With more than 17,000 people in the US sustaining a spinal cord injury (SCI) each year and an estimated combined cost to healthcare and the workforce exceeding $40 billion, the condition has significant personal and socioeconomic implications. In addition, SCIs have limited pharmacological treatment options to support the regeneration of nerve damage.
Considering the limited treatment options for this condition, the field of regenerative medicine, and specifically the use of stem cells, has recently drawn interest as a potential therapeutic treatment option for paralysis resulting from SCIs.
In this report, Bydon et al. summarize findings of the ongoing multidisciplinary phase 1 clinical trial exploring the safety and efficacy of intrathecal autologous adipose tissue-derived (AD) mesenchymal stem cells (MSCs) in patients with blunt, traumatic SCI.
Specifically, as part of this report, the authors describe the outcome of the first patient with C3-4 SCI treated with AD-MSCs. At the time of SCI, neurologic examination revealed complete loss of motor and sensory function below the level of injury; an injury diagnosed as an American Spinal Injury Association (ASIA) grade A SCI.
After undergoing initial treatment, including C2-6 posterior cervical decompression and fusion, improvement in motor and sensory function was demonstrable. However, neurological gains plateaued 6 months after sustaining injury.
Upon enrollment into the CELLTOP clinical trial 9 months after injury, the patient’s neurologic status was found to be ASIA grade C and imaging revealed bilateral myelomalacia at the C3 level and at the C2-6 decompression and fusion. Additionally, an open biopsy of adipose tissue found in the abdominal wall was performed 8 weeks prior to receiving an initial intrathecal injection.
After receiving an intrathecal injection of 100 million autologous AD-MSCs 11 months after injury, the patient was observed for clinical signs of efficacy at 3, 6, 12, and 18 months following injection.
Bydon et al. observed progressive improvement in upper extremity motor scores and considerable improvement in lower extremity scores at 18 months following injection. The patient also demonstrated consistent improvement in ASIA sensory score, including improvements in pinprick and light touch scores at follow-up after 18 months. The authors reported patient improvements in Capabilities of Upper Extremity score, quality of life (as measured by Global Health Score), and in physical and occupational therapy measures. Other than a moderate headache on day 2, no other safety issues or adverse events were reported.
While further clinical trial is required, the authors conclude that intrathecal AD-MSC administration may be a relatively noninvasive and safe therapeutic option for patients with SCI to improve their neurologic status after reaching a ceiling effect in terms of spontaneous recovery.
Spinal cord injury is one of the most complicated and serious pathological impairments affecting the central nervous system. Since the human body is unable to regenerate and repair the spinal cord after injury, there is a high likelihood of suffering permanent damage and disability.
Often compounding the issue of SCI, secondary events occurring after the initial injury to the spinal cord significantly reduce cell migration and axonal regrowth and limit repair and regeneration.
Recently, transplantation of mesenchymal stem cells (MSCs) has been shown to promote the repair of injured spinal cord tissues in animal models. However, as Qu and Zhang highlight in this review, there remain many unanswered questions that are essential for improving the effects of this MSC therapy. As such, the authors focus this review on recent information about the behavior and function of MSCs in SCI, the function of biomaterials to direct the behavior of MSCs, and the attempt to emphasize combinational strategies such as tissue engineering for functional improvements of SCI.
There are studies showing that the migratory and homing capacities of MSCs are closely related to their engraftment and regeneration ability. Considering this, the authors highlight the importance of having MSCs migrate and integrate into host spinal cord tissue. Since MSC homing toward injured tissue is not an efficient process, and to ensure a more effective stem cell therapy outcome, it is important that these transplanted cells be introduced in a way that increases the migratory potential of healthy MSCs to the site of injured tissue.
Additionally, while transplanted cells have been identified adjacent to neurons after SCI, the surviving number of grafted and differentiated neurons was too small to be considered to contribute to functional recovery after SCI. However, data suggests that the ability of MSCs to secrete soluble factors or vesicles rather than engrafting and transdifferentiating might serve an important role in SCI repair.
The authors also point to studies that indicate MSC implantation could promote a therapeutic effect and functional recovery in experimental SCI animal models. The authors believe that this is a result of MSCs ability to differentiate into specialized neuronal and glial cell lineages after transplantation. While MSC transplantation has not yet been proven to be an effective and reliable therapy for SCI, additional studies need to be done before the therapy is utilized in clinical applications.
