Objective. The role of most p38 MAPK isoforms in inflammatory arthritis is not known. This study was undertaken to evaluate p38␥ and p38␦ deficiency in the collagen-induced arthritis (CIA) model.Methods. Wild-type, p38␥ ؊/؊ , p38␦ ؊/؊ , and p38␥/␦ ؊/؊ mice were immunized with chicken type II collagen, and disease activity was evaluated by semiquantitative scoring and histologic assessment. Serum cytokine levels and in vitro T cell cytokine responses were quantified by flow cytometry and multiplex analysis, and serum anticollagen antibody levels by enzymelinked immunosorbent assay. Cytokine and p38 MAPK isoform expression in joints were determined by quantitative polymerase chain reaction.Results. Compound p38␥ and p38␦ deficiency markedly reduced arthritis severity compared with that in wild-type mice, whereas lack of either p38␥ or p38␦ had an intermediate effect. Joint damage was minimal in arthritic p38␥/␦ ؊/؊ mice compared with wild-type mice. The p38␥/␦ ؊/؊ mice had lower levels of pathogenic anticollagen antibodies and interleukin-1␤ (IL-1␤) and tumor necrosis factor ␣ than controls. In vitro T cell assays showed reduced proliferation, interferon-␥ (IFN␥) production, and IL-17 production by lymph node cells from p38␥/␦ ؊/؊ mice. IL-17 and IFN␥ messenger RNA expression in joints was significantly inhibited in p38␥/␦ ؊/؊ mice. Wild-type chimeric mice with p38␥/␦ ؊/؊ bone marrow did not show decreased CIA.Conclusion. Reduced disease severity in p38␥/␦ ؊/؊ mice was associated with lower cytokine production and anticollagen antibody responses than in controls, indicating that p38␥ and p38␦ are crucial regulators of inflammatory joint destruction in CIA. Our findings indicate that p38␥ and p38␦ are potential therapeutic targets in complex diseases, such as rheumatoid arthritis, that involve innate and adaptive immune responses.

The main strategy of cancer treatment has focused on attacking the tumor cells. Some cancers initially responsive to chemotherapy become treatment-resistant. Another strategy is to block the formation of tumor vessels. However, tumors also become resistant to anti-angiogenic treatments, mostly due to other cells and factors present in the tumor microenvironment, and hypoxia in the central part of the tumor. The need for new cancer therapies is significant. The use of nanoparticle-based therapy will improve therapeutic efficacy and targeting, while reducing toxicity. However, due to inefficient accumulation in tumor sites, clearance by reticuloendothelial organs and toxicity, internalization or conjugation of drug-loaded nanoparticles (NPs) into mesenchymal stem cells (MSCs) can increase efficacy by actively delivering them into the tumor microenvironment. Nanoengineering MSCs with drug-loaded NPs can increase the drug payload delivered to tumor sites due to the migratory and homing abilities of MSCs. However, MSCs have some disadvantages, and exosomes and membranes from different cell types can be used to transport drug-loaded NPs actively to tumors. This review gives an overview of different cancer approaches, with a focus on hypoxia and the emergence of NPs as drug-delivery systems and MSCs as cellular vehicles for targeted delivery due to their tumor-homing potential.

BackgroundThe immunosuppressive and anti-inflammatory properties of mesenchymal stromal cells (MSC) have prompted their therapeutic application in several autoimmune diseases, including rheumatoid arthritis. Adult MSC are finite and their clinical use is restricted by the need for long-term expansion protocols that can lead to genomic instability. Inhibition of Smad2/3 signaling in human pluripotent stem cells (hPSC) provides an infinite source of MSC that match the phenotype and functional properties of adult MSC. Here, we test the therapeutic potential of hPSC-MSC of embryonic origin (embryonic stem cell-derived mesenchymal stromal cells, hESC-MSC) in the experimental model of collagen-induced arthritis (CIA).MethodsCIA was induced in DBA/1 mice by immunization with type II collagen (CII) in Complete Freund’s Adjuvant (CFA). Mice were treated with either a single dose (106 cells/mouse) of hESC-MSC on the day of immunization (prophylaxis) or with three doses of hESC-MSC every other day starting on the day of arthritis onset (therapy). Arthritis severity was evaluated daily for six weeks and ten days, respectively. Frequency of Treg (FoxP3+), Th1 (IFNγ+) and Th17 (IL17+) CD4+ T cells in inguinal lymph nodes (ILN) was quantified by flow cytometry. Serum levels of anti-CII antibodies were determined by ELISA. Detection of hESC-MSC and quantification of murine and human indoleamine 2,3 dioxygenase (IDO1) expression was performed by quantitative real-time PCR. Statistical differences were analyzed by ANOVA and the Mann-Whitney U test.ResultsAdministration of hESC-MSC to mice with established arthritis reduced disease severity compared to control-treated mice. Analysis of CD4 T cell populations in treated mice showed an increase in FoxP3+ Treg and IFNγ+ Th1 cells but not in Th17 cells in the ILN. Anti-CII antibody levels were not affected by treatment. Migration of hESC-MSC to the ILN in treated mice was associated with the induction of murine IDO1.ConclusionTreatment with hESC-MSC ameliorates CIA by inducing IFNγ+ Th1 cells and IDO1 in the host. Thus, hESC-MSC can provide an infinite cellular source for treatment of rheumatoid arthritis.

Placenta-derived mesenchymal stem/stromal cells (PMSC) present several aspects that make them more attractive as cellular therapy than their counterparts from other tissues, such as MSC from bone marrow or adipose tissue in regenerative medicine. Placenta-derived MSC have been used to treat a variety of disorders, such as, cancer, liver and cardiac diseases, ulcers, bone repair, and neurological diseases. Placenta-derived MSC are relatively new types of MSC with specific immunomodulatory properties and whose mechanisms are still unknown. Placenta-derived MSC secrete some soluble factors that seem to be responsible for their therapeutic effects, i.e., they have paracrine effects. On the other hand, Placentaderived MSC can also serve as cellular vehicles and/or delivery systems for medications due to their migration capacity and their tropism for injury sites. Nanotechnology is an important field, which has undergone rapid development in recent years for the treatment of injured organs. Due to the special characteristics of placenta-derived MSC, the combination of these cells with nanotechnology will be a significant and highly promising field that will provide significant contributions in the regenerative medicine field in the near future.

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