Liver cirrhosis (LC) is a severe global health problem, contributing to an estimated two million deaths annually. LC results from chronic liver diseases such as hepatitis B and C, alcohol consumption, non-alcoholic fatty liver disease, and autoimmune liver disease. When these diseases progress unchecked, they lead to liver cirrhosis, characterized by inflammation and fibrosis. Most patients with LC die from complications due to a lack of effective treatments and poor patient compliance. While liver transplantation is effective, it is costly and comes with risks like immune rejection and recurrent infections. This has led to an urgent need for alternative treatments for LC.
Mesenchymal stem cells (MSCs) offer a promising alternative due to their ability to renew themselves and differentiate into various cell types. MSCs have gained attention for their potential to treat tissue-damaging diseases due to their low immunogenicity and ability to home to injury sites. Animal studies have shown MSCs to be safe and effective in treating LC, and clinical trials indicate improvements in liver function with no significant adverse effects.
Lu et al.’s study aims to systematically evaluate the efficacy and safety of MSCs for treating liver cirrhosis through a meta-analysis of clinical trials.
As part of this study, the authors analyzed data from PubMed/Medline, Web of Science, EMBASE, and Cochrane Library up through May 2023. Researchers used the PICOS principle for literature screening and assessed the risk of bias. Data from each study’s outcome indicators, such as liver function and adverse events, were then extracted and analyzed using Review Manager 5.4.
Eleven clinical trials met the criteria for this analysis. The pooled data showed significant improvements in primary and secondary liver function indicators. Patients who received MSC infusions had higher albumin (ALB) levels at 2 weeks, 1 month, 3 months, and 6 months, and lower MELD scores at 1 month, 2 months, and 6 months compared to the control group. Hepatic arterial injections were particularly effective in improving these scores. Importantly, none of the studies reported severe adverse effects, indicating the safety of MSC therapy.
Key Findings and Recommendations
Considering the findings of this study, the authors provide a number of key findings and recommendations, including:
Duration of MSC Therapy: The study found that prolonging MSC treatment enhances its effectiveness in end-stage liver disease, improving symptoms such as appetite loss, mental depression, and jaundice.
Types of MSCs: MSCs can be derived from various tissues, and their effectiveness may vary. Most studies evaluated used bone marrow-derived MSCs (BM-MSCs), which have shown superior therapeutic effects compared to umbilical cord-derived MSCs (UC-MSCs). However, more research is needed to determine the best type of MSC for treating LC.
Routes of Administration: Different transplantation methods can impact the efficacy of MSC therapy. The hepatic artery route was found to be the most effective, likely due to better MSC homing to the liver. However, this method has clinical limitations such as high surgical risk. Intravenous administration, while safer, was less effective. The authors call for further research to optimize the administration route.
Secondary Indicators: While primary indicators like MELD score and ALB levels showed significant improvements, secondary indicators such as ALT, AST, TBIL, and INR did not show significant differences between the MSC and control groups. The authors believe this could be due to variability in disease cause, patient population, and follow-up duration.
Complications and Prognosis: MSC therapy also showed potential in reducing LC complications, such as portal hypertension and ascites, and decreasing mortality and hepatocellular carcinoma (HCC) incidence. However, more clinical trials are needed to confirm these findings and assess the long-term prognosis of MSC therapy in LC.
Lu et al. conclude that mesenchymal stem cell therapy is a safe and effective treatment for liver cirrhosis, significantly improving liver function without severe adverse effects. However, to fully realize the potential of MSC therapy, a standardized treatment protocol is needed. This includes optimizing the timing, dosage, frequency, and administration route of MSC infusions.
Additionally, MSC-derived exosomes show promise as an alternative treatment strategy. The authors call for further research, including multicenter, large-scale, long-term RCTs, to address these questions and improve the therapeutic outcomes for LC patients.
Amyotrophic Lateral Sclerosis (ALS) is a degenerative disease that affects motor neurons in the brain and spinal cord, leading to muscle paralysis and death, typically within 3-5 years of onset. Despite two FDA-approved therapies, Riluzole, and Edravarone, which offer limited benefits, there remains no cure for ALS.
Considering this, researchers have turned to Mesenchymal Stem Cells (MSCs), which have shown promise in animal models and preliminary human trials for neurodegenerative diseases, including ALS.
