Written by: Sun Yat-sen University, Light Blue
Review expert of this article: Professor Li Jing from the Affiliated Hospital of Jiangsu University
introduction
In recent years, research has continuously confirmed that cell therapy is one of the most cutting-edge neurorehabilitation technologies. Clinical studies have also shown that mesenchymal stem cell therapy can alleviate symptoms or reverse the course of neurodegenerative diseases and nerve damage. How are mesenchymal stem cells used in clinical practice for the treatment of neurodegenerative diseases and neurological rehabilitation? This article summarizes the literature and counts the different clinical administration methods, such as intravenous infusion, direct injection of mesenchymal stem cells at the site of injury, or infusion of mesenchymal stem cell exosomes through the nasal cavity, to help you understand the rehabilitation of mesenchymal stem cells and nerves.
Every year, thousands of people develop neurodegenerative diseases that impair the body's mobility and sensitivity, often with fatal consequences. Although the body has a certain self-healing function for injuries, it is often not enough to rely solely on the recovery of peripheral nerves themselves. In this regard, cell therapy is one of the most cutting-edge neurorehabilitation technologies at present.
Neurodegeneration is a class of chronic progressive neurological damage characterized by the gradual loss of neurons or their myelin sheaths, resulting in dysfunction. These disorders usually worsen over time and may be accompanied by symptoms such as cognitive dysfunction, general numbness, and difficulty chewing.
Common neurodegenerative diseases include Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease, multiple sclerosis (MS), and Parkinson's disease. At present, the current clinical treatment methods for this type of disease still have great limitations.
In recent years, stem cell therapy, as a new type of treatment, has been fully affirmed in many clinical studies and is a very promising treatment option. Mesenchymal stem cell (MSCs) therapy has also been shown to alleviate symptoms or reverse the course of neurodegenerative diseases and neurological injuries in clinical studies [1].
最近发表在“Life Sciences”上的一篇名为“A comprehensive review on therapeutic application of mesenchymal stem cells in neuroregeneration”就揭示了MSCs在治疗神经退行性病变疾病上的强大潜力[1]。
Studies have shown that the therapeutic mechanism of mesenchymal stem cells may have the following aspects:
On the one hand, damaged cells can be preserved and/or repaired by differentiating into various alternative cell types and controlling the immune response.
On the other hand, it can also regulate the body's immune function and inflammatory factor activity through paracrine, cell-cell contact and interaction, mitochondrial transfer and extracellular vesicle release.
Due to the different mechanisms at play during the repair process, mesenchymal stem cells can adapt to different local microenvironments, and the specific action schematic diagram can be shown in the figure below.
(Image from Reference 1)
So, for the treatment of neurodegenerative diseases and neurological rehabilitation, how are mesenchymal stem cells used in clinical practice? Today, we will help you understand mesenchymal stem cells and nerve rehabilitation by summarizing the literature.
Method 1: Intravenous infusion of mesenchymal stem cells
Intravenous infusion of mesenchymal stem cells is a common clinical treatment for neurodegenerative diseases.
Recently, a phase I/II study published by Michael L Levy et al. [2] has shown that intravenous allogeneic mesenchymal stem cell infusion is effective and safe in the treatment of patients with chronic stroke and severe functional impairment, and that stroke symptoms are effectively improved.
The study injected mesenchymal stem cells (BM-MSCs) isolated from a single donor into 36 patients, and all stroke-related symptoms showed significant improvement at the subsequent 12-month follow-up.
For example, the Barthel index score increased by 6.8±11.4 points (mean±SD) (P=0.002) at 6 months after injection and 10.8±15.5 points at 12 months after injection (P<0.001). The proportion of patients achieving a superior functional prognosis (Barthel score ≥95) increased from 11.4% at baseline to 27.3% at 6 months and 35.5% at 12 months.
(Image from Ref. 2)
Method 2: Direct injection of mesenchymal stem cells at the site of injury
Traumatic brain injury, or TBI for short, is an extremely serious condition, especially in younger people. It usually occurs from the violent impact of external mechanical forces on the head, which causes great damage to nerve function and sometimes leads to death.
The damage caused by TBI can be divided into two main phases. In the early stages of an injury, direct physical impact has a direct impact on the brain, leading to serious consequences such as disruption of the blood-brain barrier (BBB), swelling of brain tissue, and intracranial hemorrhage. Unfortunately, despite a great deal of research into TBI, there is still no single treatment that can significantly reduce mortality due to TBI or effectively promote functional recovery in patients.
Researchers have found that treatment with mesenchymal stem cells can stimulate the injured brain to produce nutritional factors that help promote neurogenesis, neuroprotection, and nerve repair, and improve the clinical symptoms of patients to a certain extent.
