Intravenous transplantation of bone marrow-derived mesenchymal stromal cells in patients with multiple sclerosis, a phase I/IIa, double blind, randomized controlled study.

Multiple sclerosis (MS) is a progressive, demyelinating neurodegenerative disease of the central nervous system. MS is immune-mediated and leads to disability especially in young adults. Even though 18 MS therapy drugs were approved, they slightly inhibit disease progression and do not induce regeneration and repair in the nervous system. Mesenchymal stromal cells (MSCs) have emerged as a new therapeutic modality in regenerative medicine and tissue engineering due to their immunomodulation and bio regenerative properties. We have designed a randomized, controlled clinical trial to assess safety and possible efficacy of MSC application in MS patients. Twenty-one MS patients were enrolled. Patients were allocated in two distinct groups: treatment group, which received systemic transplantation of autologous bone marrow-derived MSCs, and control group, which received placebo at the first injections. Patients in control group received MSCs at the second injection while the treatment group received placebo. All the patients were followed for 18 months. Follow-ups included regular visits, laboratory evaluation, and imaging analysis. Control patients received MSCs six month after treatment group. No severe immediate or late adverse events were observed in both groups after interventions. We did not find any significant differences in the rate of relapses, Expanded Disability Status Scale (EDSS) score, cognitive condition, Magnetic Resonance Imaging (MRI) findings, or any biomarkers of cerebrospinal fluid between the two groups and in each group before and after cell infusion. Transplantation of autologous bone marrow-derived mesenchymal stromal cells is safe and feasible. The efficacy of transplantation of these cells should be evaluated through designing randomized clinical trials with larger sample sizes, different administration routes, other cell types (allogeneic adipose derived MSCs, allogeneic Wharton's jelly derived MSCs …), repeated injections, and longer follow-up periods.

Safety and Efficacy of Allogeneic Adipose Tissue Mesenchymal Stromal Cells in Amyotrophic Lateral Sclerosis Patients, Single-Center, Prospective, Open-Label, Single-Arm Clinical Trial, Long-Term Follow-up.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with very limited treatment options. Stem cells have been raised as a new treatment modality for these patients. We have designed a single-center, prospective, open-label, and single arm clinical trial to assess the safety, feasibility, and rather efficacy of administrating allogeneic adipose-derived mesenchymal stromal cells (Ad-MSCs) in ALS patients. We enrolled 17 patients with confirmed ALS diagnosis with ALS Functional Rating Scale-Revised (ALSFRS-R) ≥24 and predicted forced vital capacity (FVC) ≥40%. Allogeneic Ad-MSCs were transplanted intravenously for all patients. Follow-ups were done at 24 hours, 2, 4, 6, and 12 months after cell infusion by checking adverse events, laboratory tests, and clinically by ALSFRS-R and FVC. Patients were also followed five years later and ALSFRS-R score was recorded in the survived individuals. There was no report of severe adverse events related to cell infusion. Two patients experienced dyspnea and chest pain 36 and 65 days after cell infusion due to pulmonary emboli. The progressive decrease in ALSFRS-R and FVC levels was recorded and three patients died in the first year. During five years follow up, despite a notable decrease in functional scores, 5 patients survived. Intravenous (IV) infusion of allogeneic Ad-MSCs in ALS patients is safe and feasible. The survival rate of the patients is more than IV autologous MSCs (Registration number: IRCT20080728001031N26).

Corrigendum: Knock-Down of the Phosphoserine Phosphatase Gene Effects Rather N- Than S-Metabolism in Arabidopsis thaliana.

[This corrects the article DOI: 10.3389/fpls.2018.01830.].

Stem cell therapy in Alzheimer's disease: possible benefits and limiting drawbacks.

