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Abstract

The aim of this study is to explore the safety and therapeutic effect of multiple cell transplantations on patients with multiple system atrophy. Ten patients suffering from multiple system atrophy were treated by multiple cell transplantations from August 2005 to March 2011. They were six males and four females, with an average age of 51.90 ± 12.92 years (23–66 years). Multiple cell types were transplanted by intravenous, intrathecal, and intracranial routes; for example, 0.4–0.5 × 10⁶/kg umbilical cord mesenchymal cells by intravenous drip, intrathecal implantation of 2.0 × 10⁶ Schwann cells and 2.0–5.0 × 10⁶ neural progenitor cells through cerebellar cistern puncture, or 2 × 10⁶ olfactory ensheathing cells and 4 × 10⁶ neural progenitor cells injected into key points for neural network restoration (KPNNR). The neurological function was assessed before and after treatment with the International Cooperative Ataxia Rating Scale (ICARS) by the World Federation of Neurology and the Unified Multiple System Atrophy Rating Scale (UMSARS). The patients achieved neurological function amelioration after treatment, which included improvements in walking ability, gaits, standing, speech, and muscular tension; the ICARS score decreased from a preoperative 46.30 ± 14.50 points to postoperative 41.90 ± 18.40 points (p = 0.049). The UMSARS score decreased from preoperative 50.00 ± 20.65 points to postoperative 46.56 ± 23.05 points (p = 0.037). Among them, two patients remained stable and underwent a second treatment 0.5–1 year after the first therapy. After treatment, five patients were followed up for more than 6 months. Balance and walking ability improved further in four patients, while one patient remained stable for over 6 months. In conclusion, a strategy of comprehensive cell-based neurorestorative therapy for patients with multiple system atrophy is safe and appears to be beneficial. This manuscript is published as part of the International Association of Neurorestoratology (IANR) supplement issue of Cell Transplantation.

Keywords

Multiple system atrophy Multiple cells Comprehensive neurorestoration Transplantation

Introduction

Multiple system atrophy (MSA) is an unknown etiology and progressive neurodegenerative disorder leading to more severe disability and impairment. MSA is characterized by a variable combination of autonomic failure, levodopa-unresponsive parkinsonism, cerebellar ataxia, and pyramidal signs (7,35). There is no efficient treatment for MSA. Current therapeutic management focuses on symptomatic treatment of orthostatic hypotension (OH), constipation, and genitourinary and breathing disorders.

Previous studies have shown that cell therapy can provide some functional recovery in animal models of MSA and MSA patients (23,26–28,36,44,45). On the basis of functional recovery from clinical olfactory ensheathing cell (OEC) transplantation for patients with chronic spinal cord injury (SCI), amyotrophic lateral sclerosis (ALS), cerebral palsy (CP), multiple sclerosis (MS), and stroke (4,5,15–18), we treated 10 patients with MSA. Here we report the preliminary safety and therapeutic effect and possible mechanism of multiple cell transplantation for patients with MSA.

Materials and Methods

General Information

Ten patients with MSA were enrolled between August 2005 and March 2011 at the Center of Neurorestoratology of Beijing Rehabilitation Hospital. Patients were diagnosed according to the Gilman et al. (10) proposed diagnostic standards. Of the subjects, six were male, four were female, and their ages varied from 22 to 66 years; average age was 48.20 ± 15.67 years old. The course of the disease was 1.2–6 years, with an average of 2.79 ± 1.49 years. All patients and/or families were fully informed about the treatment and its attendant risks and gave their informed consent. The protocol of the treatment was approved by the hospital medical ethics committee. All cell sources were donated by individuals signing a consent donation letter without any compensation.