The research team recruited 97 patients with complex brain injury (24 cases of persistent vegetative state and 73 cases of motor activity impairment) who developed complex brain injury after traumatic brain injury to voluntarily receive autologous bone marrow mesenchymal stem cell therapy. Stem cells were isolated from the patient's bone marrow and implanted into the subarachnoid space by lumbar puncture [3].
The results showed that 38 of the 97 patients (39.2%) had some degree of improvement in brain function after transplantation. Among the 24 patients with persistent vegetative state, 11 (45.8%) had improved consciousness after treatment. Among the 73 patients with movement disorders, 27 (37.0%) began to improve their motor function. The age of the patient and the time interval between injury and treatment have an impact on the outcome of cell therapy. There was no correlation between the number of cell injections and improvement.
From this study, we can see that translumbar puncture infusion of mesenchymal stem cells for the treatment of traumatic brain injury complications such as persistent vegetative state and dyskinesia is safe and effective.
(Image from Ref. 3)
Method 3: Instillation of mesenchymal stem cell exosomes into the nasal cavity
For stem cell therapy, the blood-brain barrier (BBB) is a challenge, blocking most drugs from entering the brain through conventional means, reducing the effectiveness of treatments. And developing drugs that can bypass this barrier has always been a challenge for the medical community. Stem cell transplantation has great potential for treating neurological diseases like Parkinson's disease (PD) and Alzheimer's disease (AD). However, traditional stem cell treatments, such as stereotactic or intrathecal injections, are invasive, which limits their application in the treatment of neurological disorders.
Fortunately, researchers have discovered a new way of administration – intranasal application (INA). This approach cleverly bypasses the blood-brain barrier and delivers the drug directly to the central nervous system. Compared to stereotactic brain injections and intrathecal injections, INA is not only less invasive and less painful for patients, but it is also easy to perform and can be repeated.
Dr. Silvia Coco of Italy published a study in the international journal Stem Cell Translational Medicine [4]. Studies have shown that non-invasive nasal instillation allows stem cell-secreted exosomes (MSC-EVs) to exert anti-inflammatory effects more effectively, leading to faster treatment of Alzheimer's disease. This discovery provides a new avenue for the treatment of neurological diseases, and also demonstrates the great potential of stem cell therapy in future medicine.
(Image from Ref. 4)
The results showed that MSC-EVs could effectively inhibit the activation of microglia in the brain, increase the density of dendritic spines (structures in the brain that provide cognitive elasticity), and effectively improve the symptoms of Alzheimer's disease.
brief summary
Data from numerous clinical trials have demonstrated significant efficacy in neurological rehabilitation and in the treatment of neurological or central nervous system disorders, effectively alleviating the disease process and improving the overall condition of patients. Patients who undergo stem cell transplantation tend to achieve more significant results than traditional drug treatments. With the continuous deepening of research, stem cell therapy has brought unprecedented hope of recovery to patients with neurological diseases. This innovative treatment not only provides patients with new treatment options, but also indicates that the future of medicine is expected to achieve more effective clinical outcomes in the treatment of neurological diseases.
Bibliography:
[1] Babu, Shyamaladevi et al. “A comprehensive review on therapeutic application of mesenchymal stem cells in neuroregeneration.” Life sciences vol. 327 (2023): 121785. doi:10.1016/j.lfs.2023.121785
Link: https://pubmed.ncbi.nlm.nih.gov/37196856/
[2] Levy, Michael L et al. “Phase I/II Study of Safety and Preliminary Efficacy of Intravenous Allogeneic Mesenchymal Stem Cells in Chronic Stroke.” Stroke vol. 50,10 (2019): 2835-2841. doi:10.1161/STROKEAHA.119.026318
Link: https://pubmed.ncbi.nlm.nih.gov/31495331/
[3] Tian, Chunlei et al. “Autologous bone marrow mesenchymal stem cell therapy in the subacute stage of traumatic brain injury by lumbar puncture.” Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation vol. 11,2 (2013): 176-81. doi:10.6002/ect.2012.0053
Link: https://pubmed.ncbi.nlm.nih.gov/22891928/
[4] Losurdo, Morris et al. “Intranasal delivery of mesenchymal stem cell-derived extracellular vesicles exerts immunomodulatory and neuroprotective effects in a 3xTg model of Alzheimer's disease.” Stem cells translational medicine vol. 9,9 (2020): 1068-1084. doi:10.1002/sctm.19-0327
Link: https://pubmed.ncbi.nlm.nih.gov/32496649/