Understanding ALS and MSC Therapy
ALS is characterized by the rapid degeneration of motor neurons, leading to muscle paralysis. The exact cause of ALS is complex and not fully understood. About 10% of cases are familial, while 90% are sporadic. Existing treatments only modestly slow disease progression and extend survival by a few months.
Stem cells, particularly MSCs, have shown potential in neuroprotection and immunomodulation. MSCs can be derived from various sources, including bone marrow, adipose tissue, embryonic tissue, cord blood, reprogrammed mature cells, and perinatal tissue. They support hematopoiesis and produce mesodermal cells. MSCs have demonstrated immunomodulatory and neurotrophic effects in animal models and early human trials.
As part of this study, Petrou et al. aimed to evaluate the safety and efficacy of repeated spinal injections of autologous MSCs in ALS patients. This open-label clinical trial included patients aged 20-70, with definite ALS diagnoses and ALS Functional Rating Scale Revised (ALSFRS-R) scores above 20. The patients received 1-4 intrathecal MSC injections at intervals of 3-6 months, with safety and tolerability as primary endpoints, and efficacy as secondary endpoints.
This trial found no serious adverse events, demonstrating the safety of repeated MSC injections. As evidence, the authors point out that, 15 out of 19 patients showed a reduction in the progression rate of their ALSFRS-R scores by more than 25% between the first and second injections, with an average improvement of 107.1%. Similar improvements were observed between subsequent injections. Thirteen patients experienced a 25% improvement in their progression rate over the entire treatment period, with an average improvement of 47.4%. Seven patients showed clinical improvement after the first transplantation, and five remained improved after the second cycle. These benefits were correlated with the intervals between the injections, suggesting that regular MSC administrations might be crucial for sustained efficacy.
Previous Studies on MSCs in ALS
Several small, open-label clinical trials have suggested that MSC treatment can be beneficial for neurological diseases, including ALS. In a phase I/II trial by the same research group, ALS patients received intrathecal and intravenous MSC injections, which were safe and showed a trend toward disease stabilization over six months. Another phase I/II and IIa trial with Brainstorm® used modified MSCs producing neurotrophic factors (MSC-NTF), showing at least a 25% improvement in disease progression, particularly in the intrathecally treated group.
Additional trials, including a randomized, placebo-controlled phase II study, demonstrated mixed results. While some trials noted improvements in a subgroup of rapid progressors, others did not show significant differences between MSC-treated and placebo groups overall. These studies highlight the need for repeated injections to maintain the benefits of MSC therapy.
Implications From the Current Study
According to Petrou et al., repeated intrathecal injections of MSCs over a longer follow-up period appears to induce significant, but short-term, clinical improvements and slow disease progression in a majority of patients. This study also reaffirmed the safety profile of MSC, with only mild and transient adverse events observed.
The study highlights the potential of MSC therapy in providing neuroprotection and slowing ALS progression. The immunomodulatory effects of MSCs, possibly reducing inflammation in the central nervous system, may also contribute to their therapeutic benefits. However, the small sample size and open-label design are limitations, necessitating larger, controlled trials to confirm these findings.
Future Directions
Petrou et al. concluded that repeated intrathecal injections of autologous MSCs are safe for ALS patients and suggest potential medium-term clinical benefits. However, larger studies are needed to confirm these findings. The consistent observation of safety and indications of efficacy across multiple cycles of treatment is encouraging, indicating that MSC therapy could slow the progression of ALS and improve patients’ quality of life.
The study’s promising results support the continued exploration of MSC therapy for ALS. The authors call for future trials to focus on optimizing the timing and frequency of MSC injections to maximize clinical benefits. Larger, controlled studies are essential to validate these findings and potentially establish MSC therapy as a viable treatment option for ALS. By addressing the unmet needs in neuroprotection and immunomodulation, MSC therapy holds the potential of improving the quality of life and survival for ALS patients.
Source: Panayiota Petrou, Ibrahim Kassis, Nour Eddine Yaghmour, Ariel Ginzberg, Dimitrios Karussis. A phase II clinical trial with repeated intrathecal injections of autologous mesenchymal stem cells in patients with amyotrophic lateral sclerosis. Front. Biosci. (Landmark Ed)2021, 26(10), 693–706. https://doi.org/10.52586/4980
Neurodegenerative diseases, which include conditions like amyotrophic lateral sclerosis (ALS), motor neuron disease, Parkinson’s disease, and multiple sclerosis (MS), are characterized by the progressive loss of structure and function of neurons. These conditions are currently considered incurable and utilize treatments focusing primarily on managing symptoms rather than addressing the root causes. However, recent advancements in regenerative medicine, also known as stem cell therapy, particularly mesenchymal stem cell (MSC) therapy, have ushered in a new era of hope and potential for managing and potentially these debilitating conditions.
