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CASE REPORT
Use of Multiple Wharton Jelly Mesenchymal Stem Cell Transplants in Treatment of Incomplete Spinal Cord Injury: A Case Report

Interruption of spinal cord continuity remains an incurable condition that leads to functional loss below the lesion level. Effective treatment to enable spinal cord regeneration is lacking, although cell therapy is an evolving opportunity. Therefore, the purpose of this study was to evaluate the safety and potential efficacy of multiple Wharton jelly mesenchymal stem cell transplants in a patient with a spinal cord injury. A patient with incomplete spinal cord interruption at the T11 to T12 vertebrae was enrolled in experimental therapy. The patient scored A/B on the ASIA scale (developed by the American Spinal Injury Association) with deep paraparesis and sphincter palsy. However, full ability to fix the patient’s trunk upon admission was confirmed. Bilateral axonal damage of motor and sensory neural fibers of lower extremities was confirmed with electromyography and electroneurography. One year of standard therapy did not bring any positive results. The patient underwent 5 rounds of Wharton jelly mesenchymal stem cell transplants every 3 months (total treatment time of 18 months). There were no complications connected with therapy during the 18-month follow-up. Continuous neurological and quality of life improvements were seen after every transplant. The patient’s ASIA score changed from A/B to C/D and from 112 to 231 points. The sensation level decreased from the T12 to L3 to L4 level. The patient regained bladder control and anal sensation. Muscle strength at the left lower extremity improved. The patient gained the ability to stand in a standing frame and walk with an orthosis. Neurophysiological examinations objectively confirmed the improvement. Magnetic resonance imaging demonstrated no changes in the spinal cord signal. The treatment demonstrated an objective improvement that could be used for patients with chronic thoracic incomplete spinal cord injury.


Key words : Experimental therapy, Interruption of the spinal cord, Neuroregenerative process

Introduction

Effective treatment of a damaged spinal cord remains beyond modern medicine’s capabilities, despite significant progress in neurosurgery and the increasing knowledge of biological mechanisms responsible for damage and subsequent regeneration of the spinal cord.1 One of the new therapeutic approaches proposed is the use of stem cells, whose capabilities allow them to form complex tissues and organs and maintain their functions during an individual’s life.2 Recently, numerous clinical trials have investigated different cell types, including mesenchymal stem cells (MSCs).3 The most important properties of MSCs include the ability to differentiate into numerous effector cells, the ability to immunomodulate the immune cells, and the ability to secrete several growth factors and cytokines, including factors stimulating neurogenesis and related processes.4,5 Experiments carried out on animal models have shown that, through pleiotropic interactions with neurons and immune cells, MSCs can induce regeneration of damaged nervous tissue.6 Pilot clinical studies have demonstrated their positive potential and safety in patients with neurological7 and other disorders.8 Mesenchymal stem cells can be used as allogeneic cells because they are not easily recognized by the immune system.4

Case Report

A 27-year-old man with incomplete spinal cord injury underwent an experimental trial with Wharton jelly MSCs (WJMSCs). The man fell from a roof, which resulted in a vertebral fracture at the T11 to T12 level. Standard therapy for 1 year, which included stabilization of the destroyed region, anti-inflammatory treatment, and neurorehabilitation, brought slight neurological improvements. However, the man still presented deep paresis with sensory level at T12. The patient had a magnetic resonance imaging (MRI) scan before treatment that revealed malacia of the spine at T12 and reduction of its wedge at the T11 level (Figure 1, top).

The study was carried out at the Regenmed Hospital (Cracow, Poland) and was approved by the Bioethical Committee of the Andrzej Frycz Modrzewski Cracow University. The patient provided informed consent.

Product transplant procedure
Isolation, expansion, and final preparation of WJMSCs were carried out according to Good Manufacturing Practice rules, and the final product was treated as a hospital exemption-advanced therapy medicinal product.

The treatment was composed of 5 rounds of WJMSCs (3 × 107), administered via lumbar punc-ture every 3 months (total treatment time of 18 months). The patient benefited from intensive neurorehabilitation with each WJMSC transplant.

Pretreatment and follow-up efficacy assessments
Pretreatment and follow-up neurological examina-tions were performed according to the American Spinal Injury Association Impairment (ASIA) scale and the Frankel grading system. Sensory deficits were assessed using dermatome sensory maps. The Ashworth scale was used to evaluate posttraumatic spasticity, and the Lovett scale (graded on a scale of 0 to 5) was used to assess muscle strength. We evaluated sphincter function based on the patient’s declaration. We used neurophysiological tests (electromyography and electronystagmography) to test peripheral conductivity and the motor-evoked potentials method to test conductivity from cortex and spine to motor units. The patient underwent MRIs to assess changes in the structure of the spinal cord.

Criteria used to measure the safety of the transplant procedure included presentation of infection, fever, pain, and headache; increased levels of C-reactive protein and leukocytosis; allergic reaction shock; and perioperative complications. Criteria used to measure the safety of therapy included cancer development, deterioration of the neurological state, appearance of neuropathic pain, secondary infections, urinary tract infections, and pressure ulcers.

Results

We observed no adverse events in the patient associated with the transplant procedures or the therapy strategy during the 18-month follow-up. A slightly increased body temperature (38 °C) was observed after each implantation. We did not observe any late complications in the follow-up period.

