Clinical Efficacy of Stem Cell Therapy for Diabetes Mellitus: A Meta-Analysis

BackgroundStem cell therapy is a promising therapeutic modality for advanced diabetes mellitus (DM). This study presents a meta-analysis of relevant clinical trials to determine the efficacy of stem cell therapy in DM. We aim to critically evaluate and synthesize clinical evidence on the safety and efficiency of different types of stem cell therapy for both T1DM and T2DM.ConclusionsStem cell transplantation can represent a safe and effective treatment for selected patients with DM. In this cohort of trials, the best therapeutic outcome was achieved with CD34⁺ HSC therapy for T1DM, while the poorest outcome was observed with HUCB for T1DM. Diabetic ketoacidosis impedes therapeutic efficacy.     

Functional recovery after transplantation of bone marrow-derived human mesenchymal stromal cells in a rat model of spinal cord injury

Background aimsSpinal cord injury (SCI) is a medically untreatable condition for which stem cells have created hope. Pre-clinical and clinical studies have established that these cells are safe for transplantation. The dose dependency, survivability, route of administration, cell migration to injury site and effect on sensory and motor behavior in an SCI-induced paraplegic model were studied.MethodsA spinal cord contusion injury model was established in rats. Bone marrow (BM) mesenchymal stromal cells (MSC) were tagged to facilitate tracing in vivo. Two different doses (2 and 5 million cells/kg body weight) and two different routes of infusion (site of injury and lumbar puncture) were tested during and after the spinal shock period. The animals were tested post-transplantation for locomotor capacity, motor control, sensory reflex, posture and body position. Stem cell migration was observed 1 month post-transplantation in spinal cord sections.ResultsThe overall results demonstrated that transplantation of BM MSC significantly improved the locomotor and sensory behavior score in the experimental group compared with the sham control group, and these results were dose dependent. All the infused stem cells could be visualized at the site of injury and none was visualized at the injected site. This indicated that the cells had survived in vivo, were probably chemoattracted and had migrated to the lesion site.ConclusionsMSC transplanted with a lumbar puncture method migrate to the site of injury and are the most suitable for SCI healing. These cells demonstrate a dose-dependent effect and promote functional recovery when injected during or after the spinal shock period.     

Bone marrow-derived inducible microglia-like cells ameliorate motor function and survival in a mouse model of amyotrophic lateral sclerosis

Background aimsAmyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease. Neuroinflammation in the spinal cord plays a pivotal role in the pathogenesis of ALS, and microglia are involved in neuroinflammation. Microglia mainly have two opposite phenotypes involving cytotoxic and neuroprotective properties, and neuroprotective microglia are expected to be a novel application for the treatment of ALS. Therefore, to establish a clinically applicable therapeutic method using neuroprotective microglia, the authors investigated the effect of inducing neuroprotective microglia-like cells from bone marrow for transplantation into ALS model mice.MethodsBone marrow-derived mononuclear cells were isolated from green fluorescent protein mice and cultured using different protocols of cytokine treatment with granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-4. Cells with a high potency of proliferation and differentiation into microglia were evaluated by gene analysis, flow cytometry and direct neuroprotective effects in vitro. These cells were named bone marrow-derived inducible microglia-like (BM-iMG) cells and transplanted into the spinal cords of ALS model mice, and behavioral tests, immunohistochemistry and gene expression profiling were performed.ResultsThree-day GM-CSF and 4-day GM-CSF + IL-4 stimulations were most effective in inducing BM-iMG cells from the bone marrow. Transplantation of BM-iMG cells improved motor function, prolonged survival and suppressed neuronal cell death, astrogliosis and microgliosis in the spinal cords of ALS mice. Moreover, neuroprotective genes such as Arg1 and Mrc1 were upregulated, whereas pro-inflammatory genes such as Nos2 and Il6 were downregulated.ConclusionsIntraspinal transplantation of BM-iMG cells demonstrated therapeutic effects in a mouse model of ALS. Further studies and clinical applications in patients with ALS are expected in the future.     

