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The use of umbilical cord blood mesenchymal stem cell transplantation for 20 Patients with Multiple System Atrophy

Author Admin Views Posted at 2011/11/04

The use of umbilical cord blood mesenchymal stem cell transplantation for 20 Patients with Multiple System Atrophy

Journal of Clinal Rehabilitative Tissue Engineering Research
Xiaojuan Wang, Like Wu, Saichun Chu, Baolei Xu and Bo Cheng
OBJECTIVE: To observe the outcomes of the umbilical cord blood mesenchymal stem cell transplantation used to treat the neural function complications found in patients with multiple system atrophy (MSA).
METHODS: A total of 20 MSA patients were selected at the Beijing Wu Stem Cells Medical Center from January to October, 2008. All of the patients were given treatment for vein distention, anti-free radicals, trophic nerve and cell membrane stabilization, as well as umbilical cord blood mesenchymal stem cell transplantation through an intrathecal injection. The patients were placed in a left-lateral position, bent at the hips, knees and neck. Acupuncture was conducted at the space between the lumbar vertebra 3 and 4. Following local anesthesia, a No. 9 needle was directly inserted into the subarachnoid cavity. 2 mg dexamethasone was slowly infused, and 5 mL (5×106 stem cells) umbilical cord blood mesenchymal stem cells were obtained and slowly infused into the subarachnoid cavity within 10 minutes, once per week, for a total of four times, throughout the course of one treatment. We adopted the Unified Multiple System Atrophy Rating Scale (UMSARS) to evaluate each of the MSA patients. Higher scores represented a severe pathogenetic condition.
RESULTS: Compared with pre transplantation, the UMSARS scores had significantly decreased in 20 patients, 4 weeks following the transplantation procedure (P < 0.01). After the treatment, the patients’ clinical symptoms such as slow movement, balance disturbance, orthostatic hypotension, urinary and bowel disorders had improved noticeably. Graft versus host disease was not found.
CONCLUSION: Indications show that mesenchymal stem cell transplantation is effective, and can partly improve the MSA patients’ clinical symptoms, as well as improve the patients’ overall quality of life.
MSA (multiple system atrophy) is a kind of multiple atrophy and degenerative disease affecting the Central Nervous System (CNS) with no clear cause. In general, the disease develops progressively and the patient will have motor disturbance, tremors, difficulties with their balance, postural hypotension, dementia, etc.,until the patient becomes totally disabled. The degeneration of the neural system can not be reversed and currently there is still no completely effective treatment for MSA. 
With the development of regenerative medicine,the stem cell transplantation can provide a new method of treatment for such kinds of the disease[1].
Currently the stem cell transplantation treatment for MSA has become a real point of interest. We used implanted umbilical cord blood mesenchymal stem cells (MSCs) to treat MSA patients and observed the effects of the stem cell implantation on the MSA clinical symptoms.
1. Case Introduction
1.1) 20 MSA patients were chosen on 2008-01/10 and treated at Beijing Hezhonghuaxin Medical Center. All of the patients were diagnosed according to the standards of the 4 group clinical characteristics and diagnostics criteria issued by Gilman, etc[2] (Michigan State University, USA) in 1999.
Included in the cases were 13 males and 7 females. The age range was between 51-70, and the average age was 62 years old. The patients were fully aware of the treatment and all the risks involved and signed a consent form before the start of the stem cell treatment, according to the No. 33 regulation (regulations on administration of the hospital) issued by the State Council (China) in 2005. The treatment plan was permitted by the hospital’s Medical Ethics Committee before the study began. 
Indication of the stem cell treatment: MSA patients, excluding other neurodegenerative diseases and severe systemic diseases.
Relative contraindication of the stem cell treatment: ① hyperirritability or having a medical history of severe allergies ② unstable vital signs ③ malignant tumors ④ general or local serious infection ⑤ severe disturbance of an organ’s functioning such as the heart, lungs, liver or kidneys ⑥ coagulation defects such as hemophilia ⑦ a patient with a positive serological testing result such as HIV, syphilis, hepatitis B, etc.
1.2) Methods
Clinical examination: All the patients must be hospitalized and have regular physical checkups during the first week. In all of the 20 cases, the blood, urine and stool tests showed normal levels, the renal function and liver function were within normal levels, the tumor marker and chest X- rays were all normal, the blood sugar level of 2 of the patients were higher than normal, and after the regular diet and oral medication treatment, the blood surgar levels were controlled and within the ideal range. The blood-lipid levels of 3 of the patients were higher than normal, including the cholesterol or triacylglycerol levels. We gave these patients medication to decrease the blood lipid levels to the normal range.
Umbilical cord blood mesenchymal stem cells (MSCs) isolated and cultured in vitro: The umbilical cord blood mesenchymal stem cells (MSCs) are all from the Beijing SinoCells Biotechnology Development Co., Ltd. The cells were collected from cord blood, after the isolation and expansion, the cells were induced to differentiate into neural stem cells, after 4-6 transfer cultures, the amount of the stem cells was 1×109 L-1, , among them, 80% were CD34+ cells and 20% were neural precursor cells.
MSCs implantation:[4] During the second week, we started giving the patients an MSCs implantation through an intrathecal injection, once per week, for a total of 4 times, comprising the one course of the treatment period. During the course of the treatment, the patients were placed in the left lateral position, bent at the hips, knees and neck. The puncture point was located at the L3-L4 intervertebral space, which was sterilized and the surrounding area covered with surgical olrape. The patients were then given local anesthesia with 2% Lidocaine, then we used a No. 9 puncture needle, and injected the MSCs into the subarachnoid space vertically. The patients were initially given 2mg of Hexadecadrol slowly, and then injected with 5ml of MSCs (5 million stem cells) into the subarachnoid space within 10 minutes. We then observed each patient’s initial response. There was no signs of discomfort, so we removed the needle, sterilized the puncture area, covered it wih sterilized dressing, and let the patients lay down without a pillow for 6 hours. 
