by admin | Nov 15, 2024 | Mesenchymal Stem Cells, Regenerative Medicine, Stem Cell Research, Stem Cell Therapy, Uncategorized
Mesenchymal stem cell (MSC) therapy has gained attention as a potential treatment for decompensated liver cirrhosis (DLC), a severe form of liver disease that occurs when the liver can no longer function properly. Liver cirrhosis, especially when caused by chronic hepatitis B (HBV), leads to a significant decline in health, and current treatments do not always yield long-term benefits.
MSCs, particularly those derived from bone marrow (BM-MSC) and umbilical cord (UC-MSC), have shown promise in improving liver function in both animal and human studies. However, the long-term safety and efficacy of MSC therapy, especially in human patients with liver diseases like DLC, remain uncertain. Shi et al.’s study sought to address this gap by observing the effects of UC-MSC therapy in patients with decompensated liver cirrhosis over a follow-up period of 75 months.
Introduction
In recent years, MSC therapy has emerged as a novel approach for treating liver disease, particularly cirrhosis. Research on animal models has demonstrated that bone marrow-derived MSCs (BM-MSCs) can reduce liver fibrosis and even reverse acute liver failure. These findings have also extended to clinical settings where BM-MSC infusions have significantly improved liver function in patients with cirrhosis. Additionally, UC-MSC therapies have been explored, with early studies demonstrating their potential to safely and effectively treat autoimmune-related cirrhosis and improve outcomes in patients with chronic liver failure.
While early studies show promising short-term benefits, there is still limited knowledge about the long-term safety and efficacy of MSC treatments for liver disease. Most studies have only followed patients for up to 12 months. This study aimed to explore the long-term impact of UC-MSC therapy on patients with HBV-related decompensated liver cirrhosis over a period of 75 months, the longest follow-up recorded to date.
Effects of UC-MSC on Long-Term Survival
The primary goal of Shi et al.’s study was to evaluate the long-term survival rates of patients in both groups. Initially, there was no significant difference in survival rates between the UC-MSC group and the control group. However, by using a landmark analysis, the researchers discovered that patients in the UC-MSC group had a significantly higher survival rate during the 13 to 75-month follow-up period, although no notable difference was observed during the first 13 months.
These findings suggest that UC-MSC treatment may take some time to show its full benefits. After the initial 13 months, patients who received UC-MSC therapy experienced improved survival rates compared to those who received only conventional treatment.
Impact of UC-MSC Infusion on Liver Function
To assess the effect of UC-MSC therapy on liver function, the researchers monitored key markers such as albumin (ALB), prothrombin activity (PTA), cholinesterase (CHE), and total bilirubin (TBIL) levels. Results showed that patients in the UC-MSC group experienced significant improvements in ALB and PTA levels compared to the control group during the 48-week follow-up. Additionally, although CHE levels were initially lower and TBIL levels were higher in the UC-MSC group at baseline, these markers improved following the UC-MSC infusions.
The results suggest that UC-MSC therapy helps reduce liver inflammation and enhances liver function over time, improving the liver’s ability to produce essential proteins and process waste products.
Safety and Adverse Effects of UC-MSC Infusion
One of the key concerns in MSC therapy is its long-term safety, particularly the risk of developing hepatocellular carcinoma (HCC) or other complications. In this study, seven patients in the UC-MSC group experienced mild, self-limiting fevers after their infusions, but no other significant short-term side effects were reported.
Over the long term, both groups had similar rates of HCC development, indicating that UC-MSC therapy does not increase the risk of liver cancer compared to standard treatment. Importantly, no other major adverse effects were observed during the 75-month follow-up, suggesting that UC-MSC therapy is a safe option for patients with decompensated liver cirrhosis.
Challenges and Next Steps in UC-MSC Therapy for Liver Cirrhosis”
Despite the positive findings, this study had some limitations. For instance, liver biopsies were not performed due to the high risk for patients with decompensated liver cirrhosis, meaning that histological changes in the liver could not be directly observed. Additionally, the infused UC-MSCs were not tracked within the patients’ bodies due to technical and ethical concerns, leaving some questions about the specific mechanisms of their effect on liver function.
