Utilizing Mesenchymal Stem Cells for Spinal Cord Injury Therapy

Utilizing Mesenchymal Stem Cells for Spinal Cord Injury Therapy

Spinal cord injuries (SCI) are the most serious complication associated with spinal injuries and often result in permanent damage to the nervous system. With nearly 300,000 people in the United States living with SCI, the inability to treat these injuries has a significant impact on physical, mental, and financial health. 

Additionally, while 94% of those suffering acute traumatic SCI survive initial treatment for the condition, both long-term survival and quality of life are often reduced as a result of post-injury complications. Further complicating the issue is the fact that the current standard of SCI treatment is designed only to reduce the secondary effects of injury and not directly promote healing through neuroregeneration.

Considering that mesenchymal stem cells (MSCs) are known to have anti-inflammatory properties, promote vascular regeneration, and to release neuro-nutrients, they are becoming increasingly promising as a potential treatment for SCI.

In this article, Xia et al. examine the evidence of pathophysiological changes occurring after SCI, review the underlying mechanisms of MSCs, summarize the potential application of MSCs in clinical practice, and highlight the challenges surrounding the use of MSCs in the treatment of SCI in future applications. 

The goal of any SCI therapeutic treatment option is to promote rapid recovery of neurological function through a combination of medical and surgical interventions. However, to date, there are no optimal treatment strategies that allow for this goal to be met.   

MSCs’ multidirectional differentiation capabilities are highly viable and known to provide structural support in SCI. In terms of using MSCs in the treatment of SCI, and specifically for their role as an anti-inflammatory agent, the most attractive aspect is their unique immunomodulatory ability.

Additionally, the goal of treatment after SCI is to repair the damaged nerve cells and restore nerve function. Studies exploring differentiation of MSCs after SCI have demonstrated spontaneously expressed neuromarkers at SCI sites and have allowed for recovery of neurological function. 

The authors point out that traumatic SCI usually results in the direct destruction of blood vessels around the spinal cord which often results in ischemic necrosis and secondary injuries. Since promoting vascular recovery contributes to the recovery of motor function in patients with SCI, SCI vascular recovery is a new target for the treatment of SCI. Several studies have observed that MSCs secrete angiogenic factors that promote pericyte recruitment, a critical step in vascular maturation. The authors also report recent findings indicating that 57% of the vascular endothelial cells around the SCI of a mouse showed vascular regeneration effects after receiving MSC-EVs with an extensive vascular network formed around the injury over a period of 28 days.

Although MSCs are beneficial to the recovery of neurological function in patients with SCI, the authors call for additional research to focus on better understanding the SCI cellular mechanisms and MSC action for use in clinical practice. Additionally, Xia et al. point out that the survival rate and long-term survival of MSCs in the SCI microenvironment remain an unresolved issue.

MSCs repair SCI through anti-inflammatory effects and by promoting nerve axon regeneration and vascular regeneration. While further research is required to fully understand the mechanism underlying the effect of MSCs, the authors conclude the role of MSCs in treating SCI has been demonstrated in several clinical trials. 

Source: “Mesenchymal stem cells in the treatment of spinal cord injury.” 

https://www.frontiersin.org/articles/10.3389/fimmu.2023.1141601/full.

The Healing Benefits of Mesenchymal Stem Cells in Skin Inflammatory Conditions of Atopic Dermatitis and Psoriasis

The Healing Benefits of Mesenchymal Stem Cells in Skin Inflammatory Conditions of Atopic Dermatitis and Psoriasis

Chronic skin inflammatory diseases, including atopic dermatitis (AD) and psoriasis, are considered uncontrolled responses to systemic inflammation.

Characterized by swelling, irritation, and rash chronic skin inflammatory disease, these common skin inflammatory diseases are estimated to affect 25% of the population, with AD and psoriasis being the most common form of the disease.

Recent methods used to treat AD and psoriasis have been based on inhibition, not regulation, of the condition. Over time, these methods of treatment can result in a number of side effects and drug resistance.

Considering that mesenchymal stem cells (MSCs) have been used to treat a number of immune diseases, Yang et al. believe they present as a promising treatment for chronic skin inflammatory disease. As part of this review, the authors discuss the therapeutic effects of MSCs on AD and psoriasis, provide clinical evaluation of the administration of MSCs, and present a comprehensive vision for the application of MSCs in future research and treatment.

