Identification of microRNAs and messenger RNAs involved in human umbilical cord mesenchymal stem cell treatment of ischemic cerebral infarction using integrated bioinformatics analysis

In recent years,a large number of differentially expressed genes have been identified in human umbilical cord mesenchymal stem cell(hUMSC)transplants for the treatment of ischemic cerebral infarction.These genes are involved in various biochemical processes,but the role of microRNAs(miRNAs)in this process is still unclear.From the Gene Expression Omnibus(GEO)database,we downloaded two microarray datasets for GSE78731(messenger RNA(mRNA)profile)and GSE97532(miRNA profile).The differentially expressed genes screened were compared between the hUMSC group and the middle cerebral artery occlusion group.Gene ontology enrichment and pathway enrichment analyses were subsequently conducted using the online Database for Annotation,Visualization,and Integrated Discovery.Identified genes were applied to perform weighted gene co-suppression analyses,to establish a weighted co-expression network model.Furthermore,the protein-protein interaction network for differentially expressed genes from turquoise modules was built using Cytoscape(version 3.40)and the most highly correlated subnetwork was extracted from the protein-protein interaction network using the MCODE plugin.The predicted target genes for differentially expressed miRNAs were also identified using the online database starBase v3.0.A total of 3698 differentially expressed genes were identified.Gene ontology analysis demonstrated that differentially expressed genes that are related to hUMSC treatment of ischemic cerebral infarction are involved in endocytosis and inflammatory responses.We identified 12 differentially expressed miRNAs in middle cerebral artery occlusion rats after hUMSC treatment,and these differentially expressed miRNAs were mainly involved in signaling in inflammatory pathways,such as in the regulation of neutrophil migration.In conclusion,we have identified a number of differentially expressed genes and differentially expressed mRNAs,miRNA-mRNAs,and signaling pathways involved in the hUMSC treatment of ischemic cerebral infarction.Bioinformatics and interaction analyses can provide novel clues for further research into hUMSC treatment of ischemic cerebral infarction.

Stem Cell Ophthalmology Treatment Study(SCOTS) for retinal and optic nerve diseases: a case report of improvement in relapsing auto-immune optic neuropathy

We present the results from a patient with relapsing optic neuropathy treated within the Stem Cell Ophthalmology Treatment Study （SCOTS）. SCOTS is an Institutional Review Board ap- proved clinical trial and has become the largest ophthalmology stem cell study registered at the National Institutes of Health to date （www.clinicaltrials.gov Identifier NCT 01920867）. SCOTS utilizes autologous bone marrow-derived stem cells （BMSCs） for treatment of retinal and optic nerve diseases. Pre-treatment and post-treatment comprehensive eye exams of a 54 year old female patient were performed both at the Florida Study Center, USA and at The Eye Center of Columbus, USA. As a consequence of a relapsing optic neuritis, the patient＇s previously normal visual acuity decreased to between 20/350 and 20/400 in the right eye and to 20/70 in the left eye. Significant visual field loss developed bilaterally. The patient underwent a right eye vitrectomy with injection of BMSCs into the optic nerve of the right eyeand retrobulbar, subtenon and in- travitreal injection of BMSCs in the left eye. At 15 months after SCOTS treatment, the patient＇s visual acuity had improved to 20/150 in the right eye and 20/20 in the left eye. Bilateral visual fields improved markedly. Both macular thickness and fast retinal nerve fiber layer thickness were maximally improved at 3 and 6 months after SCOTS treatment. The patient also reduced her mycophenylate dose from 1,500 mg per day to 500 mg per day and required no steroid pulse therapy during the 15-month follow up.

