Human Umbilical Cord-Derived Mesenchymal Stem Cells in the Treatment of Multiple Sclerosis Patients: Phase I/II Dose-Finding Clinical Study.

Multiple sclerosis (MS) is a chronic neuro-inflammatory disease resulting in disabilities that negatively impact patients' life quality. While current treatment options do not reverse the course of the disease, treatment using mesenchymal stromal/stem cells (MSC) is promising. There has yet to be a consensus on the type and dose of MSC to be used in MS. This work aims to study the safety and efficacy of two treatment protocols of MSCs derived from the umbilical cord (UC-MSCs) and their secretome. The study included two groups of MS patients; Group A received two intrathecal doses of UC-MSCs, and Group B received a single dose. Both groups received UC-MSCs conditioned media 3 months post-treatment. Adverse events in the form of a clinical checklist and extensive laboratory tests were performed. Whole transcriptome analysis was performed on patients' cells at baseline and post-treatment. Results showed that all patients tolerated the cellular therapy without serious adverse events. The general disability scale improved significantly in both groups at 6 months post-treatment. Examining specific aspects of the disease revealed more parameters that improved in Group A compared to Group B patients, including a significant increase in the (CD3+CD4+) expressing lymphocytes at 12 months post-treatment. In addition, better outcomes were noted regarding lesion load, cortical thickness, manual dexterity, and information processing speed. Both protocols impacted the transcriptome of treated participants with genes, transcription factors, and microRNAs (miRNAs) differentially expressed compared to baseline. Inflammation-related and antigen-presenting (HLA-B) genes were downregulated in both groups. In contrast, TNF-alpha, TAP-1, and miR142 were downregulated only in Group A. The data presented indicate that both protocols are safe. Furthermore, it suggests that administering two doses of stem cells can be more beneficial to MS patients. Larger multisite studies should be initiated to further examine similar or higher doses of MSCs.

Safe Reversal of Motor and Sensory Deficits by Repeated High Doses of Mesenchymal Stem Cells in a Patient with Chronic Complete Spinal Cord Injury.

BACKGROUND Spinal cord injuries (SCI) resulting from various types of accidents have a known onset, unlike other progressive neurological diseases. Nonetheless, in most cases, the resulting disability permanently affects the individual's quality of life due to the limited outcome of available treatment options. The neurological deficit associated with SCI results from primary injury induced by the physical trauma and secondary injury involving inflammation, spinal tissue degeneration, and scar formation. Stem cells of different origins and using different treatment protocols have been tried to minimize aspects of secondary injury in the spinal cord. CASE REPORT In this case report, we evaluated the safety and efficacy of intrathecal injections of Wharton's Jelly-derived mesenchymal stem cells (WJ-MSCs) in a patient with chronic traumatic complete SCI. The findings indicated that the treatment was safe with no serious adverse events related to the procedure or administration of stem cells. The long-term follow-up period showed sustained sensory and motor function improvements with enhanced quality of life scores. CONCLUSIONS The results imply a potential role of WJ-MSC in the treatment of chronic and severe SCI. As indicated by previous studies, the mechanism of action points mainly to the ability of MSCs to protect the neural elements that survived the initial mechanical insult by modulating the immune response and promoting neuronal regeneration.

Ultrasound-guided intra-articular injection of expanded umbilical cord mesenchymal stem cells in knee osteoarthritis: a safety/efficacy study with MRI data.

Aim: This study has the primary objective of studying the effect of Wharton jelly mesenchymal stem cells (WJMSCs) in the treatment of knee osteoarthritis. As a secondary end point, we report on the efficacy of such therapy. Patients and methods: 16 patients with advanced Kellgren stage were treated using two doses of expanded WJMSCs given 1 month apart. Patients were followed for 48 months using the Knee Injury and Osteoarthritis Outcome Score (KOOS) and 12 months using magnetic resonance imaging (MRI). Results: Treatment was well tolerated. One patient developed moderate effusion and one superficial phlebitis. We observed functional and pain improvement at 12 and 48 months (p < 0.0001), with statistically significant improvement on MRI scans at 12 months in cartilage loss, osteophytes, bone marrow lesions, effusion and synovitis (p < 0.01), and highly significant improvement in subchondral sclerosis (p < 0.0001). Conclusion: WJMSCs are safe and potentially effective in producing significant improvement in KOOS and MRI scores when administered intra-articularly in knee osteoarthritis cases under ultrasound guidance.