Pre-Transplantation Serum Parathyroid Hormone Influences the Number of Mobilized CD34+ Hematopoietic Stem Cells in Autologous Hematopoietic Stem Cell Transplantation

Background:Parathyroid hormone (PTH) is a calcium homeostasis regulator and can affect bone marrow niche. PTH leads to the bone marrow stem cell niche expansion as well as the induction of stem cell mobilization from the bone marrow into peripheral blood. In this study, we evaluated the association between pre- transplantation serum PTH levels and the number of circulating CD34+ cells along with the platelets/white blood cells (Plt/WBC) engraftment in patients who underwent autologous Hematopoietic Stem Cell Transplantation.Methods:Subjects for the study were 100 patients who received autologous hematopoietic stem cell transplantation (auto-HSCT), retrospectively. Serum levels of PTH, calcium, phosphorus, and alkaline phosphatase were measured before mobilization. Their impacts were measured on the number of mobilized CD34+ hematopoietic stem cells, and Plt/WBC engraftment.Results:High levels of serum PTH (> 63.10 pg/mL) was significantly associated with higher number of CD34+ cells in peripheral blood after granulocyte- colony stimulating factor (G-CSF)-induced mobilization (p= 0.079*). Serum calcium at low levels were associated with higher number of circulating CD34+ cells post mobilization. Pre- transplantation serum levels of phosphorus and alkaline phosphatase on CD34+ numbers were not statistically significant. Serum Plt/WBC engraftment was not improved in presence of high levels of serum PTH.Conclusion:We suggested that serum PTH levels before transplantation could be influential in raising the number of circulating CD34+ hematopoietic stem cell after mobilization.Key Words: Auto-HSCT, CD34+ Cell, Pre- transplant PTH     

干细胞在妇产科若干疾病中研究及应用

干细胞是一类具有自我更新和增殖分化能力的细胞,按其发育阶段可分为胚胎干细胞(embryonic stem cell,ESC)和成体干细胞(adult stem cell,ASC)。由于干细胞这种特殊的增殖分化潜能,使其具备着多学科临床治疗的可塑性,研究意义巨大。随着子宫内膜干细胞的发现以及对其他类型干细胞提取手段的进步,干细胞为治疗子宫内膜相关性疾病带来了全新的思路。此外,宫内干细胞移植治疗胎儿疾病,干细胞介导损伤后血管内皮的修复以及改善生育功能、治疗不孕症等几个领域的研究也取得了显著的成果。本文参考近7年国内外文献,以干细胞治疗妇产科几种常见疾病的最新研究进展为主要内容进行综述。     

Motor neuronal protection by l-arginine prolongs survival of mutant SOD1 (G93A) ALS mice

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive paralysis due to motor neuron degeneration. Despite the fact that many different therapeutic strategies have been applied to prevent disease progression, no cure or effective therapy is currently available for ALS. We found that l-arginine protects cultured motor neurons from excitotoxic injury. We also found that l-arginine supplementation both prior to and after the onset of motor neuron degeneration in mtSOD1 (G93A) transgenic ALS mice significantly slowed the progression of neuropathology in lumbar spinal cord, delayed onset of motor dysfunction, and prolonged life span. Moreover, l-arginine treatment was associated with preservation of arginase I activity and neuroprotective polyamines in spinal cord motor neurons. Our findings show that l-arginine has potent in vitro and in vivo neuroprotective properties and may be a candidate for therapeutic trials in ALS.     

Human Motor Neurons Generated from Neural Stem Cells Delay Clinical Onset and Prolong Life in ALS Mouse Model

Amyotrophic lateral sclerosis (ALS) is the most common adult onset motor neuron disease. The etiology and pathogenic mechanisms of the disease remain unknown, and there is no effective treatment. Here we show that intrathecal transplantation of human motor neurons derived from neural stem cells (NSCs) in spinal cord of the SOD1G93A mouse ALS model delayed disease onset and extended life span of the animals. When HB1.F3.Olig2 (F3.Olig2) cells, stable immortalized human NSCs encoding the human Olig2 gene, were treated with sonic hedgehog (Shh) protein for 5–7 days, the cells expressed motor neuron cell type-specific phenotypes Hb9, Isl-1 and choline acetyltransferase (ChAT). These F3.Olig2-Shh human motor neurons were transplanted intrathecally in L5–L6 spinal cord of SOD1G93A mice, and at 4 weeks post-transplantation, transplanted F3.Olig2-Shh motor neurons expressing the neuronal phenotype markers NF, MAP2, Hb9, and ChAT were found in the ventral horn of the spinal cord. Onset of clinical signs in ALS mice with F3.Olig2-Shh motor neuron implants was delayed for 7 days and life span of animals was significantly extended by 20 days. Our results indicate that this treatment modality of intrathecal transplantation of human motor neurons derived from NSCs might be of value in the treatment of ALS patients without significant adverse effects.     