Understanding Mesenchymal Stem Cell Therapy
Mesenchymal stem cells (MSCs) are multipotent stromal cells capable of differentiating into a variety of cell types, including bone, cartilage, and fat cells. They can be derived from various tissues, such as bone marrow, adipose tissue, and umbilical cord blood. MSCs possess remarkable immunomodulatory and anti-inflammatory properties, which make them suitable for treating a wide range of medical conditions, including neurodegenerative diseases.
MSCs secrete a range of bioactive molecules that promote neuroprotection, neurogenesis, and angiogenesis. They can migrate to sites of injury or inflammation, where they modulate the immune response and promote tissue repair. Additionally, MSCs can differentiate into neuronal cells and support the survival of existing neurons by creating a favorable microenvironment.
Mesenchymal stem cells (MSCs) offer a multifaceted approach to managing neurodegenerative conditions with their unique properties and mechanisms of action. Here is how MSCs can help in neurodegenerative conditions:
1. Immunomodulation
MSCs have potent immunomodulatory effects, which can help in neurodegenerative conditions where inflammation and immune system dysregulation play significant roles. MSCs can:
Reduce Inflammation: By secreting anti-inflammatory cytokines, MSCs can reduce chronic inflammation in the central nervous system (CNS), which is a hallmark of many neurodegenerative diseases.
Modulate Immune Response: MSCs can alter the activity of various immune cells, including T-cells, B-cells, and macrophages, promoting a more balanced immune response and preventing autoimmune attacks on neural tissues.
2. Neuroprotection
MSCs can create a supportive environment for existing neurons, protecting them from further damage. They achieve this through:
Secretion of Neurotrophic Factors: MSCs secrete neurotrophic factors such as brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and nerve growth factor (NGF), which support neuron survival, growth, and function.
Anti-apoptotic Effects: MSCs release molecules that inhibit apoptosis (programmed cell death), thereby preserving the existing neuronal population.
3. Neurogenesis and Differentiation
While MSCs themselves have limited capacity to differentiate into neurons, they can support neurogenesis indirectly:
Stimulation of Endogenous Stem Cells: MSCs can create a microenvironment that stimulates the body’s own neural stem cells to proliferate and differentiate into new neurons.
Paracrine Signaling: Through the release of various signaling molecules, MSCs can enhance the differentiation and maturation of progenitor cells into functional neurons and glial cells.
4. Tissue Repair and Regeneration
MSCs play a crucial role in repairing and regenerating damaged tissues:
Angiogenesis: MSCs promote the formation of new blood vessels, improving blood supply and oxygenation to damaged areas in the CNS, which is essential for tissue repair.
Extracellular Matrix Remodeling: MSCs secrete enzymes that remodel the extracellular matrix, facilitating tissue repair and regeneration.
5. Reduction of Oxidative Stress
Oxidative stress contributes to neuronal damage in many neurodegenerative diseases. MSCs can combat this through:
Antioxidant Enzyme Production: MSCs produce enzymes such as superoxide dismutase (SOD) and catalase, which help neutralize reactive oxygen species (ROS) and reduce oxidative stress.
Regulation of Oxidative Pathways: By modulating cellular pathways involved in oxidative stress, MSCs can protect neurons from oxidative damage.
6. Enhancement of Synaptic Connectivity
MSCs can improve neuronal communication and function by:
Promoting Synaptogenesis: MSCs secrete factors that encourage the formation of new synapses, enhancing neural connectivity and plasticity.
Supporting Synaptic Function: MSCs release molecules that help maintain and improve synaptic function, which is crucial for effective neural communication.
How Can Stem Cell Therapy Help Certain Neurodegenerative Conditions:
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons, leading to muscle weakness and atrophy. MSC therapy can help manage this condition by reducing inflammation and promoting the survival of motor neurons. Clinical trials have demonstrated that MSC transplantation can improve motor function and slow disease progression in ALS patients. The neuroprotective and regenerative properties of MSCs address both the symptoms and the underlying disease mechanisms, offering a potential option for those to consider.