Alzheimer's disease (AD) is the sixth leading cause of death globally and the main reason for dementia in elderly people. AD is a long-term and progressive neurodegenerative disorder that steadily worsens memory and communicating skills eventually leads to a disabled person of performing simple daily tasks. Unfortunately, numerous clinical trials exploring new therapeutic drugs have encountered disappointing outcomes in terms of improved cognitive performance since they are not capable of halting or stimulating the regeneration of already-damaged neural cells, and merely provide symptomatic relief. Therefore, a deeper understanding of the mechanism of action of stem cell may contribute to the development of novel and effective therapies. The revolutionary discovery of stem cells has cast a new hope for the development of disease-modifying treatments for AD, in terms of their potency in the replenishment of lost cells via differentiating towards specific lineages, stimulating in situ neurogenesis, and delivering the therapeutic agents to the brain. Herein, firstly, we explore the pathophysiology of AD. Next, we summarize the most recent preclinical stem cell reports designed for AD treatment, their benefits and outcomes according to cell type. We briefly review relevant clinical trials and their potential clinical applications in order to find a unique solution to effectively relieve the patients' pain.

The Photorespiratory BOU Gene Mutation Alters Sulfur Assimilation and Its Crosstalk With Carbon and Nitrogen Metabolism in Arabidopsis thaliana.

This study was aimed at elucidating the significance of photorespiratory serine (Ser) production for cysteine (Cys) biosynthesis. For this purpose, sulfur (S) metabolism and its crosstalk with nitrogen (N) and carbon (C) metabolism were analyzed in wildtype Arabidopsis and its photorespiratory bou-2 mutant with impaired glycine decarboxylase (GDC) activity. Foliar glycine and Ser contents were enhanced in the mutant at day and night. The high Ser levels in the mutant cannot be explained by transcript abundances of genes of the photorespiratory pathway or two alternative pathways of Ser biosynthesis. Despite enhanced foliar Ser, reduced GDC activity mediated a decline in sulfur flux into major sulfur pools in the mutant, as a result of deregulation of genes of sulfur reduction and assimilation. Still, foliar Cys and glutathione contents in the mutant were enhanced. The use of Cys for methionine and glucosinolates synthesis was reduced in the mutant. Reduced GDC activity in the mutant downregulated Calvin Cycle and nitrogen assimilation genes, upregulated key enzymes of glycolysis and the tricarboxylic acid (TCA) pathway and modified accumulation of sugars and TCA intermediates. Thus, photorespiratory Ser production can be replaced by other metabolic Ser sources, but this replacement deregulates the cross-talk between S, N, and C metabolism.

COMPARE CPM-RMI Trial: Intramyocardial Transplantation of Autologous Bone Marrow-Derived CD133+ Cells and MNCs during CABG in Patients with Recent MI: A Phase II/III, Multicenter, Placebo-Controlled, Randomized, Double-Blind Clinical Trial.

This article published in Cell J (Yakhteh), Vol 20, No 2, Jul-Sep 2018, on pages 267-277, four affiliations (1, 4, 5, and 10) were changed based on authors request.

COMPARE CPM-RMI Trial: Intramyocardial Transplantation of Autologous Bone Marrow-Derived CD133+ Cells and MNCs during CABG in Patients with Recent MI: A Phase II/III, Multicenter, Placebo-Controlled, Randomized, Double-Blind Clinical Trial.

