Mesenchymal stem cells (MSCs) have been officially approved in many countries to treat graft-versus-host disease, autoimmune disorders and those associated with tissue regeneration after hematopoietic stem cell transplantation. Studies in recent years have confirmed that MSC acts mainly through paracrine mechanism, in which extracellular vesicles secreted by MSC (MSC-EV) play a central role. MSC-EV has overwhelming advantages over MSC itself in the setting of adverse effects in clinical application, indicating that MSC-EV might take the place of its parent cells to be a potentially therapeutic tool for "cell-free therapy". The pharmaceutical properties of MSC-EV largely depend upon the practical and optimal techniques including large-scale expansion of MSC, the modification of MSC based on the indications and the in vivo dynamic features of MSC-EV, and the methods for preparing and harvesting large amounts of MSC-EV. The recent progresses on the issues above will be briefly reviewed.
Humans ; Extracellular Vesicles ; Hematopoietic Stem Cell Transplantation/adverse effects* ; Mesenchymal Stem Cell Transplantation/methods* ; Mesenchymal Stem Cells ; Pharmaceutical Preparations

OBJECTIVETo evaluate the efficacy and safety of bone marrow-derived mesenchymal stem cells (MSC) from a third party donor for secondary poor graft function (PGF) following allogeneic hematopoietic stem cell transplantation(allo-HSCT).

METHODSFive patients with secondary PGF were treated with MSC at a dose of 1 x 10(6)/kg body weight at a median of 47 days (35 to 61) after secondary PGF. MSC were derived from bone marrow (BM) of HLA-disparate third party donors, cultured in vitro and infused without HSC. If absolute neutrophil cell (ANC) and platelet counts (PLT) did not reach the standardization of > 1.5 x 10(9)/L and > 50.0 x 10(9)/L, respectively, within 28-30 days after the first MSC treatment, a second MSC treatment was required.

RESULTSMSC were infused once in one patient and twice in four patients with an interval of 28 to 30 days. All patients obtained ANC and PLT recovery at a median of 34 (25 to 49) days and 47 (26 to 54) days, respectively, without toxic side effects within follow-up periods of median 761 (204-1491) days. Three patients developed Epstein-Barr virus (EBV) reactivation at 42, 48, 108 days after MSC infusion, respectively and two of the three coverted to posttransplant lymphoproliferative disorders (PTLD).

CONCLUSIONMSC from a third party donor are effective to patients with secondary PGF following allo-HSCT, whether it might increase the risk of EBV reactivation and EBV-associated PTLD need further observation.

Adolescent ; Female ; Graft vs Host Disease ; prevention & control ; Hematopoietic Stem Cell Transplantation ; adverse effects ; Humans ; Male ; Mesenchymal Stem Cell Transplantation ; methods ; Transplantation, Homologous ; Young Adult

The present study was purposed to evaluate the safety of mesenchymal stem cell (MSC)-based therapy impacting on atherosclerosis. Allogeneic MSCs were obtained from rabbit bone marrow aspirates and expanded in vitro. New Zealand white rabbits were divided into three groups: 24 rabbits with hypercholesterolemia receiving intravenous injection of either 5 x 10(7) MSCs (n = 12) or saline (n = 12) after 5 weeks on a high lipid diet and additional rabbits (n = 6) fed with standard rabbit diet were served as controls. Body weight and blood lipids were measured at weeks 0, 5, 9 and 13 during the study. All rabbits were sacrificed at week 13. Atherosclerotic lesion size and vasa vasorum were evaluated by using pathological analysis and immunocytochemical technique. The results showed that the aortic sinus lesion size significantly increased in rabbits infused with MSCs as compared with controls receiving saline (23.35 +/- 3.51% and 11.39 +/- 3.08% respectively). The lesion size in whole aortas of MSC-treated rabbits was 76.64 +/- 12.70% versus 57.61 +/- 9.00% in saline-treated animals (p < 0.05). Moreover, vasa vasorum networks in MSC-treated aortas were more numerous and had increased capillary density. It is concluded that the allogeneic MSC transfusion may result in an increase in atherosclerotic lesion size. In cell therapy with MSCs or cell populations containing MSCs a strategy to attenuate the high potential of MSCs involved in atherogenesis of atherosclerosis should be taken in account.
Animals ; Cell Differentiation ; Disease Models, Animal ; Male ; Mesenchymal Stem Cell Transplantation ; adverse effects ; methods ; Plaque, Atherosclerotic ; etiology ; Rabbits