AD and psoriasis are known to be systemic and immune-allergic inflammatory skin diseases caused primarily by the imbalance between pro- and anti-inflammatory factors. MSCs play a role in regeneration and immunomodulation and their function in skin lesions present in these conditions could provide important information about their biological function in the diseases. 

Considering that inflammation related to both AD and psoriasis begins at the MSC level, a treatment designed to address abnormal MSCs can potentially improve the pathogenesis of these diseases. While this method appears promising, the authors point out that the therapeutic methods designed to treat lesions associated with MSCs have yet to be determined and treating skin inflammatory disease with these improved MSCs requires further clinical study.

The authors also highlight the potential benefit of preconditioning MCSs as a way to improve the immune regulation capacity in treating a range of immune diseases. Specifically, precondition MSCs have been shown to alleviate allergic inflammation in keratinocytes and reduce inflammation in the skin through the JAK-STAT pathway.  

While the benefits associated with preconditioning MSCs for this purpose require further research, Yang et al. believe that preconditioning MSCs with inflammatory factors can more effectively treat skin inflammatory diseases.  

In addition to showing the benefits of MSC therapy when treating AD and psoriasis, the authors of this review also point out some limitations associated with the application of MSCs. These limitations include the need for double-blind placebo-controlled studies to indicate the potential clinical application of MSCs in AD and psoriasis and issues with the production and cost of MSCs not being able to reach the standard (making it difficult to translate into clinical treatment).

Despite these limitations, the application of MSCs has shown to be more effective in treating AD and psoriasis than other options that are currently available.

Yang et al. conclude that the advancing technology for administering MSCs and their capability of regeneration, immunomodulation, and differentiation have made them a promising strategy for the treatment of skin inflammatory diseases. The authors also call for additional studies to further uncover the mechanisms of the therapeutic effects of MSCs in AD and psoriasis to help better define therapeutic strategies for treating these diseases.

Source: Yang J, Xiao M, Ma K, Li H, Ran M, Yang S, Yang Y, Fu X and Yang S (2023) Therapeutic effects of mesenchymal stem cells and their derivatives in common skin inflammatory diseases: Atopic dermatitis and psoriasis. Front. Immunol. 14:1092668. doi: 10.3389/fimmu.2023.1092668

Phase 1 Clinical Trial Investigating the Use of Autologous Adipose Tissue-Derived Mesenchymal Stem Cells for the Treatment of Traumatic Spinal Cord Injury

Phase 1 Clinical Trial Investigating the Use of Autologous Adipose Tissue-Derived Mesenchymal Stem Cells for the Treatment of Traumatic Spinal Cord Injury

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.

Source: “First Report From a Phase 1 Trial of Autologous Adipose Tissue ….” 27 Nov. 2019, https://www.mayoclinicproceedings.org/article/S0025-6196(19)30871-7/fulltext

The Safety and Effectiveness of Stem Cell Treatment as an Emerging Approach for ALS

The Safety and Effectiveness of Stem Cell Treatment as an Emerging Approach for ALS

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by loss of upper and lower motor neurons resulting in paralysis, respiratory insufficiency, difficulties speaking and swallowing, stiffness and spasticity, and muscle atrophy. Commonly known as Lou Gehrig’s disease, after the baseball player was diagnosed with it, ALS is diagnosed in an estimated 5,000 Americans each year.

Currently, ALS has a median survival time of 4.32 years and no known cure. As part of the effort to develop new therapeutic options to slow the progression of ALS, stem cell (SC) transplantation has shown potential in recent clinical trials. 

In this review, Aljabri et al. examine the results of various clinical trials exploring the use of stem cell therapy as a viable therapy for ALS. Specifically, the authors identified six studies determined to have met the established criteria for review.

As part of this research, the authors examined the efficacy of SC transplantation in patients with ALS. Studies examined included a number of routes of administration, including subcutaneous, combined intrathecal and intramuscular, intravenous and intralumbar injections, and intrathecal approach. These studies all demonstrated slower decline or significant improvement as measured on the ALS Functional Rating Scale (ALSFRS-R).  

While there appears to be a benefit in this application, the authors of two of the studies did not observe a significant difference in the efficacy between treatment and placebo groups after injections. 

Additionally, the authors noted that all three studies using bone marrow mesenchymal stem cells (BM-MSC) demonstrated a significant decrease in the progression of disease burden and an overall slower decline in the ALSFRS-R score. On the other hand, studies that used granulocyte colony-stimulating factor (G-CSF) did not demonstrate a significant benefit.