Motor neuron diseases (MNDs) encompass a group of disorders characterized by the degeneration of motor neurons, leading to muscle weakness and paralysis. MSC therapy has emerged as a potential treatment for MNDs due to its ability to modulate the immune system and promote neuronal survival. Preclinical studies have shown that MSC transplantation can improve motor function and extend survival in animal models of MND. Ongoing clinical trials aim to evaluate the safety and efficacy of MSC therapy in patients with MND, offering hope for improved management and outcomes.
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra, leading to motor symptoms such as tremors, rigidity, and bradykinesia. MSC therapy has shown potential in PD treatment by promoting the survival of dopaminergic neurons and modulating the immune response. Preclinical studies have demonstrated that MSC transplantation can improve motor function and reduce neuroinflammation in animal models of PD. Clinical trials are underway to assess the safety and efficacy of MSC therapy in PD patients, with promising preliminary results. If successful, MSC therapy could offer a groundbreaking new approach to managing and potentially treating Parkinson’s disease.
Multiple sclerosis (MS) is an autoimmune neurodegenerative disease that affects the central nervous system, leading to a wide range of neurological symptoms. MSC therapy has shown promise in the treatment of MS due to its immunomodulatory and neuroprotective properties. MSCs can help reduce the autoimmune response, promote repair of damaged neural tissues, and improve overall neurological function. Clinical trials have indicated that MSC transplantation can reduce the frequency of relapses and slow the progression of MS, providing a new avenue of hope for patients who suffer from this chronic condition.
Advantages of MSC Therapy in Neurodegenerative Diseases
One of the significant advantages of MSC therapy is its low risk of causing immune rejection. MSCs are typically autologous (derived from the patient’s own tissues) or allogeneic (derived from a donor) and possess immunomodulatory properties. The anti-inflammatory effects of MSCs can mitigate the neuroinflammation commonly seen in neurodegenerative diseases, potentially slowing disease progression.
MSCs can also promote neurogenesis and neuroprotection, supporting the survival and function of existing neurons and enhancing overall brain health. The ability of MSCs to migrate to sites of injury or inflammation allows for targeted treatment, maximizing therapeutic benefits while minimizing potential side effects.
Case Studies and Clinical Trials
Numerous clinical trials are currently underway to evaluate the safety and efficacy of MSC therapy in various neurodegenerative diseases, including ALS, MND, PD, and MS. Early-phase trials have shown promising results, with some patients experiencing improvements in motor function and quality of life.
Case studies highlight the potential of MSC therapy to stabilize or improve disease symptoms, offering hope for patients with limited treatment options. The success of ongoing trials will provide valuable insights into the therapeutic potential of MSCs and pave the way for larger, more definitive studies.
The Potential of Mesenchymal Stem Cell Therapy in Neurodegenerative Disease Management
Mesenchymal stem cell therapy has revolutionized the management of neurodegenerative diseases by offering a novel approach to treatment that goes beyond symptom management. The ability of MSCs to modulate the immune response, promote neuroprotection, and support neuronal survival holds immense potential for conditions such as ALS, motor neuron disease, Parkinson’s disease, and multiple sclerosis.
The remarkable properties of mesenchymal stem cells, including their ability to differentiate, migrate to injury sites, and modulate immune responses, make them a powerful tool in the fight against neurodegenerative diseases. As research progresses and our understanding deepens, MSC therapy could become a cornerstone in the treatment of neurodegenerative conditions, providing relief and improved quality of life for millions of patients worldwide. The journey towards fully realizing the potential of MSC therapy is ongoing, but the strides made thus far are a testament to the incredible possibilities that stem cell research holds for the future of medicine.
According to the World Health Organization, an estimated 422 million people worldwide have diabetes. Numerous studies have demonstrated that people with diabetes are at an increased risk of developing both acute and chronic pancreatitis, which increases the risk of developing pancreatic cancer.
Considering the lack of effective therapeutic options for pancreatitis and the limited treatment options for diabetes, researchers have recently turned to the potential of using mesenchymal stem cells (MSCs) as alternative therapeutic treatment options for these conditions.
In this review, Scuteri and Monfrini evaluate the different uses of MSCs for both the treatment of diabetes and the reduction of diabetes-related disease development.