Based on their ability to differentiate into multiple cell types including hepatocytes, the transplantation of mesenchymal stem cells (MSCs) has been suggested as an effective therapy for chronic liver diseases. The aim of this study was to evaluate the safety, efficacy and therapeutic effects of MSCs in patients with chronic liver disease through a literature-based examination. We performed a systematic review (SR) and meta-analysis (MA) of the literature using the Ovid-MEDLINE, EMBASE and Cochrane Library databases (up to November 2014) to identify clinical studies in which patients with liver diseases were treated with MSC therapy. Of the 568 studies identified by the initial literature search, we analyzed 14 studies and 448 patients based on our selection criteria. None of the studies reported the occurrence of statistically significant adverse events, side effects or complications. The majority of the analyzed studies showed improvements in liver function, ascites and encephalopathy. In particular, an MA showed that MSC therapy improved the total bilirubin level, the serum albumin level and the Model for End-stage Liver Disease (MELD) score after MSC treatment. Based on these results, MSC transplantation is considered to be safe for the treatment of chronic liver disease. However, although MSCs are potential therapeutic agents that may improve liver function, in order to obtain meaningful insights into their clinical efficacy, further robust clinical studies must be conducted to evaluate the clinical outcomes, such as histological improvement, increased survival and reduced liver-related complications, in patients with chronic liver disease.
Cell Differentiation/physiology ; Cell- and Tissue-Based Therapy/adverse effects/*methods ; Hepatocytes/cytology ; Humans ; Liver/physiopathology/surgery ; Liver Diseases/*therapy ; Liver Function Tests ; Mesenchymal Stem Cell Transplantation/adverse effects/*methods ; Mesenchymal Stromal Cells/*cytology

Mesenchymal stem cells (MSCs) are self-renewing, multipotent progenitor cells with multilineage potential to differentiate into cell types of mesodermal origin, such as adipocytes, osteocytes, and chondrocytes. In addition, MSCs can migrate to sites of inflammation and exert potent immunosuppressive and anti-inflammatory effects through interactions between lymphocytes associated with both the innate and adaptive immune system. Along with these unique therapeutic properties, their ease of accessibility and expansion suggest that use of MSCs may be a useful therapeutic approach for various disorders. In the clinical setting, MSCs are being explored in trials of various conditions, including orthopedic injuries, graft versus host disease following bone marrow transplantation, cardiovascular diseases, autoimmune diseases, and liver diseases. Furthermore, genetic modification of MSCs to overexpress antitumor genes has provided prospects for clinical use as anticancer therapy. Here, we highlight the currently reported uses of MSCs in clinical trials and discuss their efficacy as well as their limitations.
Animals ; Cell Differentiation ; Cell Lineage ; Cell Movement ; Cell Proliferation ; Gene Expression Regulation ; Humans ; *Mesenchymal Stem Cell Transplantation/adverse effects ; Mesenchymal Stromal Cells/immunology/*physiology ; *Regeneration ; Regenerative Medicine/*methods ; Treatment Outcome

Radiation-induced lung injury (RILI) is the most common complication of the radiotherapy for thoracic tumor. It can lower the ratio of local control and seriously affect the patients' quality of life. At present, the clinical management of RILI is not more than the use of glucocorticoid and anti-inflammatory agent for symptomatic treatments. These treatments do not have any preventive effect but cause much side reactions. In this paper, we review the data from the contigency researches on the mechanism of RILI, from the researches on gene therapy and stem cell-therapy, and we dicuss the more safe, more stable and more efficacious treatment of RILI.
Antioxidants ; therapeutic use ; Genetic Therapy ; methods ; Humans ; Lung ; pathology ; radiation effects ; Lung Neoplasms ; radiotherapy ; Mesenchymal Stem Cell Transplantation ; methods ; Radiation Injuries ; etiology ; therapy ; Radiation Pneumonitis ; etiology ; therapy ; Radiation-Protective Agents ; therapeutic use ; Radiotherapy, Conformal ; adverse effects

To investigate the effect of bone marrow mesenchymal stem cells (BMMSC) on acute graft versus host disease (aGVHD) and graft versus leukemia (GVL) after allogeneic bone marrow transplantation (allo-BMT), both bone marrow cells and BMMSC obtained after three to four weeks of culture from donor mice were transplanted into the recipient mice injected with acute lymphocytic leukemia cells 5 days before, the control group was injected with bone marrow cells alone. The survial time after allo-BMT was recorded; the general manifestation and pathological changes of aGVHD in recipient mice were observed; the effects of BMMSC on the quatity of CD4(+) and CD8(+) T cell in vivo after allo-BMT were evaluated by flow cytometry; chimerism was detected by sex chromosome. The results showed BMMSC could increase obviously the survival time, and delay onset of aGVHD, BMMSC could decrease the amount of CD4(+) T cell and increase CD8(+) T cell in vivo. It is concluded that cotransplantation of bone marrow cells with BMMSC from the same donor mice has GVL effect. BMMSC can alleviate aGVHD and maintain GVL effect after allo-BMT.
Animals ; Bone Marrow Transplantation ; adverse effects ; methods ; CD4-Positive T-Lymphocytes ; cytology ; immunology ; CD8-Positive T-Lymphocytes ; cytology ; immunology ; Cell Line, Tumor ; Female ; Flow Cytometry ; Graft vs Host Disease ; etiology ; immunology ; prevention & control ; Graft vs Leukemia Effect ; immunology ; Leukemia P388 ; immunology ; pathology ; surgery ; Male ; Mesenchymal Stem Cell Transplantation ; adverse effects ; methods ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Transplantation, Homologous

OBJECTIVETo evaluate the effects of human mesenchymal stem cells (hMSCs) transplantation via portal vein to treat acute liver injury in mice induced with acetaminophen.