Future research should involve multi-center clinical trials to further explore the use of UC-MSC therapy and confirm the findings of this study. Understanding the precise mechanisms through which UC-MSCs improve survival rates and liver function would also be valuable in optimizing this treatment for liver cirrhosis.
The authors of this study conclude that UC-MSC therapy appears to be a safe and effective treatment option for patients with HBV-related decompensated liver cirrhosis. With improvements in liver function and survival rates becoming evident after 13 months, this treatment holds promise as a novel therapeutic strategy for managing end-stage liver disease.
Source: Shi, M., Li, YY., Xu, RN. et al. Mesenchymal stem cell therapy in decompensated liver cirrhosis: a long-term follow-up analysis of the randomized controlled clinical trial. Hepatol Int 15, 1431–1441 (2021). https://doi.org/10.1007/s12072-021-10199-2
by admin | Nov 8, 2024 | Multiple Sclerosis, Stem Cell Research, Stem Cell Therapy
Progressive multiple sclerosis (PMS) has long posed a challenge due to its lack of effective treatments that target both the immune system and nerve health. In contrast to relapsing-remitting MS (RRMS), PMS is marked by a steady progression of disability, for which neuroprotection and immunomodulation are critical. Recent studies in animals have shown promise with neural precursor cell (NPC) transplants, which appear to protect and repair nervous tissue.
The primary objective of Genchi et al.’s STEMS study was to assess if hfNPC transplantation is feasible and safe for patients with PMS. hfNPCs, derived from human fetal cells, can potentially repair damaged nervous tissue by releasing molecules that support nerve growth and reduce inflammation.
Safety and Tolerability of hfNPC
The study’s main focus was safety, particularly looking for severe adverse reactions linked to hfNPCs. At the two-year mark, no serious adverse events were attributed to the treatment, supporting the idea that hfNPC therapy is safe and well-tolerated for this patient group. Although mild or moderate side effects occurred in some patients, no cases were related directly to the hfNPCs. While one patient experienced a relapse of their MS symptoms, the authors point out that this was likely due to prior treatments rather than the experimental cell therapy.
Some patients developed new MRI-visible brain lesions, although these were not linked to clinical relapses and appeared to be part of the typical progression of PMS.
While mild side effects occurred, hfNPC treatment did not produce any severe or unexpected safety concerns in this preliminary trial.
Potential Benefits of hfNPC Treatment
In addition to the safety findings, this study provided early signs that hfNPCs might benefit brain health in PMS. Patients receiving the highest dose of hfNPCs showed lower rates of brain atrophy, or brain tissue loss, compared to typical progression rates. Brain atrophy is common in advanced MS and closely associated with increasing disability.
Importantly, Genchi et al. also found an increase in certain protective molecules in patients’ spinal fluids, which may help reduce inflammation and support nerve repair. These results hint that hfNPCs could potentially protect brain cells and foster nerve regeneration, although more research is needed to confirm these effects.
Brain Changes and hfNPC Impact
Reducing brain atrophy in MS is complex because brain volume can change for many reasons, including fluid shifts linked to inflammation. Despite these complexities, the authors found that the correlation between reduced brain atrophy and the number of hfNPCs injected remained robust even after adjusting for age, baseline disability, and other factors. These observations, while preliminary, suggest that hfNPCs may play a role in slowing brain degeneration in PMS patients.
Changes in Protective and Immune Molecules
The study also found notable changes in certain protective and immune molecules in patients’ cerebrospinal fluid (CSF) three months after treatment. Some molecules, such as GDNF and VEGF-C, are known to support neuron growth and nerve cell survival, while others, such as IL-10, have anti-inflammatory properties. Although patients were also receiving other treatments that may have influenced these results, Genchi et al. believe the rise in these molecules could imply that hfNPCs helped foster a neuroprotective environment.
Interestingly, while certain inflammatory markers also increased, they may support nerve regeneration under specific conditions. For instance, IL-15, an immune molecule, also regulates nerve cell development and may contribute to nerve repair. However, the study cannot definitively confirm that hfNPCs alone caused these changes, and the authors call for further trials to analyze this effect in more detail.