According to the authors, MSCs offer several advantages, including the ability to be isolated from different tissues in a simple way, the ability to be easily harvested and expanded in vitro, and the absence of ethical problems associated with harvesting and use.
In addition, MSCs demonstrate the ability to differentiate, release soluble factors, and migrate toward lesions and sites of inflammation. Considering that inflammation and apoptosis are significant etiopathological factors of diabetes and pancreatitis, Scuteri and Monfrini indicate that MSCs are excellent candidates for regenerative medicine purposes.
In the case of MSCs and diabetes, research has demonstrated that differentiation of MSCs into insulin-releasing cells has been demonstrated in vitro after direct contact with pancreatic islets; the release of anti-inflammatory and antioxidant factors has improved the engraftment and prolonged the survival of transplanted pancreatic islets; and inhibited the apoptotic pathways triggered by endoplasmic reticulum stress in transplanted pancreatic islets. In analyzing this research, the authors conclude that the potential exists for the safe and effective use of MSCs for treatment of diabetes.
Although there has been growing interest in exploring the potential of MSCs on pancreatitis, there have only been a few studies exploring this therapeutic option. In these studies, the presence of MSCs was observed to reduce fibrosis and parenchymal damage by reducing proinflammatory factor expression.
In regard to MSCs and pancreatic cancer, since diabetes and pancreatitis are risk factors for the development of pancreatic cancer and considering MSCs have been found to hold potential as a therapeutic option for these diseases, using MSCs to interrupt the flow of factors leading to the development of pancreatic cancer should lower the incidence of diabetes-related pancreatic cancers.
The authors conclude that MSCs are a very promising therapeutic option for the treatment of diabetes, pancreatitis, and pancreatic cancer.
The International Association for the Study of Pain defines neuropathic pain as “pain arising as a direct consequence of a lesion or disease affecting the somatosensory system”. While general neuropathy is diverse by nature, neuropathic lesions generally fall into four categories: focal or multifocal lesions of the peripheral system, general lesions of the peripheral nervous systems, lesions of the central nervous system, and complex neuropathic disorders.
Although neuropathic pain is typically characterized as chronic pain, it is also considered more severe than other types of chronic pain; this is in large part due to the increased disruption to overall quality of life when compared with other chronic pain syndromes.
As part of this review, Fortino, Pelaez, and Cheung review specific types of neuropathic pain and summarize current research being done to replace pharmacological treatments with cellular therapies, including stem cells, designed to have a longer-lasting effect on the treatment of neuropathic pain.
Neuropathic pain presents itself in many different forms, including spontaneous sensations and superficial pain. These forms of neuropathic pain differ from nociceptive pain in that nociceptive pain occurs as a result of tissue damage while neuropathic pain is the product of damage to the peripheral or central nervous system. Neuropathic pain also differs from nociceptive pain in its proportion to the intensity of the stimuli; in other words, while nociceptive pain is proportional to the intensity of the stimuli, neuropathic pain is not.
Considering that uninjured fibers that intermingle with degenerating nerve fibers participate in pain signaling, it is important for the environment surrounding these uninjured nerve fibers to be able to protect them from degeneration and exacerbation associated with neuropathic pain. Since growth factors have proven critical in promoting neuron development and survival and since neurotrophic factors are secreted by stem cells, researchers hypothesize that stem cells present a potential therapy for longer lasting treatment of neuropathic pain.
Clinical studies have demonstrated that neurotrophic factors offered by stem cells when in direct or indirect contact with the lesioned nerve, appear to provide neuroprotection and neuroregenerative effects.
Despite the potential for stem cell therapies to provide protection from neurodegeneration and to promote neuroregeneration, the authors raise several issues that need to be addressed, including determining an optimal dose for stem cell transplantation and obtaining a better understanding of the homing capabilities of stem cells.
In addition to exploring the benefits of neurotrophic factors of stem cells in treating neuropathic pain, transplantation of human mesenchymal stem cells (hMSCs) to explore potential benefits in treating diabetic peripheral neuropathy and spinal cord injuries are also currently being evaluated.
While the role of stem cells in the treatment of neuropathic pain is not yet fully understood, the authors find their ability to modify cellular processes to provide protective and restorative environments that can reverse the causes of neuropathic pain a promising therapy for the long-term treatment of this condition.
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