Assistant therapy: We gave each patient regular treatments to expand the blood vessels, anti-free radicals, treatment to nourish the neurons and treatment to stablize the cytomembrane, etc.
Evaluation standards: We evaluated each of the patient’s neural function and any symptom changes before the stem cell implantation and 4 weeks after the implantation, using the MSA evaluation form. The form is composed of 2 main scales: the first scale is a medical history review (with 12 items), the second scale is a motor skills evaluation (which includes 14 items), the score is from 0 (normal) to 4 (severely abnormal). The higher the score a patient has, the more severe the condition is.
Statistical analysis: The second author adopts the SPSS 11.5 system to deal with the data from the experiment, using pairs of the test analysis for the line number, P < 0.05 to indicate the significant statistical differences.
1.3) Case Analysis
All of the 20 cases of the stem cell implantation treatment were completed sucessfully, no one withdrew during the treatment procedure. We perform the results analysis according to the intentionality.
Clinical symptoms changes: 4 weeks post stem cell transplantation, in the 20 cases, all of the patients showed obvious improvment in their slow movement, balance disturbance, orthostatic hypotension and urine, stool disturbance.
Patient’s independent functional score: The average score of the 20 cases before the stem cell implantation was 63.0±8.8, and 4 weeks after, the average score was 53.0±9.9, there are statistically significant differences between them (P < 0.01), Tab 1.
Vital signs: During the stem cell implantation period and 4 weeks post implantation, the patients’ vital signs were stable.
Complications and side effects: 4 patients developed low fevers after the implantation, their tempretures were lower than 38 ℃, with headaches or back pain, etc. After the symptomatic treatment, the 4 patients were relieved completely. None of the 20 patients had graft versus host response (GVH).
2. Case Discussion
MSA is a kind of sporadic progressive neural degeneration disease which always affects the patient’s extrapyramidal system, pyramidal system, cerebella and autonomic nervous system. The clinical symptoms are very complicated, which include vegetative nerve functional damage, Parkinson's symptoms, ataxia and pyramidal system damage, etc. [6-7] Most MSA patients will lose a large part or all of their ability to participate in normal everyday activities of life.[8] There is still currently no completely effective treatment to cure the disease.. The basal pathological change is represented by a loss of neurons, and gliocyte hyperplasia. The specific landmark for a pathological diagnosis is the formation of oligodendrocytes inclusion body. The main constituent is α-synuclein. After this discovery was made by scientists, we divided MSA, Parkinson’s disease and Lewy dementia into the family of synuclein diseases.
Stem cells are a type of cell with great potential for self renewal. The stem cells can differentiate into many types of histocytes in the proper environment, including neurons [9-19]. In recent research, stem cell implantation was seen to improve the patient’s vegetative nervous system, cerebella, extrapyramidal system symptoms and motor disturbance[20]. On the one hand, the MSCs implanted into the patient’s own body have complicated and fine control systems that can prevent the malformation and aggregation of proteins, such as the molecular chaperone that can help the protein folding in a right form and prevent the non-natural protein’s aggregation[21]. A proper medical intervention can help the malformation protein degradation by the UPS (Ubiquitin-Proteasome System) and the phagosome-lysosome system, especially the UPS, which blocks the progression of the disease; on the other hand, stem cells, after implantation can locate to the surrounding damaged area, and rebuild the new web to repair the damaged neural tissue, helping the patient to gain some recovery of the neural function loss.
In this experiment, we used umbilical cord blood mesenchymal stem cells (MSCs) transplantation to treat MSA, and we found that after the implantation, the patient’s neural function had obvious improvements, especially in regards to the pyramidal system and extrapyramidal system symptoms. The patient’s muscles were much stronger, improved muscle force, less rigidity, tremors, slow movements and balance were all improved. The vegetative nervous function also improved a lot, and the blood pressure and urine control showed some improvement in different degrees.
The possible mechanisms are: ① The MSCs, after implantation into the patient’s brain tissue, can differentiate into neuron-like cells or astrocytes which can express protein markers of neurons, and these new cells can survive in the damaged area and within the brain global[22]. ②In the microenvironment of the central nervous system, the MSCs can produce neurotrophic factors, Basic Fibroblast Growth Factor (BFGF), or stimulate the damaged area by secreting endogenous factors to help repair the damaged area and reduce the cell apoptosis[23]. ③The MSCs are the main part of the new blood vessels in the damaged area, and they can differentiate into vascular endothelial cells and extracellular matrix, help to protect the neurons, and help the vasculogenesis[24]. ④ They can also create a proper local microenvironment, allowing the MSCs to fully differentiate into neurons proliferated in vitro or induce the differentiation method, replace the damaged neurons and rebuild the neural functional area and neural pathways[25] 

From the scores indicated by the MSA evaluation scale, before and after the stem cell transplantation, the MSA patients had obvious recovery of their neural functions. These results show that the umbilical cord blood mesenchymal stem cells (MSCs) transplantation procedure is effective in the treatment of MSA, but we still need further research to fully understand the true potential of this treatment method.


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