Cognitive and Functional Changes
One notable result was that patients showed improvement in cognitive scores, specifically in tests measuring processing speed. While the improvement may partially be due to practice effects (familiarity with the tests), it suggests that hfNPCs might help maintain cognitive function in PMS patients. Patients with the most significant cognitive difficulties before treatment showed the most improvement, though more studies are needed to understand the impact of hfNPCs on cognition fully.
Study Limitations and Future Directions
Since this early-phase trial was designed to test safety rather than efficacy, the author’s conclusions about potential benefits are limited. The small sample size and lack of a placebo control group mean that results should be interpreted cautiously. Additionally, MRI lesion activity increased in some patients, raising questions about how hfNPCs interact with the disease over time. Larger, controlled trials are needed to validate these findings and determine if hfNPCs can meaningfully slow or reverse brain damage and disability in PMS.
The researchers also noted that hfNPCs might provide lasting benefits by continuing to release protective molecules months after the initial transplant. However, the study’s short follow-up period does not allow for a complete understanding of how long these cells remain active in the body.
The Future of hfNPC Therapy in PMS
Genchi et al.’s STEMS trial provides early evidence that hfNPC therapy is feasible, safe, and potentially beneficial for patients with PMS. Although preliminary, the findings suggest that hfNPCs may help reduce brain tissue loss and support nerve repair by increasing levels of protective and anti-inflammatory molecules in the spinal fluid. These early outcomes pave the way for larger studies that will more rigorously evaluate whether hfNPCs can slow PMS progression and improve patient outcomes.
For now, hfNPC therapy shows promise as an innovative approach that could address the unmet needs of patients with PMS, particularly by combining neuroprotection and immune modulation to combat progressive disability. As this research progresses, it may represent a meaningful step forward in treating this challenging form of multiple sclerosis.
Source: Genchi, A., Brambilla, E., Sangalli, F. et al. Neural stem cell transplantation in patients with progressive multiple sclerosis: an open-label, phase 1 study. Nat Med 29, 75–85 (2023). https://doi.org/10.1038/s41591-022-02097-3
by admin | Nov 1, 2024 | Autoimmune, Mesenchymal Stem Cells, Regenerative Medicine, Stem Cell Research, Stem Cell Therapy
The purpose of Zeng et al.’s review and meta-analysis was to evaluate the efficacy and safety of mesenchymal stem cell (MSC) transplantation in the treatment of autoimmune diseases.
MSCs have been found to have powerful immune regulation functions, multi differentiation potential, and the ability to promote hematopoiesis and tissue repair. These stem cells have also been used in the treatment of refractory and severe autoimmune diseases, providing patients with several safe and effective new treatment options.
In order to evaluate the efficacy and safety of MSCs in this capacity, Zeng et al. evaluated 18 randomized controlled trials (RCTs) that involved the following autoimmune diseases: rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease, ankylosing spondylitis, and multiple sclerosis (MS).
Animal model RCTs evaluating MSC transplantation in the treatment of RA have shown that disease activity was weakened, and clinical symptoms were improved after receiving mesenchymal stem cell transplantation (MSCT).
Treating SLE with MSCs has demonstrated the ability to control disease progression, improve immune system damage, and relieve the condition of lupus in mice models. Other clinical trials demonstrated that MSCs, when transplanted, have been found to be safe while also providing significant clinical therapeutic effects.
In terms of IBS, the authors report that immune dysfunction is believed to play a key role in the occurrence and development of ulcerative colitis. Recent studies also suggest that MSCs might help tissue regeneration by suppressing inappropriate immune responses and providing various cytokines.
Additional research also demonstrated that MSC treatment for 6 months may increase the total effective rate and improve pain and activity associated with ankylosing spondylitis, while more RCTs are needed before a conclusion can be made for the effectiveness of this therapy for MS.