The patient received 5 rounds of WJMSCs with a total amount of 15 × 107 stem cells. With each implantation, 3 × 107 stem cells were administrated via lumbar puncture to the cerebrospinal fluid.

During the 18 months of follow-up, the patient demonstrated continuous neurological improvement. The first improvement appeared after the first administration and included a sensation level that decreased to L1. After the second administration, the sensation level decreased to L2 and then to L3/L4 after the fifth treatment. The first implantation also brought motor function. The muscle strength in thighs slightly increased (1 to 1+) on both sides, and muscle tense of the left gastrocnemius appeared. After the second administration, muscle strength increased (1+ to 2), especially in both thighs and knees. The patient developed the ability to stand in a standing frame and started to walk short distances using a high orthosis and with full support from a second person. After the third administration, muscle strength increased in the hips and thighs (2 to 3), and the patient gained the ability to walk supported in a hip orthosis for short distances. The deep paresis changed to a paresis in the left lower extremities (2/5 according to Lovett scale).

The fourth administration led to further increased strength in the hips and thighs (3 to 3+), and knee strength appeared in his left extremities. The man could walk with a standing frame for short distances of 3 to 4 meters. After the fifth administration, the man could walk for 5 to 10 meters using a knee orthosis or a standing frame and for 2 meters independently. The ASIA score changed from A to B after the second administration and to C at the end of the experimental treatment (Table 1 and Table 2).

After the second administration , the patient’s bladder function started to improve. He could control the bladder sphincter and stop using the Foley catheter. After the fourth administration, the patient had complete control of the bladder and stated that he had anal sensation. Improvements in deep sensation perception, which helps with feeling the interstice movement, appeared after the third administration (Table 1).

An MRI performed after the 18 months of treatment demonstrated no significant changes in the signal (Figure 1, bottom). Vertebral stabilization with transpedicular screws performed after treatment has been maintained (Figure 2). Electrophysiological tests conducted after therapy revealed slight neurophysiological improvement. Somatosensory-evoked potential tests showed restoration of normal potential down to L3 level. Motor-evoked potential tests demonstrated restoration of normal abdominal muscle activity, normal activity of both quadriceps and thigh adductor muscles, and partial function of muscle activity in the right peroneus and left tibialis muscles. In the lower extremities, we observed restoration of normal conductivity of tibialis anterior and peroneus longus nerves in both legs. Efferent conductivity from the cortex to the abdominal and lower extremities muscles was regenerated.

Discussion

Wharton jelly mesenchymal stem cells have good immunomodulating potential and produce many factors, including neurogenesis-stimulating factors.9,10 Studies on the use of WJMSCs in animal models, as well as in clinical trials, have shown that WJMSCs are safe.11 A range of neurological improvements has been reported, with more significant improvement usually observed in patients with recent spinal cord injury (from 1 to 6 months) rather than in patients with long-term trauma (>6 months).12

Our study showed considerable and continuous neurological and quality of life improvements, which were confirmed by objective MRI, somatosensory-evoked potential tests, motor-evoked potential tests, electromyography, and electronystagmography. Recovery of bladder and anal sensations and the patient’s ability to control indicated sequential regeneration of the antidromic and orthodromic conductivity of nerve routs responsible for innervation of the urogenital area. The denervation process was stopped and reversed.

Considerable improvement (from ASIA scale classification of A to ASIA scale classification of D) has been demonstrated using combined cord blood CD34+ and multiple WJMSCs implantations.13 Thus, our data are in line with previous reports.

Available data and our results seem to indicate the usefulness of a multi-implantation approach combined with intense neurorehabilitation to maximize cell therapy treatment efficacy.12,14

Motor rehabilitation is the main treatment method for patients after incomplete spinal cord injury apart from surgical treatment.15 Rehabilitation treatments should start as soon as possible to use the plasticity of the central nervous system. However, the process is usually long and difficult and does not always yield expected results. Therefore, the use of stem cells that can activate neuroregenerative processes in parallel with motor neurorehabilitation may be more effective than the use of rehabilitation alone. At the same time, it should be noted that the use of stem cell therapy alone, without motor rehabilitation, may not allow measurable clinical effects of the experimental therapy to be obtained.15

Limitations
We are aware that this case study needs confirmation in a larger group of patients.

Conclusions

We found that the use of multiple WJMSC transplants was safe and feasible in a patient with incomplete spinal cord injury. The results demonstrated the possibility to obtain considerable continuous neuro-logical and quality of life improvements in patients with such injuries.


References:


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DOI : 10.6002/ect.2021.0283


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From the 1Department of Children’s Neurosurgery, Jagiellonian University Medical College, Faculty of Medicine, Institute of Pediatrics; the 2Department of Laboratory Medicine, Andrzej Frycz – Modrzewski Cracow University; the 3RegenMed Limited Liability Company; and the 4Department of Transplantation, Jagiellonian University Medical College, Faculty of Medicine, Cracow, Poland
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Corresponding author: Olga Milczarek, Department of Children’s Neurosurgery, Jagiellonian University School of Medicine, Wielicka 265, 30-663 Cracow, Poland
E-mail: olga.milczarek@uj.edu.pl

Experimental and Clinical Transplantation (2022)