Human Glial-Restricted Progenitor Transplantation into Cervical Spinal Cord of the SOD1G93A Mouse Model of ALS

Cellular abnormalities are not limited to motor neurons in amyotrophic lateral sclerosis (ALS). There are numerous observations of astrocyte dysfunction in both humans with ALS and in SOD1^G93A rodents, a widely studied ALS model. The present study therapeutically targeted astrocyte replacement in this model via transplantation of human Glial-Restricted Progenitors (hGRPs), lineage-restricted progenitors derived from human fetal neural tissue. Our previous findings demonstrated that transplantation of rodent-derived GRPs into cervical spinal cord ventral gray matter (in order to target therapy to diaphragmatic function) resulted in therapeutic efficacy in the SOD1^G93A rat. Those findings demonstrated the feasibility and efficacy of transplantation-based astrocyte replacement for ALS, and also show that targeted multi-segmental cell delivery to cervical spinal cord is a promising therapeutic strategy, particularly because of its relevance to addressing respiratory compromise associated with ALS. The present study investigated the safety and in vivo survival, distribution, differentiation, and potential efficacy of hGRPs in the SOD1^G93A mouse. hGRP transplants robustly survived and migrated in both gray and white matter and differentiated into astrocytes in SOD1^G93A mice spinal cord, despite ongoing disease progression. However, cervical spinal cord transplants did not result in motor neuron protection or any therapeutic benefits on functional outcome measures. This study provides an in vivo characterization of this glial progenitor cell and provides a foundation for understanding their capacity for survival, integration within host tissues, differentiation into glial subtypes, migration, and lack of toxicity or tumor formation.     

The role of d-amino acids in amyotrophic lateral sclerosis pathogenesis: a review

A potential role for d-amino acids in motor neuron disease/amyotrophic lateral sclerosis (ALS) is emerging. d-Serine, which is an activator/co-agonist at the N-methyl-d-aspartate glutamate receptor subtype, is elevated both in spinal cord from sporadic cases of ALS and in an animal model of ALS. Furthermore, we have shown that a mutation in d-amino acid oxidase (DAO), an enzyme strongly localized to spinal cord motor neurons and brain stem motor nuclei, is associated with familial ALS. DAO plays an important role in regulating levels of d-serine, and its function is impaired by the presence of this mutation and this may contribute to the pathogenic process in ALS. In sporadic ALS cases, elevated d-serine may arise from induction of serine racemase, its synthetic enzyme, caused by cell stress and inflammatory processes thought to contribute to disease progression. Both these abnormalities in d-serine metabolism lead to an increase in synaptic d-serine which may contribute to disease pathogenesis.     

Mesenchymal stromal cell transplantation in amyotrophic lateral sclerosis: a long-term safety study

Background aimsMesenchymal stem cells/marrow stromal cells (MSC) represent a promising tool for stem cell-based clinical trials in amyotrophic lateral sclerosis (ALS). We present the results of long-term monitoring of 19 ALS patients enrolled in two phase I clinical trials of autologous MSC transplantationMethodsNineteen patients (11 male and eightfemale) with ALS were enrolled in two consecutive phase I clinical trials. The patients were followed-up for 6–9 months and then treated with autologous MSC isolated from bone marrow and implanted into the dorsal spinal cord with a surgical procedure. The patients were monitored regularly before and after transplantation with clinical, psychological and neuroradiologic assessments every 3 months, at the tertiary referral ALS center in Novara (Italy), until deathResultsFollow-up brain magnetic resonance imaging (MRI) revealed no structural changes (including tumor formation) relative to the baseline throughout the follow-up. There was no deterioration in the psychosocial status and all patients coped well. No clear clinical benefits were detected in these patients but the recruitment and selection of appropriate patients into larger trials will be needed to test the efficacy of the treatmentConclusionsThis study is the first to show the safety of MSC transplantation in the central nervous system during a follow-up of nearly 9 years, and is in support of applying MSC-based cellular clinical trials to neurodegenerative disorders.     