Considering the information obtained as part of this study, Zeng et al. concluded that there were no adverse events associated with MSC transplantation observed in the RCTs that were analyzed. The authors also concluded that MSCs have a certain effect on different autoimmune diseases, but additional RCTs are required to further modify or confirm these findings.
Source: Zeng L, Yu G, Yang K, Xiang W, Li J, Chen H. Efficacy and Safety of Mesenchymal Stem Cell Transplantation in the Treatment of Autoimmune Diseases (Rheumatoid Arthritis, Systemic Lupus Erythematosus, Inflammatory Bowel Disease, Multiple Sclerosis, and Ankylosing Spondylitis): A Systematic Review and Meta-Analysis of Randomized Controlled Trial. Stem Cells Int. 2022;2022:9463314. Published 2022 Mar 24. doi:10.1155/2022/9463314
by admin | Oct 25, 2024 | Exosomes, Regenerative Medicine, Stem Cell Research, Stem Cell Therapy
Respiratory diseases are a major global health concern, responsible for millions of deaths each year. Conditions like chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), pulmonary fibrosis, and pneumonia claim many lives annually, and despite advancements in medical research, there is still no cure for many of these diseases. Current treatments typically focus on managing symptoms and slowing disease progression, but there is growing interest in stem cell (SC) therapy as a potential game-changer for treating lung diseases.
Stem cell therapy is a type of regenerative medicine where stem cells, which have the ability to regenerate or repair damaged tissues, are introduced into the body. There are four main sources of stem cells: embryonic tissues, fetal tissues, adult tissues (like mesenchymal stem cells or MSCs), and genetically manipulated somatic cells, known as induced pluripotent stem cells (iPSCs). Numerous studies have shown that stem cell therapies could be safe and effective for a variety of lung diseases, including COPD, ARDS, and pulmonary fibrosis.
Researchers are increasingly focusing on a cell-free approach that uses stem cell-derived exosomes (SC-Exos). Exosomes are small particles that stem cells release into the body to help with intercellular communication. These exosomes contain beneficial properties of stem cells, including immunomodulatory, anti-inflammatory, and antifibrotic effects.
SC-Exos offer several advantages over stem cell therapy. They have a unique ability to inherit the molecular patterns of their parent stem cells, which means they can potentially mimic the therapeutic effects of stem cells.
Several studies have demonstrated that SC-Exos may be particularly useful for treating respiratory diseases. For example, preclinical and clinical studies have explored the potential of SC-Exos for treating COVID-19, an illness that severely impacts the respiratory system. SC-Exos have been shown to help reduce the severity of complications, such as pneumonia and ARDS, by modulating the immune system and reducing inflammation. In one clinical trial, the use of SC-Exos from bone marrow-derived mesenchymal stem cells (BMSCs) improved survival rates, oxygenation, and immune system regulation in patients.
To deliver SC-Exos effectively, researchers have explored various methods, including intratracheal instillation (direct delivery into the lungs via a tube) and inhalation through nebulizers. Inhalation has shown particular promise, as it allows the exosomes to directly reach the affected lung tissues. In one study involving a mouse model of lung injury caused by the bacterium Pseudomonas aeruginosa, inhaling MSC-derived exosomes significantly improved survival rates. Clinical trials are currently underway to determine if similar results can be achieved in humans.
While many studies attribute the benefits of SC-Exos to their RNA content, it is likely that other components of exosomes also play important roles in their therapeutic effects. Further research is needed to better understand these mechanisms and to optimize the use of exosomes in clinical practice.
Another area of research is focused on developing synthetic or “exosome-mimic” particles that could replicate the therapeutic effects of natural exosomes. These particles could be designed to contain the key bioactive molecules responsible for the beneficial effects of SC-Exos, while being easier and cheaper to produce. However, creating these synthetic particles will require extensive research to ensure they are safe and effective.
Looking ahead, researchers are optimistic about the future of SC-Exos as a potential treatment for respiratory diseases. As our understanding of exosome biology continues to grow, it is likely that we will see more clinical trials and eventually the development of new therapies based on exosome technology. In particular, the use of aerosolized SC-Exos delivered via inhalation holds great promise for treating lung diseases, as it allows the exosomes to directly target damaged tissues in the lungs.