MSCs respond to the local environment in multiple ways and represent the most promising exosomes for neuropathic applications. Qu and Zhang conclude this review by calling for more intensive studies examining the potential benefits of combining MSCs with nerve tissue-engineered scaffolds to direct cell behaviors after SCI, including growth, migration, and differentiation.
Spinal cord injury (SCI) is a devastating pathological condition affecting motor, sensory, and autonomic function. Additionally, recovery from a traumatic SCI (TSCI) is challenging due to the central nervous system’s limited capacity to regenerate cells, myelin, and neurological connections.
While traditional therapeutic treatments have proven ineffective in assisting in recovery, mesenchymal stem cells (MSCs) hold significant promise for the treatment of TSCIs.
As part of this systematic review, Montoto-Meijide et al. analyze the efficacy, safety, and therapeutic potential of MSC-based cell therapies in TSCI.
Specifically, the authors identified 22 studies fitting the objectives of this review, which provided the information needed to analyze changes in AIS (ASIA Impairment Scale) grade; to study changes in ASIA sensory and motor score; to evaluate chances in neurophysiological and urodynamic parameters; to identify changes in neuroimaging tests; and to test for the existence of adverse effects of MSC therapy.
Typically occurring as a result of trauma related to accidents or falls, TSCIs consist of two phases, a primary and a secondary phase. Considering the progression of SCI from the primary to secondary phase, the development of a therapeutic neuroprotective approach to prevent secondary injury continues to be a priority in both clinical and basic research.
Considering this, MSCs are currently one of the most promising therapeutic options for TCI, primarily due to their capacity for neuronal differentiation and regeneration, as well as their anti-apoptotic, anti-inflammatory, and angiogenic properties.
The 22 studies analyzed as part of this review included 463 patients. When analyzed in terms of the objectives listed above, Montoto-Meijide et al. reported that in controlled studies patients who received MSC therapy improved their AIS by at least one grade, with most studies also demonstrating improvement in sensory cores and motor scores.
In terms of neuroimaging evidence, the authors reported decreased lesion cavity size and decreased lesion hyperintensity. In addition, one-third of trials reported mild or moderate adverse effects related to the route of administration, and no reported serious treatment-related adverse effects.
The authors of this review reported that their results were consistent with the findings of other recent meta-analyses conducted by other researchers and were also consistent with studies that used a large number of patients but were not included in their review.
In addition, the authors also raise several interesting points that required further study, including determining the ideal stem cell type to use, identifying the most effective route and dose of administration, and finding out which degree and stage of development of the TSCL is most receptive to MSC therapy.
While MSC therapy continues to demonstrate promising potential results, Montoto-Meijide et al. also highlight future potential therapies currently in development. These therapies include gene therapies, nanomaterials, and neurostimulation combined with rehabilitation; all three of these potential treatments have shown promise when used in patients with SCI.
Limitations of this review include the relative newness of cell therapy in TSCI made it difficult to find relative studies and most of the studies used did not have a control group, were not randomized, showed low methodological quality, and lacked detail about the process and/or patient follow-up. Considering this, the authors emphasize the need for multi-center, randomized, and controlled trials with larger numbers of patients over a long period of time as a way to draw firm conclusions regarding this therapy.
Montoto-Meijide et al. conclude the positive changes in AIS grade and in ASIA sensory and motor scores, in addition to the short- and medium-term safety of this therapy, demonstrate the potential benefit of MSC therapy in TSCI patients.
Source: Montoto-Meijide R, Meijide-Faílde R, Díaz-Prado SM, Montoto-Marqués A. Mesenchymal Stem Cell Therapy in Traumatic Spinal Cord Injury: A Systematic Review. International Journal of Molecular Sciences. 2023; 24(14):11719. https://doi.org/10.3390/ijms241411719
Amyotrophic lateral sclerosis (ALS) is a rare, deadly progressive neurological disease that affects the upper and lower motor neurons. Characterized by weakening and gradual atrophy of the voluntary muscles, ALS gradually affects the ability to eat, speak, move, and eventually breathe.
With an estimated survival rate of 2 to 5 years from disease onset, 90% of ALS patients develop sporadic ALS and there is no known cure. Although the cause of ALS remains unknown, there is scientific evidence that both genetics and environment are key contributors. This evidence includes over 30 different gene mutations and a number of environmental factors (exposure to toxins, heavy metals, pesticides, smoking, and diet) have been found to be associated with neurological destruction and ALS development. Additionally, ALS has been found to be approximately 2 times more likely to occur in men than women.
