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.
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.
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.
Acute and chronic pancreatitis are associated with local and systemic inflammation that is linked to a host of serious health issues. A result of the digestive juices and enzymes attacking the pancreas, pancreatitis currently has no definite treatment.
Currently, it is estimated that over 6 million people worldwide are afflicted by acute or chronic pancreatitis with the number of diagnoses appearing to be steadily increasing.
The rising interest in stem cell therapy being used to potentially treat a wide variety of other diseases has led to interest in exploring it as a way to aid in the treatment of both acute and chronic pancreatitis.
As part of this review, Chela et al. examine numerous studies using commonly used stem cells to explore their promise in the treatment of pancreatitis.
A number of studies are utilizing stem cells to repair and replace tissue damaged as a result of numerous gastrointestinal diseases, including acute and chronic pancreatitis. In the case of using stem cells, and specifically mesenchymal stem cells (MSCs), to treat pancreatitis, researchers are interested in the ability of these stem cells to regenerate damaged cells and to influence the immunological and inflammatory response resulting from this condition.
A significant issue that has stymied progress in the ability of the pancreas to self-repair and regenerate when affected by pancreatitis is the perceived lack of stem cells found specifically in the tissue of the pancreas. While there has been conflicting research into whether or not stem cells exist in pancreatic tissue, the research reviewed by the authors indicates that there appears to be a tiny amount of stem cells located within pancreatic tissue.
Considering this and considering that additional research indicates that other stem cells found in the pancreas appear to originate from bone marrow (BM), the authors believe the ability of MSCs’ ability to differentiate will support the healing of the pancreas; these include stem cell sources from BM, adipose tissue, umbilical cord, and induced pluripotent stem cells (iPSCs).
Neuropathic pain (NP) occurs when the nerves located either inside or outside of the brain and spinal cord are damaged by a lesion or a condition. To date, pharmacological and surgical treatments to address NP have focused on providing symptomatic relief without treating the underlying cause of the condition. These treatment approaches have not been overwhelmingly successful with over 50% of NP patients attaining adequate pain relief.
Recently, an increasing amount of pre-clinical and clinical research has demonstrated cell transplantation-based therapy for NP to be a promising treatment alternative.
In this review, Yin et al. summarize the use of cell grafts for the treatment of NP, synthesize the latest advances and adverse effects, and discuss possible mechanisms to further the development of cell transplant-based therapies for NP.
Neural stem cells (NSCs) demonstrate the ability to divide, self-renew, and differentiate into neurons, astrocytes, and oligodendrocytes; they are also present in a wide array of tissues throughout the body. Considering they are capable of differentiating into neurons and glial, NSCs are considered an ideal candidate cell for replacing damaged nerve cells and delivering trophic factors to the site of lesions contributing to NP. Additional studies have demonstrated NSCs ability to regenerate nerves, offer neuroprotective effects, and secrete a number of factors that enhance the survival of motor and sensory neurons. NSCs transplantation coils also ease NP caused by peripheral nerve injury, a potential benefit that has been observed in animal models.
Olfactory ensheathing cells (OECs) are glial cells that surround and enclose the olfactory nerve bundle and possess the unique ability to transgress the peripheral nervous system (PNS) and central nervous system (CNS). Considering OECs have been shown to have neuro-regenerative functions, they are also considered to be a good choice for treating nerve injury and NP. Studies using animal models have confirmed that OECs transplantation could promote motor recovery and mitigate pain. Although OECs have good prospects of being used for treating NP, the authors call for additional research with longer observation time to verify their long-term effects and safety.
Mesenchymal stem cells (MSCs) can be obtained from a wide variety of sources and can be induced to differentiate into endoderm, mesoderm, and ectoderm cell lines. MSCs are often used for the treatment of diseases involving neuroinflammatory components and have been shown in animal studies to potentially alleviate NP symptoms.
Other cell therapies currently being evaluated for use as a treatment for NP include bone marrow mononuclear cells, GABAergic cells, and genetically modified cells.
The authors conclude that, despite the small number of clinical studies and the lack of systematic evidence, cell therapy as a treatment alternative for NP should be further explored. Specifically, further research should examine the optimal transplantation route, transplantation timing, number of transplanted cells, and transplantation survival rate.
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