Azhdari et. al conclude that SC-Exos represent an exciting new frontier in the treatment of respiratory diseases. With further research and development, they could offer a powerful new tool for managing and potentially curing conditions like COPD, ARDS, and pulmonary fibrosis, providing hope to millions of patients around the world.
Source: Azhdari MH, Goodarzi N, Doroudian M, MacLoughlin R. Molecular Insight into the Therapeutic Effects of Stem Cell-Derived Exosomes in Respiratory Diseases and the Potential for Pulmonary Delivery. International Journal of Molecular Sciences. 2022; 23(11):6273. https://doi.org/10.3390/ijms23116273
by admin | Aug 27, 2024 | Mesenchymal Stem Cells, Neurodegenerative Diseases, Stem Cell Research, Stem Cell Therapy
Intrathecal cell delivery has emerged as a promising approach for improving the quality of life for patients with neurological conditions, thanks to previous studies showing its safety and potential benefits.
As part of this review, Mesa Bedoya et al. summarize the findings of a systematic review and meta-analysis aimed at evaluating the safety of intrathecally delivered mesenchymal stem cells (MSCs).
Neurological disorders, such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis, significantly impact patients’ quality of life and contribute to a substantial global disease burden. With limited treatment options available, MSC therapy has gained attention due to its ability to differentiate into various cell types, secrete growth factors, and provide neuroprotection. MSCs can be delivered through several routes, including intrathecal administration, which allows for direct delivery to the central nervous system (CNS) and has been shown to enhance cell bioavailability near damaged areas.
The authors’ primary goal was to assess the safety of intrathecal MSC administration by analyzing randomized controlled trials (RCTs) comparing this method to control treatments in adult patients with neurological conditions.
As part of this review, Mesa Bedoya et al. conducted a thorough search of several databases up through April 2023, including RCTs that compared intrathecal MSC delivery with control treatments. They focused on adverse events (AEs) and performed a meta-analysis using statistical models to evaluate the overall safety. The authors also examined potential factors influencing the occurrence of AEs and assessed publication bias.
A total of 303 records were reviewed, with nine RCTs involving 540 patients meeting the inclusion criteria. The analysis revealed that intrathecal MSCs were associated with an increased probability of AEs related to musculoskeletal and connective tissue disorders. Specifically, fresh MSCs had a higher probability of causing AEs compared to cryopreserved MSCs. Additionally, multiple doses of MSCs were associated with a 36% reduction in the probability of AEs compared to single doses.
Despite these findings, the data did not show significant associations between AEs and various study covariates. The review highlighted that, while there was a higher incidence of musculoskeletal and connective tissue disorders, no serious adverse events (SAEs) were reported. The most common AEs, which included back pain, pain in extremities, and muscle aches, were generally transient and minimal in risk if patients were monitored appropriately.
Mesa Bedoya et al’s study supports the notion that intrathecal MSC delivery is a generally safe procedure, with an increased risk of specific, minor AEs. It also confirms previous findings that suggest this method is a viable option for delivering MSC therapy to patients with neurological conditions.
However, the authors also acknowledge limitations, including potential small-study effects and issues related to the crossover design of some included trials. These limitations suggest that the results should be interpreted with caution, and the findings highlight the need for larger, well-designed RCTs with longer follow-up periods to validate the safety and efficacy of intrathecal MSC delivery.
The authors conclude that this review indicates that intrathecal delivery of MSCs results in a minor increase in AEs related to musculoskeletal and connective tissue disorders but no serious adverse events. This supports the safety of intrathecal MSC therapy for neurological conditions, though further research with larger sample sizes and more rigorous study designs is needed to confirm these findings and address the limitations identified.