In the search for a definitive cure for ALS, the use of mesenchymal stem cells (MSCs) for both treatment and management of the condition has been increasingly more common in preclinical and clinical studies.
In this review, Najafi et al. discuss multiple aspects of ALS and focus on MSCs’ role in disease management as demonstrated in clinical trials.
MSCs are multipotent cells with immunoregulatory, anti-inflammatory, and differentiation abilities that make them a strong candidate for use in therapeutic applications intending to expand the lifespan of ALS patients.
To date, preclinical research investigating the cause and potential treatment of ALS primarily relies on data gathered from rat and mouse models. As part of these models, researchers have discovered that the transplantation of MSCs through multiple routes (including intrathecal, intravenous, intramuscular, and intracerebral) can be a safe and effective way to delay the decline of motor function and promote neurogenesis.
These preclinical studies have also demonstrated that the administration of MSCs from specific tissues has shown significant advantages in delaying the degeneration of motor neurons, improving motor function, and extending lifespan.
Over 20 years of clinical research have found that direct injection of autologous expanded MSCs is safe and well tolerated and demonstrated a significant decrease in disease progression and increase in life expectancy in patients.
The authors conclude that ALS is a fatal neurodegenerative disease with no definitive cure. However, several preclinical and clinical studies have shown that MSC’s anti-inflammatory, immunoregulator, and differentiation properties, have demonstrated to be a good therapeutic approach for treating ALS.
Source: Najafi S, Najafi P, Kaffash Farkhad N, et al. Mesenchymal stem cell therapy in amyotrophic lateral sclerosis (ALS) patients: A comprehensive review of disease information and future perspectives. Iran J Basic Med Sci. 2023;26(8):872-881. doi:10.22038/IJBMS.2023.66364.14572
Systemic lupus erythematosus (SLE) is a common multisystemic autoimmune disease that often results in multi-organ damage when left untreated. Currently affecting over 1.5 million Americans, the etiology and pathogenesis of SLE continue to remain unclear.
At present, glucocorticoids and immunosuppressants are the most prescribed course of therapeutic treatment and mostly as a way to manage and treat symptoms of SLE, not the cause itself.
Considering that the etiology and pathogenesis of SLE are accompanied by immune disorders including abnormal proliferation, differentiation, and activation and dysfunction of T cells, and that mesenchymal stem cells (MSC) and MSC-derived extracellular vesicles (EVs) play important roles in the immunity process, researchers are increasingly turning their attention to MSCs and EVs as potential therapeutic treatment options for SLE.
In this review, Yang et al. examine the immunomodulatory effects and related mechanisms of MSCs and EVs in SLE with hopes of better understanding SLE pathogenesis and guiding biological therapy.
Examining the potential use of MSC and MSC-EVs in SLE treatment the authors found some studies have established that MSCs reduce adverse effects of immunosuppressive drugs and when combined have demonstrated distinct effects on T cell activation and bias.
Additionally, Yang et al. report that MSCs are able to participate in the immune response in two distinct ways: paracrine effect and directly through cell-to-cell interaction. Since reconstruction of immune tolerance and tissue regeneration and repair are required parts of SLE treatment and since MSCs possess high self-renewal ability, rapid expansion in vitro and in vitro, and low immunogenicity, allogeneic MSC transplantation has demonstrated strong evidence for the therapeutic potential of MSC in SLE.
Besides the ability to repair and regenerate tissue, MSCs, and MSC-EVs have strong anti-inflammatory and immunomodulatory effects, making them a potentially ideal treatment option as part of a therapeutic strategy for SLE. Considering that MSC-EVs have similar biological functions with MSCs, but are also considered cell-free, the authors point out that MSC-EVs could be the better choice for SLE treatment in the future.
Despite the potential of MSC and MSC-EVs, Yang et al. point out that genetic modification, metabolic recombination, and other priming of MSCs in vitro should be considered before MSC/MSC-EVs application for SLE treatment. The authors also recommend further clinical evaluation of the time of infusion, appropriate dosage, interval of treatment, and long-term safety of MSC/MSC-EVs in the treatment of SLE before any form of the combination is used as a treatment option.
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