Vein transplantation using human umbilical cord blood stem cells in the treatment of stroke sequela

BACKGROUND: Transplanted mononuclear cell (MNC) of umbilical blood can survive in central nervous system (CNS) of host through blood brain barrier, differentiate into nerve cells, migrate to damaged site and integrate morphological structure and function with nerve cells of host so as to improve deficiencies of sensatory function, motor function and cognitive function and influence on stroke sequela. OBJECTIVE: To observe the vein transplantation of human umbilical cord blood stem cells (HUCBSC) for improving neurological function, limb function and activity of daily living of patients with stroke and evaluate the reliability. DESIGN: Self-controlled study. SETTING: Department of Neurosurgery, the Second People's Hospital of Zhengzhou City; Red-crossed Blood Center of Henan Province; Department of Neurosurgery, the Fist Affiliated Hospital of Zhengzhou University. PARTICIPANTS: A total of 10 patients with stroke sequela were selected from Department of Cerebral Surgery, the Second People's Hospital of Zhengzhou City from April to December 2005. There were 9 males and 1 female aged from 35 to 75 years with the mean age of 56 years. All of them were diagnosed with CT and MRI examination and coincidence with diagnostic criteria of stroke established by the Fourth National Academic Meeting for Cerebrovascular Disease. All patients provided informed consent. METHODS: 80-140 mL umbilical blood of term birth of newborn was selected hermetically and maintained in sterile plastic bag. And then, the blood was centrifugated at the speed of 1 500 r/min for 30 minutes at 22 ℃ in order to separate MNC, i.e., HUCBSC. In addition, after final diagnosis during hospitalization, stroke patients were perfused with HUCBSC through superficial vein of back of the hand. Each patient was averagely perfused with 6 portions of HUCBSC (cellular numbers ≥ 1×108/portion) and the interval between each portion was 1-7 days with the mean interval of 4 days. MAIN OUTCOME MEASURES: ① Neurological function of stroke patients was evaluated with neurological function deficiency (NFD) before treatment and at 3 months after treatment. The scale includes consciousness, level fix function, facial paralysis, language, muscle force of upper limbs, muscle force of lower limb and step function. The total scores ranged from 0 to 45; meanwhile, the lower the scores were, the better the neurological function was. ② Motor function of injured limbs was evaluated with Fugl-Meyer Assessment (FMA), including motor function of upper limbs, motor function of lower limbs, balance ability, sensory function and motion of joint. The total scores ranged from 0 to 226; meanwhile, the higher the scores were, the better the motor function of limbs was. ③ Activities of daily living (ADL) was evaluated with Barthel Index (BI), including having meals, taking a bath, dressing oneself, putting on clothes, walking in balance and stair activity. The total scores ranged from 0 to 100; meanwhile, the higher the scores were, the stronger the ADL was. RESULTS: A total of 10 patients were involved in the final analysis. After treatment, NFD of stroke patients was (10.9±5.09) points, which was lower than that before treatment [(25.4±6.09) points, t =8.213, P < 0.01]. In addition, after treatment, FMA and BI of stroke patients were (80.9±25.00) points and (81.1±15.93) points, respectively, which were higher than those before treatment [(31.9±21.85) points, (36.2±19.41) points, t =13.024, 13.670, P < 0.01]. Immuno-suppressive drugs were not used during the whole therapeutic procedure; moreover, immunological rejection and allergic reaction were not observed during the same period. CONCLUSION: Transplanting HUCBSC through superficial vein of back of the hand is regarded as a simple and safe method for the treatment of stroke sequela.

Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: Prophylaxis and treatment controversies

Hepatic veno-occlusive disease(VOD), also known as sinusoidal obstruction syndrome, is a major complication of hematopoietic stem cell transplantation and it carries a high mortality. Prophylaxis for hepatic VOD is commonly given to transplant recipients from the start of conditioning through the early weeks of transplant. However, high quality evidence from randomized controlled trials is scarce with small sample sizes and the trials yielded conflicting results. Although various treatment options for hepatic VOD are available, most have not undergone stringent evaluation with randomized controlled trial and therefore it remains uncertain which treatment offers real benefit. It remains controversial whether VOD prophylaxis should be given, which prophylactic therapy should be given, who should receive prophylaxis, and what treatment should be offered once VOD is established.

Stem cells for treatment of cerebral ischemia

Three articles regarding the effects of gene-modified stem cell transplantation and the reinfocing effects of dl-3-butylphthalide on hematopoietic stem cell transplantation and endogenous stem cell mobilization in the treatment of cerebral ischemia were published in Neural Regeneration Research. We hope that our readers find these papers useful to their research.