OBJECTIVES: The regenerative potential of bone marrow-derived mononuclear cells (MNCs) and CD133+ stem cells in the heart varies in terms of their pro-angiogenic effects. This phase II/III, multicenter and double-blind trial is designed to compare the functional effects of intramyocardial autologous transplantation of both cell types and placebo in patients with recent myocardial infarction (RMI) post-coronary artery bypass graft. MATERIALS AND METHODS: This was a phase II/III, randomized, double-blind, placebo-controlled trial COMPARE CPM-RMI (CD133, Placebo, MNCs - recent myocardial infarction) conducted in accordance with the Declaration of Helsinki that assessed the safety and efficacy of CD133 and MNCs compared to placebo in patients with RMI. We randomly assigned 77 eligible RMI patients selected from 5 hospitals to receive CD133+ cells, MNC, or a placebo. Patients underwent gated single photon emission computed tomography assessments at 6 and 18 months post-intramyocardial transplantation. We tested the normally distributed efficacy outcomes with a mixed analysis of variance model that used the entire data set of baseline and between-group comparisons as well as within subject (time) and group×time interaction terms. RESULTS: There were no related serious adverse events reported. The intramyocardial transplantation of both cell types increased left ventricular ejection fraction by 9% [95% confidence intervals (CI): 2.14% to 15.78%, P=0.01] and improved decreased systolic wall thickening by -3.7 (95% CI: -7.07 to -0.42, P=0.03). The CD133 group showed significantly decreased non-viable segments by 75% (P=0.001) compared to the placebo and 60% (P=0.01) compared to the MNC group. We observed this improvement at both the 6- and 18-month time points. CONCLUSIONS: Intramyocardial injections of CD133+ cells or MNCs appeared to be safe and efficient with superiority of CD133+ cells for patients with RMI. Although the sample size precluded a definitive statement about clinical outcomes, these results have provided the basis for larger studies to confirm definitive evidence about the efficacy of these cell types (Registration Number: NCT01167751).

Knock-Down of the Phosphoserine Phosphatase Gene Effects Rather N- Than S-Metabolism in Arabidopsis thaliana.

The aim of present study was to elucidate the significance of the phosphorylated pathway of Ser production for Cys biosynthesis in leaves at day and night and upon cadmium (Cd) exposure. For this purpose, Arabidopsis wildtype plants as control and its psp mutant knocked-down in phosphoserine phosphatase (PSP) were used to test if (i) photorespiratory Ser is the dominant precursor of Cys synthesis in autotrophic tissue in the light, (ii) the phosphorylated pathway of Ser production can take over Ser biosynthesis in leaves at night, and (iii) Cd exposure stimulates Cys and glutathione (GSH) biosynthesis and effects the crosstalk of S and N metabolism, irrespective of the Ser source. Glycine (Gly) and Ser contents were not affected by reduction of the psp transcript level confirming that the photorespiratory pathway is the main route of Ser synthesis. The reduction of the PSP transcript level in the mutant did not affect day/night regulation of sulfur fluxes while day/night fluctuation of sulfur metabolite amounts were no longer observed, presumably due to slower turnover of sulfur metabolites in the mutant. Enhanced contents of non-protein thiols in both genotypes and of GSH only in the psp mutant were observed upon Cd treatment. Mutation of the phosphorylated pathway of Ser biosynthesis caused an accumulation of alanine, aspartate, lysine and a decrease of branched-chain amino acids. Knock-down of the PSP gene induced additional defense mechanisms against Cd toxicity that differ from those of WT plants.

Intravitreal Injection of Bone Marrow Mesenchymal Stem Cells in Patients with Advanced Retinitis Pigmentosa; a Safety Study.

PURPOSE: To examine the safety of a single intravitreal injection of autologous bone Marrow Mesenchymal stem cells (MSCs) in patients with advanced retinitis pigmentosa (RP). METHODS: A prospective, phase I, nonrandomized, open-label study was conducted on 3 eyes of 3 volunteers with advanced RP. Visual acuity, slit-lamp examination, fundus examination, optical coherence tomography, fundus auto-fluorescence, fluorescein angiography and multifocal electroretinography were performed before and after an intravitreal injection of approximately one-million MSCs. The patients were followed for one year. Further evaluation of MSCs was performed by injection of these cells into the mouse vitreous cavity. RESULTS: No, adverse events were observed in eyes of 2 out of 3 patients after transplantation of MSCs. These patients reported improvements in perception of the light after two weeks, which lasted for 3 months. However, severe fibrous tissue proliferation was observed in the vitreous cavity and retrolental space of the third patient's eye, which led to tractional retinal detachment (TRD), iris neovascularization and formation of mature cataract. Injection of this patient's MSCs into the vitreous cavity of mice also resulted in fibrosis; however, intravitreal injections of the two other patients' cells into the mouse vitreous did not generate any fibrous tissue. CONCLUSION: Intravitreal injection of autologous bone marrow MSCs into patients' eyes with advanced RP does not meet safety standards. Major side effects of this therapy can include fibrosis and TRD. We propose thorough evaluation of MSCs prior to transplantation by intravitreal injection in the laboratory animals.\.