Safety and Efficacy of 2 Intracavernous Injections of Allogeneic Wharton's Jelly-Derived Mesenchymal Stem Cells in Diabetic Patients with Erectile Dysfunction: Phase 1/2 Clinical Trial.

BACKGROUND AND OBJECTIVES: Stem cell therapy is a novel treatment with regenerative ability that can treat erectile dysfunction (ED). This phase 1/2 clinical trial (NCT02945449) using 2 consecutive intracavernous (IC) injections of allogeneic Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) was studied for the first time in the treatment of diabetic patients with ED. The primary outcome was to assess the safety and tolerability, and the secondary outcome was to assess the efficacy of 2 consecutive IC injections of allogeneic WJ-MSCs in diabetic ED. PATIENTS AND METHODS: Twenty-two diabetic patients with refractory ED were included. Two consecutive IC injections of allogeneic WJ-MSCs were performed. Tolerability was assessed immediately, and at 24 h, safety was evaluated for 12 months. Efficacy was assessed using International Index of Erectile Function-5 (IIEF-5), Erection Hardness Score (EHS), and Color Duplex Doppler Ultrasound for 12 months. RESULTS: The procedure was well-tolerated. Minimal and transient adverse events were redness and bruising at the site of injections. There were no patient-reported serious adverse effects. There were significant improvements in IIEF-5, EHS, peak systolic velocity (PSV) basal, and 20-min PSV, all over the follow-up time points in comparison to the baseline. CONCLUSION: This is the first human study with proven tolerability, safety, and efficacy of IC injections of allogeneic WJ-MSCs for the treatment of diabetic patients with ED.

An insight into the whole transcriptome profile of four tissue-specific human mesenchymal stem cells.

Aim: Variations in the clinical outcomes using mesenchymal stem cells (MSCs) treatments exist, reflecting different origins and niches. To date, there is no consensus on the best source of MSCs most suitable to treat a specific disease. Methods: Total transcriptome analysis of human MSCs was performed. MSCs were isolated from two adult sources bone marrow, adipose tissue and two perinatal sources umbilical cord and placenta. Results: Each MSCs type possessed a unique expression pattern that reflects an advantage in terms of their potential therapeutic use. Advantages in immune modulation, neurogenesis and other aspects were found. Discussion: This study is a milestone for evidence-based choice of the type of MSCs used in the treatment of diseases.

Intra-articular injection of expanded autologous bone marrow mesenchymal cells in moderate and severe knee osteoarthritis is safe: a phase I/II study.

BACKGROUND: Knee osteoarthritis (KOA) is a major health problem especially in the aging population. There is a need for safe treatment that restores the cartilage and reduces the symptoms. The use of stem cells is emerging as a possible option for the moderate and severe cases. This study aimed at testing the safety of autologous bone marrow mesenchymal stem cells (BM-MSCs) expanded in vitro when given intra-articularly to patients with stage II and III KOA. As a secondary end point, the study tested the ability of these cells to relieve symptoms and restore the knee cartilage in these patients as judged by normalized knee injury and Osteoarthritis Outcome Score (KOOS) and by magnetic resonance imaging (MRI). METHODS: Thirteen patients with a mean age of 50 years suffering from KOA stages II and III were given two doses of BM-MSCs 1 month apart totaling 61 × 106 ± 0.6 × 106 by intra-articular injection in a phase I prospective clinical trial. Each patient was followed for a minimum of 24 months for any adverse events and for clinical outcome using normalized KOOS. Cartilage thickness was assessed by quantitative MRI T2 at 12 months of follow-up. RESULTS: No severe adverse events were reported up to 24 months follow-up. Normalized KOOS improved significantly. Mean knee cartilage thickness measured by MRI improved significantly. CONCLUSION: BM-MSCs given intra-articularly are safe in knee osteoarthrosis. Despite the limited number of patients in this study, the procedure described significantly improved the KOOS and knee cartilage thickness, indicating that they may enhance the functional outcome as well as the structural component. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02118519.