Stem cell transplantation for the treatment of end-stage liver disease

The past two decades have witnessed an explosion of research and clinical application of stem cells, transforming the field of regenerative medicine. Stem cell transplantation has already been performed to treat patients with cancer,liver diseases, and various types of chronic diseases. Indeed, stem cell-based therapies are effective in many diseases, and provide novel insights into the treatment of end-stage liver disease. Several clinical trials have indicated the efficacy profiles of stem cell transplantation in patients with end-stage liver disease, including liver cirrhosis, liver failure, and liver tumors. Animal models of acute liver failure have also provided important insights into the safety,mechanisms, and efficacy of stem cell therapies. Nevertheless, excitement due to this promising field must be tempered with careful and calculated research. In particular, studies on the quality, safety, and efficacy of stem cell transplantation are needed to ensure that qualified products are tested in well-designed clinical trials and approved by governments. Therefore, further investigations are required to effectively balance the safety with the innovation of stem cell transplantation research toward the effective treatment of end-stage liver disease.

Stem cells for treatment of spinal cord injury

Three articles regarding the effects of （gene-modified） bone marrow mesenchymal stem cells transplantation for treatment of spina cord injury and the migration process and distribution of transplanted stem cells observed by in vivo magnetic resonance imaging tracking, providing experimental evidence for spinal cord injury treatment with stem cell transplantation were reported in Neural Regeneration Research. We hope that our readers find these papers useful to their research.

Editor's Choice--Umbilical cord mesenchymal stem cell transplantation for the treatment of peripheral nerve injury

Schwann cells are the predominant seed cells for cell transplantation in the treatment of peripheral nerve injury. However, the source of Schwann cells is limited and amplification remains difficult. Studies have shown that mesenchymal stem cells, an alternative cell type, can be used for transplantation treatment of peripheral nerve defects. Umbilical cord mesenchymal stem cells are pluripotent stem cells derived from newborn umbilical cord tissues.

Overview of Hematopoietic Stem Cells in Systemic Cancer Treatment, Aging, Pregnancy, and Radiation Hormesis

Background: The unavoidable links between the benefits of conventional systemic treatment of cancer and the side effects such as lymphopenia. Objective: To analyze this phenomenon in view of the newly discovered trophic function of circulating hematopoietic stem cells (HSC) and their lymphocyte descendants. Method: We used population statistics and recent current research involving natural aging and preliminary aging with cancer, its cytotoxic therapy, eclampsia at pregnancy, and radiation hormesis. Results: In contrast to immune-defense interpretations of these health conditions, the trophic influence of HSC and morphogenic lymphocytes on natural tissue renewal and regeneration after sublethal injuries eliminates the majority of covered inconsistencies, which are inherent to the dominating idea of cellular immunity. Conclusion: Our examination led to the feeding influence of lymphopoiesis on tumor progression, an indirect mechanism of tumor growth control by systemic therapy via either destruction of trophic cells, or by competitive distraction from malignant tissue via reparation of sublethal injuries in normal tissues. Analyses also involved similarities of the mechanisms of systemic chemotherapy and total body/half body radiotherapy in low doses, as well as the futility of the theoretical opposition of the radiation hormesis phenomenon to the linear non-threshold model, dominant in radiobiology.

Use of Human Embryonic Stem Cell-Derived Cardiomyocyte Clusters to Assess Potential for Chronic Treatment with Compounds to Cause QT Prolongation

Drug-induced QT prolongation is a serious clinical issue in developing novel drug candidates and marketing drugs. A major cause of QT prolongation is direct inhibition of human ether-à-go-go-related gene (hERG) channels. Reduction in repolarization-related channel expression levels on plasma membranes is another mechanism that induces QT prolongation. Recently, we established a system for assessing the risk of QT prolongation by using human embryonic stem cell-derived cardiomyocyte clusters (hES-CMCs) in which the field potential duration (FPD) or corrected FPD (FPDc) was measured as an indicator of drug-induced QT interval prolongation. Here, we examined whether this system was able to detect FPDc prolongation caused by pentamidine or probucol, both of which can induce QT prolongation after long-term treatment. hES-CMCs were treated with pentamidine or probucol, and the FPDc of the same clusters was measured 10 min, 4 h, and 24 h after the start of treatment. Concentration-dependent FPDc prolongation was observed at 24 h, but not at 10 min, with pentamidine or probucol treatment. These results suggest that the hES-CMC-based assessment system can be used to detect both acute (at 10 min) and delayed (at 24 h) QT prolongation risk on the same platform by simple alteration of the extended culture period.