Source: Mesa Bedoya, L.E., Camacho Barbosa, J.C., López Quiceno, L. et al. The safety profile of mesenchymal stem cell therapy administered through intrathecal injections for treating neurological disorders: a systematic review and meta-analysis of randomised controlled trials. Stem Cell Res Ther 15, 146 (2024). https://doi.org/10.1186/s13287-024-03748-7
by admin | Aug 20, 2024 | Multiple Sclerosis, Neural Stem Cells, Stem Cell Research, Stem Cell Therapy
Multiple sclerosis (MS) is a long-term inflammatory disease that affects the central nervous system (CNS) of an estimated 3 million people worldwide. Characterized by the loss of the protective covering (myelin) of nerve fibers and degeneration of the nerve fibers themselves, MS damage disrupts communication between the brain and the rest of the body. Most MS patients start with a form known as relapsing-remitting MS (RRMS), where symptoms flare up at intervals and then partially or fully improve. Typical symptoms during these flare-ups include lack of muscle control, fatigue, and sensory impairments.
As the disease progresses, many individuals transition from RRMS to a progressive form of MS. Progressive MS is marked by a steady decline in function and an accumulation of disabilities, rather than periodic attacks. Unfortunately, the treatment options for progressive MS (PMS) are limited and often ineffective. The few available medications can help with active forms of PMS but are generally poor at slowing down the disease’s progression or promoting repair of damaged tissues.
The Promise of Stem Cell Therapy
Stem cell therapy has emerged as a promising approach to addressing the needs of patients with PMS. Stem cells have the unique ability to develop into various types of cells and offer several potential benefits, including providing support to nerve cells, modulating the immune system, and even replacing damaged cells. These characteristics make stem cells an attractive option for treating the complex pathology of PMS.
Current State of Stem Cell Therapy Research
In this review, Smith et al. explore the current state of preclinical and clinical evidence supporting the use of stem cells in treating PMS and discuss prospective hurdles impeding their translation into revolutionary regenerative medicines.
According to the authors, preclinical studies suggest that stem cells might help by reducing inflammation and protecting nerve cells in the CNS. However, translating these findings into effective treatments for humans remains a challenge.
Existing disease-modifying therapies (DMTs) have improved the treatment of RRMS by targeting the immune system to prevent the attacks that cause demyelination and nerve damage. These therapies work well for RRMS because they address the inflammatory processes that drive the disease. Unfortunately, as patients transition to the progressive phase of MS, conventional DMTs become less effective. PMS is characterized by a different set of pathological processes, including persistent inflammation behind a closed blood-brain barrier and activation of microglia (the brain’s immune cells) rather than T and B cells.
Stem Cell Therapy’s Potential Benefits
According to Smith et al. stem cell therapy offers potential benefits in several ways, including
- Neuroprotection: Stem cells can potentially protect nerve cells from damage and death, which is crucial in progressive forms of MS.
- Immunomodulation: Stem cells might help modulate the immune system, reducing harmful inflammation that contributes to disease progression.
- Cell Replacement: Stem cells have the potential to replace damaged cells and promote the repair of damaged tissues.
While these potential benefits are compelling, the authors have found that the effectiveness of stem cell therapy in PMS is still largely unproven in clinical settings. The majority of current stem cell research focuses on the relapsing forms of MS or other diseases, with fewer studies dedicated specifically to PMS.
Current Status and Future Prospects
Stem cell therapy has demonstrated safety and feasibility across different types of cells and administration methods. The most promising results so far have been in studies involving neural stem cells (NSCs), which have shown potential in preclinical models for reducing chronic neuroinflammation. However, substantial clinical research is needed to validate these findings and determine the practical benefits of stem cell therapy for PMS.
The authors conclude that while stem cell therapy holds considerable promise for treating progressive multiple sclerosis, more research is needed. Future studies should focus on large, well-designed clinical trials to assess the benefits and risks of stem cell treatments. If proven effective, Smith et al. believe that stem cell therapy could become a revolutionary treatment for PMS and offer hope to millions of patients affected by this debilitating condition.
Source: Smith JA, Nicaise AM, Ionescu RB, Hamel R, Peruzzotti-Jametti L, Pluchino S. Stem Cell Therapies for Progressive Multiple Sclerosis. Front Cell Dev Biol. 2021;9:696434. Published 2021 Jul 9. doi:10.3389/fcell.2021.696434
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