Numbers studies also showed that the MSCs have the

Numbers studies also showed that the MSCs have the capacity to differentiate into multiple mesenchymal tissues both in vitro and in vivo, including osteoblast [25,34], condrocyte [35,36], adipocyte [37,38], tendon [39,40], skeletal muscle cells [39], cardiomyocyte [41,42] and hematopoietic supporting stroma cells [43]. In addition, MSCs also have capability for differentiating into tissues of ectodermal, including skin [44], neurons [45]. Furthermore, MSCs can differentiate into tissues of endodermal including lung [46,47], hepatocytes [27,48], renal [49,50], and pancreatic β-cells [51,52], endothelial cells [53,54] (Fig. 1). Actually, the tissue repair capability of MSCs is mainly ABT737 manufacturer on their multi-lineage differentiation potential.
The safety of MSCs in clinical application MSCs have been used in several approaches for regenerative cell therapy, as well as in the perspective of modulating immune response. Therefore, the biosafety features of MSCs need to be carefully investigated to exclude the occurrence of functional or genetic alterations before their release for clinical use. Bernardo et al. show that human BM-derived MSCs can be cultured long-term in vitro, without losing their morphologic, phenotypical, and functional characteristics. Moreover, MSCs propagated in culture continuously for up to 44 weeks maintained a normal karyotype [55]. Meza-zepeda et al. also report that adipose derived MSCs do not bypass senescence even after two months of post-senescence culture. MSCs show no evidence of transformation in vitro on the basis of re-entry into the cell cycle, mitotic index, acquisition of a rounded phenotype and loss of anchorage-dependence [56]. In addition, Poloni et al. show that human MSCs from BM, chorionic villi and amniotic fluid are not susceptible to transformation after extensive in vitro expansion [57]. Chen et al. reported that human umbilical cord MSCs (hUC-MSCs) maintain their biological character and function after long-term in vitro culturing (P15). Since hUC-MSCs can be safely expanded in vitro and are not susceptible to malignant transformation in serum-free medium [58]. Therefore, basically MSCs can maintain a stable immunophenotype and chromosome structure and will not be malignant transformation after long term in vitro culture expansion. At the same time, increased evidences show that MSCs is also safe in vivo normal animal or animal disease model cell infusion therapy. Wang et al. evaluate the overall toxicology of hUC-MSCs in cynomolgus monkeys with repeated administrations and show that transplantation of hUC-MSCs did not affect the general health of cynomolgus monkeys [16]. Feng et al. evaluated the safety of human MSCs transplanted in cerebrum of Macaca fascicularis. Their results show that the transplantation of human MSCs in monkeys did not affect total IgM, IgG, CD3, CD4, or CD8 values. And transplantation of hMSCs to the cerebrum represents a safe alternative for clinical application of neurological disorders [59]. Francois et al. infused intravenously human MSCs to NOD/SCID mice with total body irradiation or local abdominal or leg irradiation and investigated the long term side-effect. Their results demonstrated that no tissue abnormality or abnormal human MSCs proliferation was observed at 120 days after irradiation. Meanwhile, These results showed that MSCs injection is safe and efficient for long-term treatment of severe complications after radiotherapy for patients refractory to conventional treatments [60]. Finally, human MSCs is also safe according to numerous clinical trial reports. Shi et al. assessed the safety and initial efficacy of UC-MSCs transfusions for acute-on-chronic liver failure (ACLF) patients associated with hepatitis B virus (HBV) infection. Their results suggest that UC-MSCs transfusions are safe in the clinic and may serve as a novel therapeutic approach for HBV-associated ACLF patients [61]. Wang et al. assess the safety and efficacy of human UC-MSCs in the treatment of rheumatoid arthritis (RA). Their results show that no serious adverse effects were observed during or after infusion. Furthermore, the treatment of UC-MSCs induced a significant remission of disease according to the 28-joint disease activity score [62]. Rodrigo et al. evaluates the safety and feasibility of intramyocardial MSCs injection in nine patients, shortly after AMI during short-term and 5-year follow-up. Their results suggest that intramyocardial injection of MSCs in patients shortly after AMI is feasible and safe up to 5-year follow-up [63]. Gupta et al. conducted a prospective double blind randomized placebo controlled multi-center study to determine the safety of BM-MSCs in patients with critical limb ischemia. Their results show that BM-MSCs are also safe when injected intramuscularly at a dose of 2 million cells/kg body weight [64]. In addition, Lee et al. performed a randomized pilot study to investigate the safety and efficacy of MSCs in patients with AMI. Their results showed that there was no treatment-related toxicity during intracoronary administration of MSCs. Meanwhile, no significant adverse cardiovascular events occurred during follow-up [65]. Futhermore，Pak et al. evaluate the safety of adipose tissue derived MSCs (AT-MSCs) that was used for patients suffering from orthopedic conditions. Ninety one patients suffering from orthopedic conditions were treated with autologous AT-MSCs. AT-MSCs were injected with PRP into various joints (n = 100). No neoplastic complications were detected at any AT-MSCs implantation sites. Based on longitudinal cohort, the autologous and uncultured ADSCs/PRP therapy could be considered to be safe when used as percutaneous local injections [66]. Till now, scientists evaluate the safety of MSCs through three different level including in vitro culture expansion, animal disease model and clinical trials and get a conclusion that MSCs is safe cell. In addition, MSCs preparation and production must be manipulated in GMP or GTP laboratory and only qualified MSCs can be used for clinical application for safety and achieving ideal clinical effect.