Effect of Rougan Huaqian granules combined with human mesenchymal stem cell transplantation on liver fibrosis in cirrhosis rats

Objective:To observe the effect of Rougan Huaqian granules combined with human mesenchymal stem cell(hMSC)transplantation on the liver fibrosis in carbon tetrachlorideinduced cirrhosis rats.Methods:Sixty SD rats were randomly divided into live groups.The rats in control group received intraperitoneal injection of saline,while those in model control group,treatment group A,group B and group C received intraperitoneal injection of carbon tetrachloride oily solution to induce liver cirrhosis within 8 weeks.Then,the rats in the model control group,treatment group A,treatment group B,treatment group C received vein tail injection of saline,Rougan Huaqian granules,hMSC suspension and Rougan Huaqian granules combined with hMSC suspension.Results:The treatment groups had significantly different liver function(AST levels),liver fibrosis index(laminin and HA),hepatic sinusoidal wallsα-smooth muscle actin,Ⅳcollagen and laminin protein expression andⅠ,Ⅲcollagen from the model group(P<0.05).The transplanted cells showed human hepatocyte-like cells differentiation trend in the liver.Conclusions:The Rougan Huaqian granules combined with hMSC transplantation can alleviate liver fibrosis in cirrhosis rats.

New insights into pancreatic cancer stem cells

Pancreatic cancer(PC) has been one of the deadliest of all cancers, with almost uniform lethality despite aggressive treatment. Recently, there have been important advances in the molecular, pathological and biological understandingof pancreatic cancer. Even after the emergence of recent new targeted agents and the use of multiple therapeutic combinations, no treatment option is viable in patients with advanced cancer. Developing novel strategies to target progression of PC is of intense interest. A small population of pancreatic cancer stem cells(CSCs) has been found to be resistant to chemotherapy and radiation therapy. CSCs are believed to be responsible for tumor initiation, progression and metastasis. The CSC research has recently achieved much progress in a variety of solid tumors, including pancreatic cancer to some extent. This leads to focus on understanding the role of pancreatic CSCs. The focus on CSCs may offer new targets for prevention and treatment of this deadly cancer. We review the most salient developments in important areas of pancreatic CSCs. Here, we provide a review of current updates and new insights on the role of CSCs in pancreatic tumor progression with special emphasis on Dcl K1 and Lgr5, signaling pathways altered by CSCs, and the role of CSCs in prevention and treatment of PC.

Autologous Stem Cell Therapy for Cerebral Palsy

Introduction: We describe treatment of Cerebral Palsy with adult stem cells derived from bone marrow and fat of the same patient. Adult stem cells are of two types, the mesenchymal and haemopoietic stem cells which have potential to duplicate, indefinitely produce 50 types of growth factors that repair and regenerate tissues in an epigenetic manner. Every organ has its own stem cells, for example kidney stem cells, liver stem cells, etc. When specialized cells in an organ get damaged, the local stem cells come forward and get differentiated into specialized cells and the tissue damage is replenished. But when the stock of this reserve of local stem cell is over, the organ starts failing. In autologous stem cell therapy, we harvest stem cells from other healthy organs like fat and bone marrow which have abundant stem cells and put them into the diseased organ. Adult stem cells differentiate into neurons in vitro when added with nerve growth factor which is present in every nerve tissue. Our stem cell research was done by following all the guidelines set at national and international level. In India the incidence of cerebral palsy is around 5/1000 live births. In cerebral Palsy the upper motor neuron is weak, hence the lower motor neuron becomes hyper active leading to spasticity. The treatment involves mainly physiotherapy and prognosis is poor. Physiotherapy is a palliation and does not repair damage in the brain. The conventional therapy has failed to give any satisfactory results in these children hence something new needs to be done. Materials and Methods: In last 2 years we did stem cell therapy for 21 cases of CP in our center with age of 9 months to 17 years. Out of 21 cases of CP, 7 (33.3%) cases had quadriplegia, 6 (28.57%) paraplegia and 1 (4.76%) monoplegia, 2 (9%) hypotonic, 5 (23.8%) hemiplegia, 4 (19.04%) with mental retardation and 3 (14.28) had features of ADHD and Autism. 18 patients had squint in the eyes, 8 patients had food regurgitation and drooling of saliva, 2 patients had audiovisual impairment, 3 patients had bronchial asthma and one patient had menstrual irregularity. 26 cases were put as control with age range of 9 months to 19 years. 9 (34.61%) patients had quadriplegia, 8 (30.76%) paraplegia and 3 (11.53) had monoplegia, 3 (11.53%) hypotonic, 5 (19.23) with mental retardation and 6 (23.07) had features of ADHD and autism. 21 patients had squint in the eyes, 11 patients had food regurgitation and drooling of saliva, 4 patients had audiovisual impairment, 5 patients had bronchial asthma in the control group. 11 patients were subjected to adipose tissue derived stem cell therapy and 10 with bone marrow derived stem cell therapy. All patients were examined at 3 monthly intervals. Maximum follow up was 2.5 years and minimum of one year. Results: The results of bone marrow derived stem cells and adipose tissue derived stem cells were almost the same. Results took 3 months to appear and positive outcome came till one year since therapy. The spasticity was significantly reduced in 15 out of 18 patients in 6 months. Out of 18 patients who had squint, it was regressed completely in 12 (66.66%) patients and partially in 3 (16.66%) in 6 months’ time. 8 patients had faulty deglutition and 75% of them had 90%