Molecular Chaperone Mediated Late-Stage Neuroprotection in the SOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective loss of motor neurons in the spinal cord, brain stem, and motor cortex. Mutations in superoxide dismutase (SOD1) are associated with familial ALS and lead to SOD1 protein misfolding and aggregation. Here we show that the molecular chaperone, HSJ1 (DNAJB2), mutations in which cause distal hereditary motor neuropathy, can reduce mutant SOD1 aggregation and improve motor neuron survival in mutant SOD1 models of ALS. Overexpression of human HSJ1a (hHSJ1a) in vivo in motor neurons of SOD1^G93A transgenic mice ameliorated disease. In particular, there was a significant improvement in muscle force, increased motor unit number and enhanced motor neuron survival. hHSJ1a was present in a complex with SOD1^G93A and led to reduced SOD1 aggregation at late stages of disease progression. We also observed altered ubiquitin immunoreactivity in the double transgenic animals, suggesting that ubiquitin modification might be important for the observed improvements. In a cell model of SOD1^G93A aggregation, HSJ1a preferentially bound to mutant SOD1, enhanced SOD1 ubiquitylation and reduced SOD1 aggregation in a J-domain and ubiquitin interaction motif (UIM) dependent manner. Collectively, the data suggest that HSJ1a acts on mutant SOD1 through a combination of chaperone, co-chaperone and pro-ubiquitylation activity. These results show that targeting SOD1 protein misfolding and aggregation in vivo can be neuroprotective and suggest that manipulation of DnaJ molecular chaperones might be useful in the treatment of ALS.     

MTOR-independent,autophagic enhancer trehalose prolongs motor neuron survival and ameliorates the autophagic flux defect in a mouse model of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder caused by selective motor neuron degeneration. Abnormal protein aggregation and impaired protein degradation pathways may contribute to the disease pathogenesis. Although it has been reported that autophagy is altered in patients and animal model of ALS, little is known about the role of autophagy in motor neuron degeneration in this disease. Our previous study shows that rapamycin, an MTOR-dependent autophagic activator, accelerates disease progression in the SOD1^G93A mouse model of ALS. In the present report, we have assessed the role of the MTOR-independent autophagic pathway in ALS by determining the effect of the MTOR-independent autophagic inducer trehalose on disease onset and progression, and on motor neuron degeneration in SOD1^G93A mice. We have found that trehalose significantly delays disease onset prolongs life span, and reduces motor neuron loss in the spinal cord of SOD1^G93A mice. Most importantly, we have documented that trehalose decreases SOD1 and SQSTM1/p62 aggregation, reduces ubiquitinated protein accumulation, and improves autophagic flux in the motor neurons of SOD1^G93A mice. Moreover, we have demonstrated that trehalose can reduce skeletal muscle denervation, protect mitochondria, and inhibit the proapoptotic pathway in SOD1^G93A mice. Collectively, our study indicated that the MTOR-independent autophagic inducer trehalose is neuroprotective in the ALS model and autophagosome-lysosome fusion is a possible therapeutic target for the treatment of ALS.     

Stem cells in animal asthma models: a systematic review

Background aimsAsthma control frequently falls short of the goals set in international guidelines. Treatment options for patients with poorly controlled asthma despite inhaled corticosteroids and long-acting β-agonists are limited, and new therapeutic options are needed. Stem cell therapy is promising for a variety of disorders but there has been no human clinical trial of stem cell therapy for asthma. We aimed to systematically review the literature regarding the potential benefits of stem cell therapy in animal models of asthma to determine whether a human trial is warranted.MethodsThe MEDLINE and Embase databases were searched for original studies of stem cell therapy in animal asthma models.ResultsNineteen studies were selected. They were found to be heterogeneous in their design. Mesenchymal stromal cells were used before sensitization with an allergen, before challenge with the allergen and after challenge, most frequently with ovalbumin, and mainly in BALB/c mice. Stem cell therapy resulted in a reduction of bronchoalveolar lavage fluid inflammation and eosinophilia as well as Th2 cytokines such as interleukin-4 and interleukin-5. Improvement in histopathology such as peribronchial and perivascular inflammation, epithelial thickness, goblet cell hyperplasia and smooth muscle layer thickening was universal. Several studies showed a reduction in airway hyper-responsiveness.ConclusionsStem cell therapy decreases eosinophilic and Th2 inflammation and is effective in several phases of the allergic response in animal asthma models. Further study is warranted, up to human clinical trials.     