While these results are promising, the authors point out limitations of the study that make it difficult to identify the long-term effects and long-term benefits associated with SC therapy. These limitations include short follow-up periods of either 6 or 12 months and the loss of patients during follow-up, both of which compromise the ability to determine long-term benefits and effects with fidelity.

Aljabri et al. also highlights many challenges associated with the introduction of SCs into the CNS. Among these challenges include the increased risk of AEs associated with the multiple SC injections required to deliver therapeutic doses and determining the most appropriate route of injection for therapeutic benefits.

The authors conclude that early clinical trials have made great progress in delineating the safety of SC therapy in the treatment of ALS. What remains to be determined is how effective SCs are compared to other forms of therapy. While the current data of SC therapy hold great promise, more properly designed clinical trials are needed to verify their benefit.

Source: Aljabri A, Halawani A, Bin Lajdam G, Labban S, Alshehri S and Felemban R (2021) The Safety and Efficacy of Stem Cell Therapy as an Emerging Therapy for ALS: A Systematic Review of Controlled Clinical Trials. Front. Neurol. 12:783122. doi: 10.3389/fneur.2021.783122

Peptides with Neurotrophic Properties: Promising Therapeutics for Amyotrophic Lateral Sclerosis and Alzheimer’s Disease.

Peptides with Neurotrophic Properties: Promising Therapeutics for Amyotrophic Lateral Sclerosis and Alzheimer’s Disease.

Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS) are two of the more common neurodegenerative diseases, with nearly seven million people in the US living with the conditions in 2023. While AD is more prevalent than ALS, they are both characterized by the progressive loss of specific neurons and glial cells in the central nervous system.

Research has demonstrated that the onset and progression of neurodegenerative diseases appear to be delayed or improved by the application of neurotrophic factors and that the derived peptide factors from these neurotrophic factors have been found to potentially restore neuronal function, improve behavioral deficits, and prolong their survival.

In this review, Ciesler and Sari review the role of trophic peptides in the improvement of AD and ALS with the goal of developing a better understanding of potential therapies for these neurodegenerative diseases.

While neurodegenerative diseases, including AD and ALS, are well documented to result in debilitating loss of memory and motor function, respectively, the specific mechanisms of action in these diseases are yet to be fully understood. However, research has found that the potential underlying mechanisms can be divided into two categories. The first, which is unique to each neurodegenerative disease, is a specific trigger that activates cell death machinery and the second, which appears to be universal among neurodegenerative diseases, is a directorial process to complete death of a neuron.

While there are currently no effective drugs for the treatment of neurodegenerative diseases, treatments of the symptoms associated with neurodegenerative diseases include neuroprotective factors, encompassing neurotrophins, and neuroprotective peptides. The authors focus this review on NAP peptide derived from activity neuroprotective protein and ADNF-9 peptide derived from activity-dependent neurotrophic factor (ADNF); both of these peptides have been shown to enhance cell survival and outgrowth of dendrites in the form of D-acid analogues.

NAP’s parent protein, ADNP, is essential for brain development and was found to protect neurons against severe oxidative stress. Studies examining NAP have found them to protect against neurotoxins while not affecting cell division.  Considering these findings, NAP is now in phase II clinical trials with a primary focus on AD-related cognitive impairment. Additional studies are also evaluating the effects of NAP in ALS models associated with cytoskeletal dysfunction. NAP has been found to extend life span in ALS mouse models when administered prior to disease onset.

ADNF is released in response to vasoactive intestinal peptide that protects neurons from tetrodotoxin-induced cell death and is suggested to be essential for neuronal survival. ADNF-9 showed greater prevention of cell death associated with stress than other ADNF peptides; additional studies demonstrate that ADNF-9 suppressed SOD-1-mediated cell death. While prolonged survival of ALS mouse model was reported to be marginal, the authors highlight that the study did provide insight into a possible treatment for ALS. 

The authors also highlight colivelin, a hybrid synthetic peptide of ANDF-9 and humanin, which was found to provide neuroprotection against AD-related memory loss and have a more potent neuroprotective effect than humanin and ADNF-9 when they are tested alone against neurotoxicity.

Ciesler and Sari conclude that in contrast to neurotrophic factors these trophic peptides have the ability to cross the blood-brain barrier for efficacy and have potential for future treatment of ALS and AD.  


Source: “Neurotrophic Peptides: Potential Drugs for Treatment of Amyotrophic ….” 8 Apr. 2013, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3686488/.

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