Ruxolitinib add-on in corticosteroid-refractory graft-vs-host disease after allogeneic stem cell transplantation:Results from a retrospective study on 38 Chinese patients

BACKGROUND Graft-vs-host disease (GVHD) is a major cause of mortality after allogeneic hematopoietic stem cell transplantation.Some patients have steroid-refractory(SR) GVHD.AIM To evaluate the effect and safety of ruxolitinib add-on in the treatment of patients with SR acute (a) and chronic (c) GVHD.METHODS We retrospectively analyzed 38 patients administered ruxolitinib add-on to standard immunosuppressive therapy for SR-aGVHD or SR-cGVHD following allogeneic hematopoietic stem cell transplantation.Ruxolitinib was administered5-10 mg/d depending on disease severity,patient status,and the use of antifungal drugs.Overall response rate,time to best response,malignancy relapse rate,infection rate,and treatment-related adverse events were assessed.RESULTS The analysis included 10 patients with SR-aGVHD (gradeⅢ/Ⅳ,n=9) and 28patients with SR-cGVHD (moderate/severe,n=24).For the SR-aGVHD and SRcGVHD groups,respectively:Median number of previous GVHD therapies was 2(range:1-3) and 2 (1-4);median follow-up was 2.5 (1.5-4) and 5 (1.5-10) mo;median time to best response was 1 (0.5-2.5) and 3 (1-9.5) mo;and overall response rate was 100%(complete response:80%) and 82.1%(complete response:10.7%) with a response observed in all GVHD-affected organs.The malignancy relapse rates for the SR-aGVHD and SR-cGVHD groups were 10.0%and 10.7%,respectively.Reactivation rates for cytomegalovirus,Epstein-Barr virus,and varicella-zoster virus,respectively,were 30.0%,10.0%,and 0%for the SR-aGVHD group and 0%,14.3%,and 7.1%for the SR-cGVHD group.CONCLUSION Ruxolitinib add-on was effective and safe as salvage therapy for SR-GVHD.

WJSC 6^(th) Anniversary Special Issues(2):Mesenchymal stem cells Mesenchymal stem cells in treating autism:Novel insights