MTOR-independent,autophagic enhancer trehalose prolongs motor neuron survival and ameliorates the autophagic flux defect in a mouse model of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder caused by selective motor neuron degeneration. Abnormal protein aggregation and impaired protein degradation pathways may contribute to the disease pathogenesis. Although it has been reported that autophagy is altered in patients and animal model of ALS, little is known about the role of autophagy in motor neuron degeneration in this disease. Our previous study shows that rapamycin, an MTOR-dependent autophagic activator, accelerates disease progression in the SOD1^G93A mouse model of ALS. In the present report, we have assessed the role of the MTOR-independent autophagic pathway in ALS by determining the effect of the MTOR-independent autophagic inducer trehalose on disease onset and progression, and on motor neuron degeneration in SOD1^G93A mice. We have found that trehalose significantly delays disease onset prolongs life span, and reduces motor neuron loss in the spinal cord of SOD1^G93A mice. Most importantly, we have documented that trehalose decreases SOD1 and SQSTM1/p62 aggregation, reduces ubiquitinated protein accumulation, and improves autophagic flux in the motor neurons of SOD1^G93A mice. Moreover, we have demonstrated that trehalose can reduce skeletal muscle denervation, protect mitochondria, and inhibit the proapoptotic pathway in SOD1^G93A mice. Collectively, our study indicated that the MTOR-independent autophagic inducer trehalose is neuroprotective in the ALS model and autophagosome-lysosome fusion is a possible therapeutic target for the treatment of ALS.     

Stem Cell Therapy for Erectile Dysfunction of Cavernous Nerve Injury Rats: A Systematic Review and Meta-Analysis

Introduction

Stem cell treatment is a novel therapeutic strategy for erectile dysfunction (ED) patients with bilateral cavernous nerve injury (CNI). The relative animal studies provide important clues to design pre-clinical studies and clinical studies further in the future.

Purpose

This study aims to evaluate the effects and influential factors of stem cell transplantation on ED rats with CNI.

Materials and Methods

We searched PubMed and EBSCO databases published before April 30, 2014 for pre-clinical studies to evaluate the efficacy of stem cell transplantation in the treatment of ED rats with CNI. A systematic review and a planned subgroup analysis were performed to identify whether or not some certain influential factors could bring significant effects on stem cell treatment.

Results

12 studies with 319 rats were enrolled in this meta-analysis. Pooled analysis results confirmed the efficacy of stem cell transplantation. Subgroup analysis results showed that treatment effects were not related to CNI models, follow-up time, stem cell species, stem cell sources, markers and delivery approaches in the transplantation. Uncultured stem cells were poorly effective compared with cultured stem cells. Periprostatic implantation (PPI) with acellular scaffolds could promote cavernous nerve regeneration, but was less effective for smooth muscle cell recovery. Stem cells modified by NGF or BDNF combined with udenafil/bFGF seemed to be more effective than those modified by BDNF alone.

Conclusion

This meta-analysis shows that stem cell therapy can be performed to recover erectile function. Future studies should focus on nerve restoration and vascular cell recovery. The synergistic actions of multiple growth factors following stem cell transplantation should also be considered as beneficial strategies to obtain preferable effects.     

Effect of mesenchymal stromal cell transplantation on long-term survival in amyotrophic lateral sclerosis