Cell Preparation

Olfactory ensheathing cells (OECs): OECs were isolated from the olfactory bulb of aborted human fetuses (genders unknown) with the proper consent of the donors. The OECs were cultured in Dulbecco's modified Eagle's medium/Ham's F12 (DMEM/F12) (Hyclone, Logan, UT, USA) with 10% fetal bovine serum (FBS) (Hyclone), propagated for 2–3 weeks, and characterized by immunostaining with antibodies against p75 (a neurotrophin receptor that is specific for OECs, Sigma, St. Louis, MO, USA) (30). OECs from one fetus, which represents 2 × 10⁶ cells/100 μl, were transplanted for each patient. The cell culture method has been described previously (4,5,30,56).

Schwann cells (SCs): Human fetal sciatic nerve was removed from aborted fetuses (genders unknown) with the proper consent of the donors. The tissue was sliced, digested in trypsin (Invitrogen, Carlsbad, CA, USA), and made into a monoplast suspension. Cells were cultured in DMEM/F12 and 15% FBS for 7 days before harvesting. Double-label immunofluorescence staining of S100 (Sigma) and Hoechst (Sigma) were obtained to calculate the purified rate of Schwann cells (51). The donors were the same as for OECs.

Neural progenitor cells (NPCs): Under aseptic conditions, tissue from the subependymal zone of the fetal brain was taken. Cell suspension was prepared after repeated mechanical percussion by pushing media through a suction tube and culturing in DMEM/F12 with 20% FBS on poly-l-lysine (PLL)-coated dishes (Corning, Corning, NY, USA). Some of the cells were then immunostained for nestin (Chemicon, Temecula, CA, USA) (20). The donors were the same as for OECs.

Umbilical cord mesenchymal stromal cells (UCMSCs): Umbilical cord tissue from human fetuses were harvested, and tissue blocks were implanted into dishes (Corning) and then incubated in DMEM/F12 with 10% FBS in a 37°C, 5% CO₂ incubator. After 10 days, the cells, which migrated from the tissue block, were digested by using 0.25% trypsin + EDTA (Invitrogen) and were then cultured from one to five passages. Cultivation method was as previously described (21).

Cell Therapy

Intravenous drip: UCMSCs (dose 0.4–0.5 × 10⁶/kg or 2.0–3.0 × 10⁷) in 100 ml saline, 3–4 ml/min by intravenous drip.

Intrathecal injection: SCs (dose 2.0 × 10⁶) + NPCs (dose 2.0–5.0 × 10⁶) were mixed in 500 ml media and then added to 5 ml of the patient's cerebrospinal fluid (CSF) and infused via cerebellar cistern puncture.

Brain transplantation: OECs (dose 2.0 × 10⁶) + NPCs (dose 2.0–4.0 × 10⁶) were mixed together in 50 ml media and injected into the bilateral corona radiata of the frontal lobes (key point for neural network restoration, KPNNR) using stereotactic techniques under local anesthesia (Fig. 1), which was first proposed in 2003 by Dr. Huang, based on successful cases in clinical practice (17). This site is where the frontal corona radiata pyramidal tract passes through and represents a point at which numerous projection fibers, association fibers, and commissural fibers converge.

Figure 1.

The key point for neural network repair. MRI films showing the targets of cell transplantation: two injection sites of OECs in the corona radiate on both-sided frontal lobes, that is, the key point for neural network restoration (KPNNR).

Additional combination treatments included neurotrophic medicine, active movement–target enhancement–neurorehabilitation therapy (AMTENT) for 2–4 h/day; neuroelectric stimulation for 20 min, two times per day; acupuncture therapy for 20 min/day; physical therapy of four limbs for 60 min daily; electric bicycle exercises of legs for 30 min, two times per day; focused massages for 30 min daily, etc.

Outcome Measures

The neurological function of the patients was evaluated by qualified and trained neurologists in a double-blind fashion before treatment and 4 weeks after treatment by using the International Cooperative Ataxia Rating Scale (ICARS) (42) and the Unified MSA Rating Scale (UMSARS) (24). ICARS is a neurologist-completed rating scale developed to assess the symptoms of ataxia. It has four clinically sensible subscales: posture and gait disturbances (PG), kinetic functions (KF), speech disorders (SD), and oculomotor disorders (OD). Nine scores for each subscale quantified the extent of ataxia in each clinically important area. Subscale scores are summed to give a total score ranging from 0 to 100. High scores indicated worse ataxia. UMSARS comprised the following components: Part I, historical, 12 items; Part II, motor examination, 14 items; Part III, autonomic examination; and Part I V, global disability scale. The main outcome measures were patient ICARS, UMSARS score change, and the occurrence of adverse events.