Autism spectrum disorders(ASDs)are complex neurodevelopmental disorders characterized by dysfunctions in social interactions,abnormal to absent verbal communication,restricted interests,and repetitive stereotypic verbal and non-verbal behaviors,influencing the ability to relate to and communicate.The core symptoms of ASDs concern the cognitive,emotional,and neurobehavioural domains.The prevalence of autism appears to be increasing at an alarming rate,yet there is a lack of effective and definitive pharmacological options.This has created an increased sense of urgency,and the need to identify novel therapies.Given the growing awareness of immune dysregulation in a significant portion of the autistic population,cell therapies have been proposed and applied to ASDs.In particular,mesenchymal stem cells(MSCs)possess the immunological properties which make them promising candidates in regenerative medicine.MSC therapy may be applicable to several diseases associated with inflammation and tissue damage,where subsequent regeneration and repair is necessary.MSCs could exert a positive effect in ASDs through the following mechanisms:stimulation of repair in the damaged tissue,e.g.,inflammatory bowel disease;synthesizing and releasing anti-inflammatory cytokines and survival-promoting growth factors;integrating into existing neural and synaptic network,and restoring plasticity.The paracrine mechanisms of MSCs show interesting potential in ASD treatment.Promising and impressive results have been reported from the few clinical studies published to date,although the exact mechanisms of action of MSCs in ASDs to restore functions are still largely unknown.The potential role of MSCs in mediating ASD recovery is discussed in light of the newest findings from recent clinical studies.

Clinical Evaluation after Introduction of Stem Cell Supernatant Biocell Shot 65 by Electroporation

Objectives: The objective of this study is clinical evaluation after introduction of stem cell supernatant Biocell Shot 65 by electroporation. Background: There is a clinical report of psoriasis treatment by umbilical cord blood-derived stem cells, in which there was a beneficial result. These clinical results are the result of cord blood-derived cell growth factors. The umbilical cord blood-derived stem cell culture supernatant contains a high amount of TGF-β, PDGA, etc., and promotes wound healing. In addition, we suppose that the supernatant has the esthetic effect of improving skin condition, thus, we planned to make a clinical evaluation. However, it is difficult to set judgement criteria, and human judgement tends to be subjective. Therefore, in this study, as a new clinical evaluator, we used an AI skin diagnostic device with learning function. Methods: Stem cell culture supernatant Biocell Shot 65 was used as an introduction solution. After it was applied to the full faces of four patients, electroporation with BeBe pinocchio DM-5 SUPER DX Plus promoted infiltration deep in the keratinized layer. The patients were all healthy women in their forties. This procedure was performed every two weeks for three months. Wrinkles, fine lines around eyes, stains, pores, and 4V, which is considered as one diagnostic criteria, were evaluated at baseline and after each procedure with the skin diagnostic device HiMirror-Professional. In this study, macroscopic findings were not examined. Results: In all four patients, 4V did not change remarkably. Patient 1 showed improvement after the procedure in wrinkles, fine lines around eyes, stains, and pores. Patient 2 revealed improvement only in fine lines around eyes, but did not show improvement in other items. Patient 3 improved in wrinkles, stains, and pores only after the second procedure, but did not show improvement in the other procedures. Patient 4 improved in all items except 4V after the fourth procedure. In addition, when the mean values of all the patients were plotted and compared before and after each procedure, there was a trend toward improvements after the fifth procedure. Conclusion: In addition to application of supernatant culture to the skin, introduction of the solution to the skin by electroporation might improve stains, wrinkles, and pores. Our evaluation was performed with a facial diagnostic device three months after the start of the procedure.

Involvement of blood mononuclear cells in the infertility, age-associated diseases and cancer treatment

Blood mononuclear cells consist of T cells and monocyte derived cells. Beside immunity, the blood mononuclear cells belong to the complex tissue control system(TCS), where they exhibit morphostatic function by stimulatingproliferation of tissue stem cells followed by cellular differentiation, that is stopped after attaining the proper functional stage, which differs among various tissue types. Therefore, the term immune and morphostatic system(IMS) should be implied. The TCS-mediated morphostasis also consists of vascular pericytes controlled by autonomic innervation, which is regulating the quantity of distinct tissues in vivo. Lack of proper differentiation of tissue cells by TCS causes either tissue underdevelopment, e.g., muscular dystrophy, or degenerative functional failures, e.g., type 1 diabetes and age-associated diseases. With the gradual IMS regression after 35 years of age the gonadal infertility develops, followed by a growing incidence of age-associated diseases and cancers. Without restoring an altered TCS function in a degenerative disease, the implantation of tissue-specific stem cells alone by regenerative medicine can not be successful. Transfused young blood could temporarily restore fertility to enable parenthood. The young blood could also temporarily alleviate aging diseases, and this can be extended by substances inducing IMS regeneration, like the honey bee propolis. The local and/or systemic use of honey bee propolis stopped hair and teeth loss, regressed varicose veins, improved altered hearing, and lowered high blood pressure and sugar levels. Complete regression of stage Ⅳ ovarian cancer with liver metastases after a simple elaborated immunotherapy is also reported.