Background aimsThanks to their immunomodulatory, tissue-protective and regenerative properties, mesenchymal stromal cells (MSCs) are a promising approach for amyotrophic lateral sclerosis (ALS); however, trials are limited and few follow-up studies have been published. This post-hoc analysis aims to describe the potential long-term effects of MSCs in ALS, analyzing data from two phase 1 clinical trials in ALS patients conducted by our group in 2002 and 2006.MethodsWe conducted two consecutive phase 1 prospective, open, pilot clinical trials, enrolling a total of 19 ALS patients. We followed patients for the duration of the disease. For each patient, we used the European Network to Cure ALS (ENCALS) survival prediction model to retrospectively calculate the expected survival at diagnosis. We then compared the predicted disease duration with the observed survival, analyzing patients at a single-patient level.ResultsUsing the ENCALS model, we predicted short survival in one patient, intermediate survival in three patients, long survival in three patients and very long survival in 12 patients. The difference between predicted and observed survival for the whole group was significant and demonstrated a mean predicted survival of 70.79 months (standard deviation [SD], 27.53) and a mean observed survival of 118.8 months (SD, 89.26) (P = 0.016). Based on the monthly ALS Functional Rating Scale–Revised progression rate (median, 0.64/month), we considered 10 of 19 patients slow progressors and nine of 19 patients fast progressors. Of the slow progressors, eight of 10 (80%) had significantly increased disease duration compared with predicted, and only two (20%) had decreased estimated disease duration. By contrast, five of nine (55%) fast progressors had increased disease duration, whereas four (45%) had decreased disease duration. To date, four patients are still alive.ConclusionsThe current study represents the first very long-term analysis of survival as an effect of MSC focal transplantation in the central nervous system of ALS patients, demonstrating that MSC transplantation could potentially slow down ALS progression and improve survival. Due to the interindividual variability in clinical course, at the current state of our knowledge, we cannot generalize the results, but these data provide new insights for planning the next generation of efficacy MSC clinical trials in ALS.     

Caprylic Triglyceride as a Novel Therapeutic Approach to Effectively Improve the Performance and Attenuate the Symptoms Due to the Motor Neuron Loss in ALS Disease

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of motor neurons causing progressive muscle weakness, paralysis, and finally death. ALS patients suffer from asthenia and their progressive weakness negatively impacts quality of life, limiting their daily activities. They have impaired energy balance linked to lower activity of mitochondrial electron transport chain enzymes in ALS spinal cord, suggesting that improving mitochondrial function may present a therapeutic approach for ALS. When fed a ketogenic diet, the G93A ALS mouse shows a significant increase in serum ketones as well as a significantly slower progression of weakness and lower mortality rate. In this study, we treated SOD1-G93A mice with caprylic triglyceride, a medium chain triglyceride that is metabolized into ketone bodies and can serve as an alternate energy substrate for neuronal metabolism. Treatment with caprylic triglyceride attenuated progression of weakness and protected spinal cord motor neuron loss in SOD1-G93A transgenic animals, significantly improving their performance even though there was no significant benefit regarding the survival of the ALS transgenic animals. We found that caprylic triglyceride significantly promoted the mitochondrial oxygen consumption rate in vivo. Our results demonstrated that caprylic triglyceride alleviates ALS-type motor impairment through restoration of energy metabolism in SOD1-G93A ALS mice, especially during the overt stage of the disease. These data indicate the feasibility of using caprylic acid as an easily administered treatment with a high impact on the quality of life of ALS patients.     

Magnetically empowered bone marrow cells as a micro-living motor can improve early hematopoietic reconstitution

Background aimsBone marrow-derived hematopoietic stem cell transplantation/hematopoietic progenitor cell transplantation (HSCT/HPCT) is widely used and one of the most useful treatments in clinical practice. However, the homing rate of hematopoietic stem cells/hematopoietic progenitor cells (HSCs/HPCs) by routine cell transfusion is quite low, influencing hematopoietic reconstitution after HSCT/HPCT.MethodsThe authors developed a micro-living motor (MLM) strategy to increase the number of magnetically empowered bone marrow cells (ME-BMCs) homing to the bone marrow of recipient mice.ResultsIn the in vitro study, migration and retention of ME-BMCs were greatly improved in comparison with non-magnetized bone marrow cells, and the biological characteristics of ME-BMCs were well maintained. Differentially expressed gene analysis indicated that ME-BMCs might function through gene regulation. In the in vivo study, faster hematopoietic reconstitution was observed in ME-BMC mice, which demonstrated a better survival rate and milder symptoms of acute graft-versus-host disease after transplantation of allogeneic ME-BMCs.ConclusionsThis study demonstrated that ME-BMCs serving as MLMs facilitated the homing of HSCs/HPCs and eventually contributed to earlier hematopoietic reconstitution in recipients. These data might provide useful information for other kinds of cell therapies.     