Statistical Analysis

The data were expressed as mean ± standard deviation (SD). Using SPSS 13.0 for Windows (version 13.0; SPSS, Inc., Chicago, IL, USA), paired-sample t tests were performed for the comparisons of the two states made before and 4 weeks after the treatment. A value of p < 0.05 was considered statistically significant.

Results

All patients achieved neurological function amelioration after treatment, which included walking ability, gaits, standing, speech, and muscular tension; ICARS scores decreased from preoperative 46.30 ± 14.50 points to postoperative 41.90 ± 18.40 points (p = 0.049). The UMSARS scores decreased from preoperative 50.00 ± 20.65 points to postoperative 46.56 ± 23.05 points (p = 0.037). Two of the patients who remained stable received a second treatment 0.5–1 year after the first cell therapy. Five patients were followed up for over 6 months by phone or e-mail. Four of them continued to show improvements in balance and walking ability, while one patient remained stable. Orthostatic hypotension and urine control also improved. There were no complications, such as long-term fever, headache, or dizziness (Table 1).

Table 1.

Ten MSA Patients' Data Before and After Treatment

						ICARS Score		UMSARS Score
No.	Sex	Age	Nationality	Course (Year)	Treatment Time	Pre	Post	Pre	Post	Follow-up	Complication
1	F	59	Germany	2	2005-08-22	35	16	17	12		None
2	M	39	China	1.7	2008-01-07	27	20	34	24	2008-12-26 speech clear walking stable 2011-7-28 keep stable	None
3	M	62	Turkey	3	2008-01-15	60	60	77	77		Pulmonary infection
4	M	48	Korea	1.2	2008-05-18	32	23	36	26	2008-10-21 walking	None
					2008-10-21	24	24	26	26	stable	None
5	M	59	China	5	2008-10-12	51	46	43	42	2009-10-26 keep stable for 1 year	Pneumocephalus
6	M	51	China	5	2010-01-17	58	54	79	75	2012-1-18 balance	None
					2011-3-20	54	54	76	76	improvement	None
7	F	66	China	1.7	2010-04-17	36	36	54	53		None
8	M	23	China	1.8	2010-05-31	63	63	70	70	2011-2-23 balance improvement	None
9	F	61	China	4.5	2010-06-08	65	65	73	73		None
10	M	51	China	2	2010-05-31	36	36	44	44		None

MSA, multiple system atrophy; ICARS, International Cooperative Ataxia Rating Scale; UMSARS, Unified Multiple System Atrophy Rating Scale.

Discussion

MSA is characterized clinically by symptoms that can be subdivided into pyramidal, extrapyramidal, cerebellar, and autonomic categories. Extrapyramidal motor abnormalities such as bradykinesia, rigidity, and postural instability are classed as either parkinsonian type (MSA-P) or cerebellar (MSA-C) and reflect damage to the basal ganglia (striatonigral degeneration) or cerebellum (olivopontocerebellar atrophy), respectively (49). The fundamental pathological performance for lack of neurons and glia hyperplasia includes decreasing neuron density and smaller and atrophic neurons, as well as vacuolar degeneration, glial hyperplasia, and abnormal formation of an inclusion body (19). Pathological changes are extensive, including the substantia nigra compacta, locus coeruleus, cerebellum, putamen, pedunculopontine tegmental nucleus, inferior olivary nucleus, spinal cord Onuf's nuclear, and intermediolateral cell column (41,46). Specific glial cytoplasmic inclusions (GCIs) also form.