Rat Mesenchymal Stem Cells from Adipose Tissue Reduce Bleomycin-Induced Lung Remodeling in Late Stage

Idiopathic pulmonary fibrosis (IPF) is progressive fibrosing interstitial pneumonia of unknown cause, chronic and incurable interstitial lung disease, associated with high mortality rates and unresponsive to treatments currently available. The prevalence of IPF is estimated at approximately 20/100,000 in men and 13/100,000 in women, and the mean age at the time of diagnosis is 67 years and the median survival is 2 to 5 years. Therapies available to date, proved, therefore, only palliative measures with doubtful or unsatisfactory result. Many experimental models of pulmonary fibrosis are described. Bleomycin-induced pulmonary fibrosis is a widely used experimental model to identify and validate new therapeutic targets. We have induced pulmonary fibrosis by intratracheal bleomycin and late instillation of mesenchymal stem cells (MSC) from adipose tissue as a therapeutic proposal was used. MSC have the capacity to modulate inflammatory and immune response. Furthermore, the long-term effect of MSCs could also regulate and control to collagen deposition of the myofibroblasts, a final and pivo cell of pulmonary fibrosis. MSC from adipose tissue is an effective therapy to decrease collagen synthesis and expression in late stage of bleomycin-induced pulmonary fibrosis model, which may contribute to new therapeutic targets.

Emerging potential of exosomes for treatment of traumatic brain injury

Traumatic brain injury（TBI） is one of the major causes of death and disability worldwide.No effective treatment has been identified from clinical trials.Compelling evidence exists that treatment with mesenchymal stem cells（MSCs） exerts a substantial therapeutic effect after experimental brain injury.In addition to their soluble factors,therapeutic effects of MSCs may be attributed to their generation and release of exosomes.Exosomes are endosomal origin small-membrane nano-sized vesicles generated by almost all cell types.Exosomes play a pivotal role in intercellular communication.Intravenous delivery of MSC-derived exosomes improves functional recovery and promotes neuroplasticity in rats after TBI.Therapeutic effects of exosomes derive from the exosome content,especially micro RNAs（mi RNAs）.mi RNAs are small non-coding regulatory RNAs and play an important role in posttranscriptional regulation of genes.Compared with their parent cells,exosomes are more stable and can cross the blood-brain barrier.They have reduced the safety risks inherent in administering viable cells such as the risk of occlusion in microvasculature or unregulated growth of transplanted cells.Developing a cell-free exosome-based therapy may open up a novel approach to enhancing multifaceted aspects of neuroplasticity and to amplifying neurological recovery,potentially for a variety of neural injuries and neurodegenerative diseases.This review discusses the most recent knowledge of exosome therapies for TBI,their associated challenges and opportunities.

Pancreatic ductal adenocarcinoma: Treatment hurdles, tumor microenvironment and immunotherapy

Pancreatic ductal adenocarcinoma(PDAC)is one of the most lethal diseases,with an average 5-year survival rate of less than 10%.Unfortunately,the majority of patients have unresectable,locally advanced,or metastatic disease at the time of diagnosis.Moreover,traditional treatments such as chemotherapy,surgery,and radiation have not been shown to significantly improve survival.Recently,there has been a swift increase in cancer treatments that incorporate immunotherapybased strategies to target all the stepwise events required for tumor initiation and progression.The results in melanoma,non-small-cell lung cancer and renal cell carcinoma are very encouraging.Unfortunately,the application of checkpoint inhibitors,including anti-CTLA4,anti-PD-1,and anti-PD-L1 antibodies,in pancreatic cancer has been disappointing.Many studies have revealed that the PDAC microenvironment supports tumor growth,promotes metastasis and consists of a physical barrier to drug delivery.Combination therapies hold great promise for enhancing immune responses to achieve a better therapeutic effect.In this review,we provide an outline of why pancreatic cancer is so lethal and of the treatment hurdles that exist.Particular emphasis is given to the role of the tumor microenvironment,and some of the latest and most promising studies on immunotherapy in PDAC are also presented.