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

This study was aimed to investigate the curative effect and safety of human umbilical cord mesenchymal stem cells (hUCMSC) to treat acute graft-versus-host disease (aGVHD) of children after hematopoietic stem cell transplantation (HSCT). HUCMSC were isolated and cultured by collagenase digestion and passage culture. The 3rd to the 5th passage of hUCMSC were used for clinical treatment. Five cases of children acute leukemia achieved complete remission after chemotherapy. Two cases received HLA 3/6 loci matched haploidentical bone marrow HSCT. One case received HLA-matched sibling bone marrow and peripheral blood HSCT. One case received unrelated HLA 4/6 loci matched umbilical cord blood HSCT. One case received unrelated HLA 5/6 loci matched umbilical cord blood HSCT. The children received immunosuppressive therapy after III-IV aGVHD occurring. They received 0.5×10(6)/kg hUCMSC infusion when conventional therapy was ineffective. The results showed that 5 cases of children acute leukemia achieved hematopoietic reconstitution and developed the III-IV grade aGVHD. The five cases of children were infused with hUCMSC. The rash subsided, the liver function was normalized and the gastrointestinal symptoms were improved. The infusion-related adverse reaction did not happen. At present, the 5 children are in remission. It is concluded that allogeneic HSCT is an effective therapeutic method for children with acute leukemia. HUCMSC infusion can be safely and effectively used for the treatment of refractory aGVHD.
Child ; Child, Preschool ; Cord Blood Stem Cell Transplantation ; Female ; Graft vs Host Disease ; therapy ; Hematopoietic Stem Cell Transplantation ; adverse effects ; Humans ; Male ; Mesenchymal Stem Cell Transplantation ; Treatment Outcome

Child ; Cord Blood Stem Cell Transplantation ; adverse effects ; Cystitis ; therapy ; Hemorrhage ; therapy ; Humans ; Mesenchymal Stem Cell Transplantation ; adverse effects ; Postoperative Complications ; therapy

OBJECTIVETo evaluate the safety of human umbilical cord derived-mesenchymal stem cell (UC-MSC) transplantation therapy in patients with decompensated liver cirrhosis.

METHODSUC-MSCs were transplanted intravenously into patients with decompensated liver cirrhosis. Serum levels of glucose (GLU), total cholesterol (TC), blood urea nitrogen (BUN), alpha fetoprotein (AFP), white blood cells (WBC), and prothrombin activity (PA) were detected at different time points after UC-MSCs transplantation.

RESULTSMost UC-MSC transplanted patients experienced an improvement in quality of life, to varying degrees. With the exception of low-grade fever in a few patients, side effects and oncogenic events were rare (treatment group: 1/38 vs. control group: 1/16; P more than 0.05). The UC-MSCs transplantation showed no effect on GLU, TC, BUN, AFP, WBC, or PA.

CONCLUSIONUC-MSCs transplantation in patients with decompensated liver cirrhosis is safe and may improve the patient's quality of life.

Adult ; Aged ; Cord Blood Stem Cell Transplantation ; adverse effects ; Female ; Humans ; Liver Cirrhosis ; complications ; surgery ; Male ; Mesenchymal Stem Cell Transplantation ; adverse effects ; Middle Aged ; Prospective Studies

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

With the capacities of multiple differentiation, immunoregulatory activities and easy handling for isolation and culture expansion, human bone marrow mesenchymal stem cells (MSCs) have been utilized in clinical trials for the prevention and treatment of graft-versus-host disease in allogeneic bone marrow transplantation, repair of bone and cartilage defects and treatment of cardiac infarction and liver injury. However, increasingly experimental data indicate that a great deal of issues, such as intra-neutralization of calf serum proteins into cultured MSCs, survival of engrafted cells and subsequent cell differentiation tendency, should be in stringent consideration before clinical trials are designed. In this paper, these issues that should be raised and solved in clinical trials with MSCs were reviewed.
Bone Marrow Transplantation ; adverse effects ; Clinical Trials as Topic ; Graft vs Host Disease ; prevention & control ; Humans ; Mesenchymal Stem Cell Transplantation ; Mesenchymal Stromal Cells ; cytology ; drug effects ; Research Design

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

The multipotent differentiation and immunosuppression capability of mesenchymal stem cells (MSCs) make it attractive source for stem cell therapy to treat serious diseases, including neural system diseases and immune disorders. For large scale clinical applications, MSCs have to be expanded to produce sufficient quantity for multiple treatments. While conventional passaging is not appropriate for such a task, bioreactor can be used to expand MSCs more efficiently. Yet the efficacy and biosafety of expanded MSCs must be properly assessed before the expanded MSCs can be implanted. This review presented state-of-the-art in expanding MSCs focusing on the progress on the assessment of the efficacy and biosafety of in vitro expanded MSCs. Current obstacles were discussed and future research directions were outlined.
Animals ; Bioreactors ; Cell Differentiation ; Cell Proliferation ; Cells, Cultured ; Colony-Forming Units Assay ; Humans ; Mesenchymal Stem Cell Transplantation ; adverse effects ; Mesenchymal Stromal Cells ; cytology

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

OBJECTIVETo observe the effect of bone marrow mesenchymal stem cell transplantation on postangioplasty aortic restenosis in rats.

METHODS48 SD rats were randomly divided into normal control group, balloon injury group, balloon injury and MSCs transplantation group. MSCs were pre-labeled by DAPI (25 microg/ml) and then infused into aorta through the balloon catheter (MSCs 2 x 10(6)/animal). Thoracic aorta were taken for histological examination (frozen and paraffin sections) at 1, 2, 6 weeks post angioplasty, respectively. DAPI labeled MSCs were detected under immunofluorescence microscopy. Expressions of c-kit, proliferating cell nuclear antigen (PCNA), smooth muscle alpha-actin (alpha-SMA) in aorta were determined by immunocytochemistry using related antibodies.

RESULTSThe DAPI-labeled MSCs could be detected on impaired intimae and alpha-SMA expression was seen in these cells 1 weeks after MSCs transplantation. Similar weak c-kit expression in neointima was found in both injury and transplantation group at 2 weeks (P > 0.05). Expressions of PCNA and alpha-SMA in the neointima were significantly higher in transplantation group than in injury group at 2 weeks. Intima/tunica media area ratio and luminal stenosis ratio were significantly increased in transplantation group than injury group at 6 weeks (all P < 0.05).

CONCLUSIONBone marrow MSCs transplanted post aortic angioplasty could home to serious wounded aortic intima, differentiate into smooth muscle like cells, promote neointima cellular proliferation and aggravate postangioplasty aortic restenosis in rats.

Angioplasty, Balloon ; adverse effects ; Animals ; Aorta ; pathology ; Bone Marrow Transplantation ; adverse effects ; Coronary Restenosis ; etiology ; pathology ; Disease Models, Animal ; Male ; Mesenchymal Stem Cell Transplantation ; adverse effects ; Rats ; Rats, Sprague-Dawley