At present, MSA treatment is only symptomatic, and it mainly targets parkinsonism and autonomic failure because there is no treatment that can provide MSA patients consistent long-term benefits. This creates a strong need for the development of new therapeutic approaches.

Current Experimental and Clinical Studies of Cell Therapy for MSA

Neuroprotective or regenerative strategies, including cell transplantation, appear to be an alternative therapeutic approach for managing MSA patients. Experimentally, different cell types for neurorestoration in MSA models have been tried (23,36,44,45). E14 embryonic striatal allografts have been shown to restore responsiveness to l-DOPA in tasks of complex motor behavior, such as stepping behavior in toxin-based MSA models (23). Intravenous administration of human mesenchymal stem cells (hMSCs) has also demonstrated prevention of the loss of neurons in the substantia nigra (SN) and the striatum by possibly modulating the inflammatory state in a double toxin-induced MSA-P model (36) and in the proteolipid protein promoter (PLP) α-synuclein (αSYN) MSA model (45).

Recently, many clinical studies have also proven that MSCs have a potential therapeutic value in MSA (12, 26–29,50,54). The preliminary results showed that cell-based treatment partially improved the neurological function and their quality of life in some degree for a period or kept the function stable in patients with MSA. In an open-label study design, 11 patients with MSA demonstrated a delay in the advance of neurological deficits following intra-arterial and intravenous MSC therapy compared to 18 nontreated MSA patients (26). In a randomized trial of intra-arterial and intravenous MSC therapy, 30 patients with probable MSA-C were randomly assigned to receive (4 × 10⁷ cells/injection) or placebo. The MSC group had a smaller increase in their functional scores compared with the placebo group, which showed greater worsening of frontal cognition (27). Intrathecal injection of four doses of 1 × 10⁶/kg umbilical cord mesenchymal stromal cells has also been shown to improve the symptoms of patients with spinocerebellar ataxia and MSA-C (12).

Possible Mechanisms of Action for Cell Therapy

Human OECs derived from fetal tissue have shown a remarkable ability to restore neurological functions in various types of disorders, such as spinal cord injury, stroke, peripheral nerve injury, optic nerve injury, amyotrophic lateral sclerosis, cognitive dysfunction, demyelinating diseases, Parkinson's disease, hearing loss, and retinopathy (17). They are a good source of growth factors and adhesion molecules that contribute toward neuronal support, enhancing cellular survival (22,38). Releasing neurotrophic factors can modify the local lesion environment, to promote neuron survival, and accelerate angiogenesis (4,5,18,47). OECs can support axonal regeneration and remyelination of demyelinated axons, and also prevent or reverse motor neuron apoptosis or neuron damage (3,31,34,59). In some cases, OEC transplantation into the brain's KPNNR can stimulate myelin repair, improve the local environment of transplantation sites, and promote spinal cord and brain function recovery (55).

Umbilical cord and bone marrow-derived (blood) mesenchymal cells also have been widely used to treat MSA and can improve patients' symptoms with regard to autonomic failure, balance, and motor movement (12,26–29,54). MSCs may work through the following mechanisms: releasing a variety of growth factors or stimulating the injury area to release endogenous factors, promoting the repair of injured tissue, and reducing cell apoptosis, differentiating into vascular endothelial cells and the extracellular matrix, protecting neurons and promoting angiogenesis (54), and modulating the neural inflammatory state in neurodegenerative disease, which may suppress the chronic inflammatory reaction (29). Umbilical cord blood MSC transplantation has also been shown to improve MSA patients' muscle strength, stiffness, tremor, and the cerebellum balance function, orthostatic hypotension, and urine control to varying degrees (54).

Neural progenitor cells (NPCs) are capable of generating new neurons, astrocytes, and oligodendrocytes. Transplantation of NPCs or their derivatives into a host brain or their proliferation and differentiation from endogenous stem cells by pharmacological manipulation are promising treatments for many neurodegenerative diseases and brain injuries (13). Under the influence of the local microenvironment, the cells differentiate into relevant cell types and secrete neurotrophic factors or protective factors, thereby inhibiting neurodegeneration and/or promoting neuroregeneration (48).