METHODSA model of acute liver injury was established by acetaminophen gavage with a dose of 500 mg/kg. Twenty severe combined immune deficient mice (SCID mice) were randomly divided into 2 groups; one with hMSCs transplantation via their portal veins, the other group served as controls and only saline was infused into their veins. Liver function tests, fluorescein staining and reticular fiber staining of liver histological preparations and fluorescence- and light-microscopy were applied to observe the biochemical and pathological changes in the mice before and after the transplantation of hMSCs.

RESULTSLiver function of the hMSCs group was significantly better than that of the controls (P less than 0.05). Fluorescence microscopy revealed that the hMSCs appeared in the areas of the periportal veins at first and then extended to the central vein areas; the reticular fiber staining indicated that hMSCs could repair the architecture of the hepatic acini. No prominent fibrosis and pseudolobules were found.

CONCLUSIONShMSCs transplantation via portal vein to SCID mice with acute liver injury induced by acetaminophen can improve their liver function effectively; hMSCs growth in their livers and acinus reconstruction can be affected. We think it is a good method to treat acute liver injury.

Acetaminophen ; adverse effects ; Animals ; Bone Marrow Cells ; Chemical and Drug Induced Liver Injury ; surgery ; Disease Models, Animal ; Humans ; Male ; Mesenchymal Stem Cell Transplantation ; methods ; Mice ; Mice, SCID ; Portal Vein ; surgery

Currently, the most effective treatment for end-stage liver fibrosis is liver transplantation; however, transplantation is limited by a shortage of donor organs, surgical complications, immunological rejection, and high medical costs. Recently, mesenchymal stem cell (MSC) therapy has been suggested as an effective alternate approach for the treatment of hepatic diseases. MSCs have the potential to differentiate into hepatocytes, and therapeutic value exists in their immune-modulatory properties and secretion of trophic factors, such as growth factors and cytokines. In addition, MSCs can suppress inflammatory responses, reduce hepatocyte apoptosis, increase hepatocyte regeneration, regress liver fibrosis and enhance liver functionality. Despite these advantages, issues remain; MSCs also have fibrogenic potential and the capacity to promote tumor cell growth and oncogenicity. This paper summarizes the properties of MSCs for regenerative medicine and their therapeutic mechanisms and clinical application in the treatment of liver fibrosis. We also present several outstanding risks, including their fibrogenic potential and their capacity to promote pre-existing tumor cell growth and oncogenicity.
Animals ; Cell Differentiation ; Cell Proliferation ; Hepatocytes/immunology/metabolism/pathology/*transplantation ; Humans ; Liver/immunology/metabolism/pathology/physiopathology/*surgery ; Liver Cirrhosis/diagnosis/immunology/metabolism/physiopathology/*surgery ; Liver Regeneration ; *Mesenchymal Stem Cell Transplantation/adverse effects ; *Mesenchymal Stromal Cells/immunology/metabolism/pathology ; Phenotype ; Regenerative Medicine/*methods ; Risk Factors ; Signal Transduction ; Treatment Outcome

OBJECTIVETo study the effects of cluster of differentiation 40 ligand immunoglobulin (CD40LIg) gene-modified bone marrow mesenchymal stem cells (MSCs) on liver graft rejection in rats.

METHODSThe orthotopic liver transplantation models were established with DA rats as the donors and Lewis rats as the recipient. MSCs infected with the recombinant adenoviruses containing CD40LIg gene were infused into the liver graft after transplantation. The liver function, survival of the recipient rats and the morphological changes of the liver grafts were observed after the transplantation. The serum levels of the cytokines interferon-γ (INF-γ) and interleukin-2 (IL-2) in the recipient rats were quantified by ELISA.

RESULTSThe survival of the recipient rats receiving transplantation of genetically modified MSCs (group D) was significantly prolonged compared with that of the control group (group A), MSCs group (group B) and gene transfection group (group C); the survival of groups B and C were significantly longer than that of group A (F=7.615, P<0.05). The level of serum alanine aminotransferase, total bilirubin, IL-2 and INF-γ were significantly higher in group A than in the other 3 groups (F=8.738, P<0.05). HE staining of the liver grafts showed severe acute rejection in group A, mild acute graft rejection in groups B and group C, but no rejection in group D.

CONCLUSIONCD40LIg gene-modified MSCs can prolong the survival of the recipient rats and suppress graft rejection following liver transplantation.

Adenoviridae ; genetics ; metabolism ; Animals ; Bone Marrow Cells ; cytology ; metabolism ; Graft Rejection ; prevention & control ; Liver Transplantation ; adverse effects ; Male ; Mesenchymal Stem Cell Transplantation ; methods ; Mesenchymal Stromal Cells ; cytology ; metabolism ; Rats ; Rats, Inbred Dahl ; Rats, Inbred Lew ; Recombinant Fusion Proteins ; biosynthesis ; genetics ; Recombinant Proteins ; biosynthesis ; genetics ; Transfection