Clinical effects of intrathecal administration of expanded Wharton jelly mesenchymal stromal cells in patients with chronic complete spinal cord injury: a randomized controlled study

Background aimsSpinal cord injury (SCI) represents a devastating condition leading to severe disability related to motor, sensory and autonomic dysfunction. Stem cell transplantation is considered a potential emerging therapy to stimulate neuroplastic and neuroregenerative processes after SCI. In this clinical trial, the authors investigated the safety and clinical recovery effects of intrathecal infusion of expanded Wharton jelly mesenchymal stromal cells (WJ-MSCs) in chronic complete SCI patients.MethodsThe authors designed a randomized, double-blind, crossover, placebo-controlled, phase 1/2a clinical trial (NCT03003364). Participants were 10 patients (7 males, 3 females, age range, 25–47 years) with chronic complete SCI (American Spinal Injury Association A) at dorsal level (T3-11). Patients were randomly assigned to receive a single dose of intrathecal ex vivo-expanded WJ-MSCs (10 × 10⁶ cells) from human umbilical cord or placebo and were then switched to the other arm at 6 months. Clinical evaluation (American Spinal Injury Association impairment scale motor and sensory score, spasticity, neuropathic pain, electrical perception and pain thresholds), lower limb motor evoked potentials (MEPs) and sensory evoked potentials (SEPs), Spinal Cord Independence Measure and World Health Organization Quality of Life Brief Version were assessed at baseline, 1 month, 3 months and 6 months after each intervention. Urodynamic studies and urinary-specific quality of life (Qualiveen questionnaire) as well as anorectal manometry, functional assessment of bowel dysfunction (Rome III diagnostic questionnaire) and severity of fecal incontinence (Wexner score) were conducted at baseline and at 6 months after each intervention.ResultsIntrathecal transplantation of WJ-MSCs was considered safe, with no significant side effects. Following MSC infusion, the authors found significant improvement in pinprick sensation in the dermatomes below the level of injury compared with placebo. Other clinically relevant effects, such as an increase in bladder maximum capacity and compliance and a decrease in bladder neurogenic hyperactivity and external sphincter dyssynergy, were observed only at the individual level. No changes in motor function, spasticity, MEPs, SEPs, bowel function, quality of life or independence measures were observed.ConclusionsIntrathecal transplantation of human umbilical cord-derived WJ-MSCs is a safe intervention. A single intrathecal infusion of WJ-MSCs in patients with chronic complete SCI induced sensory improvement in the segments adjacent to the injury site.     

Stem Cell Therapy for Diabetic Erectile Dysfunction in Rats: A Meta-Analysis

IntroductionStem cell therapy is a novel method for the treatment of diabetic erectile dysfunction (ED). Many relative animal studies have been done to evaluate the efficacy of this therapy in rats.AimsThis meta-analysis was performed to compare the efficacy of different stem cell therapies, to evaluate the influential factors and to determine the optimal stem cell therapeutic strategy for diabetic ED.MethodsWe searched the studies analyzing the efficacy of stem cell therapy for diabetic ED in rats published before September 30, 2015 in PubMed, Web of Science and EBSCO. A random effects meta-analysis was conducted to assess the outcomes of stem cell therapy. Subgroup analysis was also performed by separating these studies based on their different characteristics. Changes in the ratio of intracavernous pressure (ICP) to mean arterial pressure (MAP) and in the structure of the cavernous body were compared.Results10 studies with 302 rats were enrolled in this meta-analysis. Pooled analysis of these studies showed a beneficial effect of stem cell therapy in improving erectile function of diabetic rats (SMD 4.03, 95% CI = 3.22 to 4.84, P< 0.001). In the stem cell therapy group, both the smooth muscle and endothelium content were much more than those in control group. There was also significant increase in the expression of endothelial nitric oxide synthase (eNOS) and neuronal nitric oxide synthase (nNOS), the ratio of smooth muscle to collagen, as well as the secretion of vascular endothelial growth factor (VEGF). Besides, apoptotic cells were reduced by stem cell treatment. The subgroup analysis indicated that modified stem cells were more effective than those without modification.ConclusionsOur results confirmed that stem cell therapy could apparently improve the erectile function of diabetic rats. Some specific modification, especially the gene modification with growth factors, could improve the efficacy of stem cell therapy. Stem cell therapy has potential to be an effective therapeutic strategy for diabetic ED.