Schwann cells (SCs) play a pivotal role in the axon maintenance and regeneration in the peripheral nervous system (PNS) due to their ability to differentiate, migrate, proliferate, express growth-promoting factors, and myelinate regenerating axons (25). SCs also have been shown to form myelin after transplantation into the demyelinated CNS (2,53,60). Efforts are therefore focused on enhancing their migration and functional integration into the lesioned CNS (13).

Strategy of Comprehensive Neurorestoration

Normally, transplantation approaches are [1] intravascular implantation by artery or vein, [2] intrathecal implantation by lumbar puncture or cerebellar cistern puncture, and [3] intracerebral implantation by stereotactic techniques.

Commonly, a single kind of cell was administered by just one route. Combined cells or multiple routes may increase effect (9,32,33,43,58). Studies have suggested that a combination of therapies may enhance results and may be more effective than a single therapy. Combination therapies aim to create a neuroprotective environment, foster regeneration, and counter inhibitory factors released after CNS injury (40). These therapies could include neurotrophins and cell grafts (11,52), cotransplantation of different grafts (8,37,57), cell therapy with neurorehabilitation (18), or cell therapy with Laserponcture and neurorehabilitation (1).

Based on the studies and ideas summarized above, our team proposed the strategy of comprehensive neurorestoration; that is, multiple cell types by multiple routes acting via multiple processes (if necessary, cell therapy should be performed more than one time) and in combination with multiple method treatments, which include appropriate nerve–muscular stimulation, neurorestorative medicine or factors, and AMTENT. The aim of the strategy is to provide the maximum help to patients and provide the most effective neurorestoration by all currently known effective therapeutic methods, which are suitable for each individual patient's medical status.

After being transplanted into the KPNNR of the brain, the cells can initiate an extensive bidirectional remodeling in the entire neural network, including cerebrum, cerebellum, and spinal cord. Thus, the key point of cell transplantation should be of great importance in approaching the functional neurorestoration (4,6,17). This study also shows similar positive results as other kind of diseases treated by cell transplant into KPNNR.

Randomizing Double Blind Control Studies and Self-Comparison Studies

Randomizing double blind control studies are an important assessment method for most top clinical studies, but it is not the only gold standard for clinical study. Self-comparison is sometimes a better option for some special clinical conditions (14). Rama et al.'s clinical study with a self-comparison design marks the beginning of a new trend for clinical studies, and its importance has been emphasized (39). Its value is fully recognized and accepted for clinical studies of some incurable diseases, such as the heart, kidney, liver, and cornea transplant, and lesions that require surgical intervention. The use of a sham operation is questionable and ethically ambiguous as it inflicts unnecessary harm on the control patients (14).

Immunosuppression Application

We did not prescribe the immunosuppression drug for our patients because it is not clear whether immunosuppressive therapy is required following cell transplantation. Considering that most MSA patients are aged subjects, immunosuppressive therapy may be more harmful for them. However, more experience is required before any conclusions can be drawn.

In conclusion, the data of this study demonstrated that the strategy of comprehensive cell-based neurorestorative therapy seemed to be safe and provide benefit for patients with MSA. Further study is warranted to confirm this promising treatment.

Footnotes

Acknowledgment

The authors declare no conflict of interest.

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Preliminary Report of Multiple Cell Therapy for Patients with Multiple System Atrophy

Abstract

Keywords

Introduction

Materials and Methods

General Information

Cell Preparation

Cell Therapy

Outcome Measures

Statistical Analysis

Results

Discussion

Current Experimental and Clinical Studies of Cell Therapy for MSA

Possible Mechanisms of Action for Cell Therapy

Strategy of Comprehensive Neurorestoration

Randomizing Double Blind Control Studies and Self-Comparison Studies

Immunosuppression Application

Footnotes

Acknowledgment

References