Journal of immunology and regenerative medicine最新文献

The immunosuppressive capacity of human mesenchymal stromal cells (MSCs) renders them promising candidates for treating diverse immune disorders. However, after hundreds of clinical trials, there are still no MSC therapies approved in the United States. MSCs require specific cues to adopt their immunosuppressive phenotype, and yet most clinical trials use cells expanded in basic culture medium and growth conditions. We propose that priming MSCs prior to administration will improve their therapeutic efficacy. Interferon-gamma (IFN-γ) priming are cues common to situations of immune escape that have individually shown promise as MSC priming cues but have not been systematically compared. Using mixed lymphocyte reactions, we show that priming MSCs with either cue alone improves T-cell inhibition. However, combining the two cues results in additive effects and markedly enhances the immunosuppressive phenotype of MSCs. We demonstrate that IFN-γ induces expression of numerous immunosuppressive proteins (IDO, PD-L1, HLA-E, HLA-G), whereas hypoxia switches MSCs to glycolysis, causing rapid glucose consumption and production of T-cell inhibitory lactate levels. Dual IFN-γ/hypoxia primed MSCs display both attributes and have even higher induction of immunosuppressive proteins over IFN-γ priming alone (IDO and HLA-G), which may reflect another benefit of metabolic reconfiguration.

The aim of this study was to characterize cells from carious teeth (DPSCs-CT) in terms of proliferation, mesoderm differentiation and gene expression profile as compared to DPSCs. Up-regulated genes in DPSCs-CT was detected via qPCR array and downstream trans-differentiation toward hepatocyte-like cells was performed. Additionally, qPCR array was employed to describe the genes pertaining to EMT and their possible mechanism. Despite basic characterizations favoured DPSCs, peculiarly DPSCs-CT had expressed a tremendous expression of hepatocyte growth factor gene (HGF; > 20 fold). To ascertain the notion that DPSCs-CT can be utilized for generating hepatic-like cells, we further de-toured the cells into hepatic lineage. As expected, DPSCs-CT expressed higher (>3 fold) hepatic markers such as SOX17, HNF3β, GATA4, AFP, TAT, TDO, AAT and ALB at both gene and protein levels. Improved homing capacity of DPSCs-CT and overall liver function were observed in bile duct ligation (BDL) treated rats. Mesenchymal-epithelial transition (MET) profiling was further conducted to elucidate the role HGF in promoting differentiation of DPSCs-CT and surprisingly, more than 40 genes related to MET were highly expressed in DPSCs-CT. To conclude, this information highlighted the potential of DPSCs-CT to differentiate into putative hepatocyte and subsequent usage for liver regeneration.

Mechanisms underlying early inflammation and subsequent muscle repair after injury are typically described in terms of the coordinated action of numerous waves of immune cells. It is now emerging, however, that a complex network of leukocyte- and stromal cell-derived cytokines orchestrate the early infiltration and function of pro-inflammatory leukocytes and underlies subsequent immune-mediated repair and regenerative responses. This review discusses how recently defined cytokines fit into the previously outlined cytokine networks shaping tissue damage and repair after injury. We also discuss new roles for previously well-characterized cytokines in muscle injury and repair responses. Finally, we summarize how modulation of local and systemic cytokine networks involved in muscle injury and repair by synthetic and naturally-derived biomaterials and stem cells is showing promise as a clinically applicable means to promote muscle regeneration and improve function after volumetric muscle loss and other muscle diseases.

Introduction

The development of novel immunomodulatory strategies that might decrease the need for systemic immune suppression would greatly enable the utility of cell-based therapies. Cell transplantation on biomaterial scaffolds offers a unique opportunity to engineer a site to locally polarize immunogenic antigen generation. Herein, we investigated the localized delivery of IL-33, which is a novel cytokine that has been shown to have beneficial immunomodulatory effects in certain transplant models as mediating anti-inflammatory properties in the adipose tissue, to determine its feasibility for use as an immunomodulatory agent.

Results

Localized IL-33 delivery from poly(lactide-co-glycolide) (PLG) scaffolds implanted into the epididymal fat specifically increased the Foxp3⁺ population of CD4⁺ T cells in both blank scaffold implants and scaffolds seeded with allogeneic islets. In allogeneic islet transplantation, we found IL-33 delivery results in a local upregulation of graft-protective T cells where 80% of the local CD4⁺ population is Foxp3⁺ and overall numbers of graft destructive CD8⁺ T cells are decreased, resulting in a prolonged graft survival. Interestingly, local IL-33 also delayed islet engraftment by primarily inducing a local upregulation of Th2 cytokines, including IL-4 and IL-5, leading to increased populations of ST2⁺ Type 2 innate lymphoid cells (ILC2s) and Siglec F⁺ eosinophils.

Conclusions

These results suggest that local IL-33 delivery from biomaterial scaffolds can be used to increase Tregs enriched in adipose tissue and reduce graft-destructive T cell populations but may also promote innate cell populations that can delay cell engraftment.

Extracellular matrix biomaterials have been shown to promote constructive remodeling in many preclinical and clinical applications. This response has been associated with the promotion of a timely switch from pro-inflammatory (M1) to anti-inflammatory (M2) macrophages. A previous study has shown that this beneficial response is lost when these biomaterials are derived from aged animals. This study examined the impact of small intestine submucosa (SIS) derived from 12, 26 and 52 week old pigs on the phenotype and function of bone marrow macrophages derived either from 2 or 18 month old mice. Results showed that 52 week old SIS promoted less iNOS in 2 month macrophages and Fizz1 expression in 2 and 18 month compared to 12 week SIS. Pro-inflammatory cytokine exposure to 52 week SIS-treated macrophages resulted in higher iNOS in 18 month macrophages and reduced MHC-II expression in 2 month macrophages, as well as reduced nitric oxide production in comparison to 12 week SIS. These results indicate that ECM derived from aged animals promotes an altered macrophage phenotype compared to young controls. This suggests that sourcing of ECM from young donors is important to preserve constructive remodeling outcomes of ECM biomaterials. Alteration of macrophage phenotype by aged ECM also raises the hypothesis that alterations in aged ECM may play a role in immune dysfunction in aged individuals.