understanding of various techniques for MSC extractions and the subsequent potential for differentiation has continued to advance.
This review, presented by Han et al., provides a brief overview of MSC extraction methods and their subsequent potential for differentiation and summarizes the future applications and challenges of various MSCs in the field of regenerative medicine.
It has now been well established that MSCs can be isolated from various tissues, including bone marrow, adipose, synovium, and human umbilical cord blood. The general process for MSC extraction involves the isolation of various tissues, digestion to obtain cells, culturing for three to five days, and continuous culturing of adherent cells to the desired passage.
Interestingly, the authors point out that rabbits are the most frequently used animal models for experiments involving cartilage or bone tissue regeneration. Considering this, the authors call for the surface markers of rabbit tissue-derived MSC to receive increased focus and further verification.
Han et al. also discuss the differentiation potentials of MSC types, highlighting that bone marrow-derived MSCs display superior capabilities for differentiation into osteogenesis and chondrogenesis under standard differentiation protocols. They also point out that umbilical cord blood-derived MSCs (UCB-MSCs) demonstrate biological advantages relative to other adult sources, including their capability for longer culture times, larger-scale expansion, and higher anti-inflammatory effects. Considering that differentiation conditions vary based on the type of MSC, the authors highlight that it is becoming increasingly necessary to choose the desired MSC type according to the specific purpose being sought.
MSC-based regenerative medicine has been widely studied and applied to many aspects of the field. This review summarizes several reports concerning the latest preclinical and clinical trials of various MSC types for tissue engineering, most notably the reconstruction of fragile tissue associated with the musculoskeletal system, nervous system, myocardium, liver, cornea, trachea, and skin.
In order to improve the therapeutic effectiveness of MSCs, while also reducing the potential identified risks, the authors suggest reducing excessive cytokines, further exploring the immunomodulatory effects of MSCs, and establishing strict preclinical biosafety testing rules. Additionally, longer and larger controlled clinical trials are required to further determine the safety of MSCs.
While there have been tremendous advances in the field of regenerative medicine, especially as they relate to MSCs, Han et al. share a number of challenges that have to be overcome before the clinical application of MSC therapy, with the primary challenge being the implementation of a standardized method of isolation and culturing for MSCs.
The authors conclude this review by summarizing three distinct properties of MSCs that make them an optimal source of tissue regeneration: their immunoregulatory capacity, paracrine or autocrine functions that generate growth factors, and their ability to differentiate into target cells.
Mesenchymal stromal cells (MSCs) have repeatedly demonstrated the capacity to limit injury and promote regeneration through signaling and secretion of trophic factors. Considering this, MSCs have been increasingly used as a treatment for a wide variety of injuries and immune-related, infectious, and degenerative diseases.
In this review, Jahromi et al. provide a brief overview of the fate and efficacy of intramuscular (IM) delivered MSCs and identify the gaps that require additional study before IM-delivered MSCs are adopted as a primary treatment of systemic diseases.
Specifically, a recent study has demonstrated significant advantages of using skeletal muscle for the delivery of MSC. While skeletal muscle has been used as a delivery route for myopathic, neurodegenerative, and vascular diseases, these studies have identified 3 main advantages of skeletal muscle MSC delivery.
Research has identified two key factors that profoundly affect observed dwell-time variations of 72 hours to 8 months observed in MSCs transplanted in the skeletal muscle; these factors include immune rejection and the methods used for MSC detections. Considering this, the authors point out that allotransplantation provides an advantage since MSCs exhibit low immunogenicity and are expected to evade the immune system.
Although little information on the IM delivery of MSCs currently exists, previously conducted clinical trials demonstrated no therapeutic advantage of using higher doses of MSCs; other studies demonstrated medium doses of MSCs to be more effective than either a lower or higher dose.
While IM-delivery has been shown to be clinically safe and increases the longevity of the secretory activity of the delivered cells, the authors point out that it is important to further evaluate the fate of MSCs post-delivery in skeletal muscle.
Ankylosing spondylitis (AS) is a chronic and progressive inflammatory disease that primarily affects the sacroiliac joints and the spine; in rare cases, AS can also cause issues for the peripheral joints and extra-articular organs, including the skin, eyes, and cardiovascular system.
While there are a number of drugs prescribed to treat symptoms associated with AS, there is currently not a cure for AS nor is there a non-pharmaceutical method for treating the condition and its symptoms.
Considering the potent immune-modulated activity and their ability to inhibit B cell differentiation, T cell activation, and proliferation, researchers have increasingly been exploring the use of mesenchymal stem cells (MSCs) as a potential treatment option for a number of autoimmune diseases.
In this current study, Li et al. evaluated the therapeutic effects of umbilical cord MSC (uMSC) transplantation in patients with AS. This review summarizes the authors’ findings.
Specifically, Li et al.’s study evaluated 5 patients with AS after receiving intravenous transfusions of uMSCs.
After receiving an intravenous uMSC transfusion, the authors reported lower levels of inflammation, slowed progression of AS, and reduced levels of ESR, CRP, and other specific markers indicative of improved spinal functions and spinal movement in subjects with AS.
Considering these findings, the authors conclude that uMSC transplantation is feasible and safe and induces limited side effects.
The authors of this study also highlight a number of limitations, including the low number of patients, limited statistical analysis, and lack of a control group that did not receive an infusion.
In light of these results, Li et al. call for future studies using a larger cohort of patients with AS to enable the systematic evaluation of uMSC in treating symptoms of AS.
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