Safety and Efficacy of Repeated Bone Marrow Mononuclear Cell Therapy in Patients with Critical Limb Ischemia in a Pilot Randomized Controlled Trial.

BACKGROUND: Critical limb ischemia is a manifestation of peripheral arterial disease characterized by insufficient arterial blood flow for maintaining tissue viability in the lower extremities. Therapeutic angiogenesis is used for peripheral arterial disease patients who are not candidates for surgical revascularization or radiological intervention. There is accumulating evidence for the beneficial impact of autologous bone marrow mononuclear cell transplantation for treatment of critical limb ischemia in humans. This study aims to investigate the safety and efficacy of repeated bone marrow mononuclear cell injections in comparison with a single bone marrow mononuclear cell injection in critical limb ischemia patients. METHODS: Patients with critical limb ischemia (n = 22) were randomized (http://clinicaltrials.gov/ct2 show/NCT01480414) to receive either a single (n = 11) or four (n = 11) intramuscular injections of bone marrow mononuclear cells as a cell therapy product. RESULTS: There were no reported adverse events during the 24-week follow-up period after cell delivery. Efficacy assessment indicated that after cell injections, there was significant improvement in Ankle-Brachial Index, Visual Analog Scale, pain-free walking distance, and Wagner stage as well as reduction in ulcer size. There was no significant difference between the two groups in terms of clinical parameters. However, by the 24th week the pain-free walking distance improved significantly in the group who received four injections of cells. CONCLUSION: Favorable clinical outcomes strongly indicate the long-term benefit of bone marrow mononuclear cell transplantation, either as one or several injections, for retrieval from critical limb ischemia. Repeated cell injections have shown increased improvement of pain-free walking distance in patients. These findings warrant further exploration in later-phase clinical trials with repeated injections.

Intrathecal injection of CD133-positive enriched bone marrow progenitor cells in children with cerebral palsy: feasibility and safety.

BACKGROUND AIMS: Recent studies have proposed that cellular transplantation may have some regenerative and functional efficacy in the treatment of cerebral palsy (CP); however, much remains to be understood regarding its safety, feasibility and efficacy. This study was initiated to evaluate the safety of autologous bone marrow-derived CD133(+) cell intrathecal injection. METHODS: Children (n = 12), aged 4 to 12 years, who were diagnosed with different types of CP underwent BM aspiration. CD133(+) cells were enriched from the BM samples and intrathecally injected. The Gross Motor Function Measure (GMFM-66), Gross Motor Function Classification System (GMFCS), UK FIM+FAM, Functional Independence Measure (FIM) and Functional Assessment Measure (FAM) were assessed at baseline and 6 months after the procedure. Patients' ability to balance was measured by the Berg Balance Scale (BBS), and severity of spasticity was evaluated by the Modified Ashworth Scale. Magnetic resonance imaging was done at baseline and 6 months after therapy. This study was registered in ClinicalTrials.gov (NCT01404663). RESULTS: There were no adverse events detected by clinical and laboratory tests or imaging studies, with the exception of a seizure in 1 patient. A significant improvement was observed 6 months after cell transplantation versus baseline according to GMFM, GMFCS, FIM+FAM, Ashworth Scale, and BBS outcomes. CONCLUSIONS: Subarachnoid injection of CD133-positive enriched bone marrow progenitor cells in children with CP is a safe approach. The results suggest a possible short-term improvement in neurological function.