Dataset Information

Local control of the host immune response performed with mesenchymal stem cells: perspectives for functional intracerebral xenotransplantation.

ABSTRACT: Foetal pig neuroblasts are interesting candidates as a cell source for transplantation, but xenotransplantation in the brain requires the development of adapted immunosuppressive treatments. As systemic administration of high doses of cyclosporine A has side effects and does not protect xenotransplants forever, we focused our work on local control of the host immune responses. We studied the advantage of cotransplanting syngenic mesenchymal stem cells (MSC) with porcine neuroblasts (pNb) in immunocompetent rat striata. Two groups of animals were transplanted, either with pNb alone or with both MSC and pNb. At day 63, no porcine neurons were detected in the striata that received only pNb, while four of six rats transplanted with both pNb and MSC exhibited healthy porcine neurons. Interestingly, 50% of the cotransplanted rats displayed healthy grafts with pNF70+ and TH+ neurons at 120 days post-transplantation. qPCR analyses revealed a general dwindling of pro- and anti-inflammatory cytokines in the striata that received the cotransplants. Motor recovery was also observed following the transplantation of pNb and MSC in a rat model of Parkinson's disease. Taken together, the present data indicate that the immunosuppressive properties of MSC are of great interest for the long-term survival of xenogeneic neurons in the brain.

SUBMITTER: Leveque X

PROVIDER: S-EPMC4288356 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Local control of the host immune response performed with mesenchymal stem cells: perspectives for functional intracerebral xenotransplantation.

Lévêque Xavier X Mathieux Elodie E Nerrière-Daguin Véronique V Thinard Reynald R Kermarrec Laetitia L Durand Tony T Haudebourg Thomas T Vanhove Bernard B Lescaudron Laurent L Neveu Isabelle I Naveilhan Philippe P

Journal of cellular and molecular medicine 20141014 1

Foetal pig neuroblasts are interesting candidates as a cell source for transplantation, but xenotransplantation in the brain requires the development of adapted immunosuppressive treatments. As systemic administration of high doses of cyclosporine A has side effects and does not protect xenotransplants forever, we focused our work on local control of the host immune responses. We studied the advantage of cotransplanting syngenic mesenchymal stem cells (MSC) with porcine neuroblasts (pNb) in immu ...[more]

PMID: 25310920

Similar Datasets

Project description:Xenogeneic chondrocytes and allogeneic mesenchymal stem cells (MSC) are considered a potential source of cells for articular cartilage repair. We here assessed the immune response triggered by xenogeneic chondrocytes when injected intraarticularly, as well as the immunoregulatory effect of allogeneic bone marrow-derived MSC after systemic administration. To this end, a discordant xenotransplantation model was established by injecting three million porcine articular chondrocytes (PAC) into the femorotibial joint of Lewis rats and monitoring the immune response. First, the fate of MSC injected using various routes was monitored in an in vivo imaging system. The biodistribution revealed a dependency on the injection route with MSC injected intravenously (i.v.) succumbing early after 24 h and MSC injected intraperitoneally (i.p.) lasting locally for at least 5 days. Importantly, no migration of MSC to the joint was detected in rats previously injected with PAC. MSC were then administered either i.v. 1 week before PAC injection or i.p. 3 weeks after to assess their immunomodulatory function on humoral and adaptive immune parameters. Anti-PAC IgM and IgG responses were detected in all PAC-injected rats with a peak at week 2 postinjection and reactivity remaining above baseline levels by week 18. IgG2a and IgG2b were the predominant and long-lasting IgG subtypes. By contrast, no anti-MSC antibody response was detected in the cohort injected with MSC only, but infusion of MSC before PAC injection temporarily augmented the anti-PAC antibody response. Consistent with a cellular immune response to PAC in PAC-injected rats, cytokine/chemokine profiling in serum by antibody array revealed a distinct pattern relative to controls characterized by elevation of multiple markers at week 2, as well as increases in proliferation in draining lymph nodes. Notably, systemic administration of allogeneic MSC under the described conditions did not diminish the immune response. IL-2 measurements in cocultures of rat peripheral blood lymphocytes with PAC indicated that PAC injection induced some T-cell hyporesponsiveness that was not enhanced in the cohorts additionally receiving MSC. Thus, PAC injected intraarticularly in Lewis rats induced a cellular and humoral immune response that was not counteracted by the systemic administration of allogeneic MSC under the described conditions.

Project description:The host immune system (T-lymphocytes and their pro-inflammatory cytokines) has been shown to compromise bone regeneration ability of mesenchymal stem cells (MSCs). We have recently shown that hydrogel, used as an encapsulating biomaterial affects the cross-talk among host immune cells and MSCs. However, the role of hydrogel elasticity and porosity in regulation of cross-talk between dental-derived MSCs and immune cells is unclear. In this study, we demonstrate that the modulus of elasticity and porosity of the scaffold influence T-lymphocyte-dental MSC interplay by regulating the penetration of inflammatory T cells and their cytokines. Moreover, we demonstrated that alginate hydrogels with different elasticity and microporous structure can regulate the viability and determine the fate of the encapsulated MSCs through modulation of NF-kB pathway. Our in vivo data show that alginate hydrogels with smaller pores and higher elasticity could prevent pro-inflammatory cytokine-induced MSC apoptosis by down-regulating the Caspase-3- and 8- associated proapoptotic cascades, leading to higher amounts of ectopic bone regeneration. Additionally, dental-derived MSCs encapsulated in hydrogel with higher elasticity exhibited lower expression levels of NF-kB p65 and Cox-2 in vivo. Taken together, our findings demonstrate that the mechanical characteristics and microarchitecture of the microenvironment encapsulating MSCs, in addition to presence of T-lymphocytes and their pro-inflammatory cytokines, affect the fate of encapsulated dental-derived MSCs. STATEMENT OF SIGNIFICANCE:In this study, we demonstrate that alginate hydrogel regulates the viability and the fate of the encapsulated dental-derived MSCs through modulation of NF-kB pathway. Alginate hydrogels with smaller pores and higher elasticity prevent pro-inflammatory cytokine-induced MSC apoptosis by down-regulating the Caspase-3- and 8- associated proapoptotic cascade, leading to higher amounts of ectopic bone regeneration. MSCs encapsulated in hydrogel with higher elasticity exhibited lower expression levels of NF-kB p65 and Cox-2 in vivo. These findings confirm that the fate of encapsulated MSCs are affected by the stiffness and microarchitecture of the encapsulating hydrogel biomaterial, as well as presence of T-lymphocytes/pro-inflammatory cytokines providing evidence concerning material science, stem cell biology, the molecular mechanism of dental-derived MSC-associated therapies, and the potential clinical therapeutic impact of MSCs.

Project description:Extracellular vesicles (EVs) are on the edge of innovation aimed at regenerative and therapeutic applications, including wound healing, by containing therapeutic agents originating from secreting cells. Moreover, silver nanoparticles (AgNPs) play a role in wound healing because they have antiseptic activities. Therefore, in this study, we used sequencing technology to investigate the mRNA profile in UCMSC-derived exosomes (EXs). We also attempted to determine the role of the transcriptome, particularly in cutaneous wound healing, using bioinformatics analysis. Additionally, we investigated the efficacy of utilising a combination of UCMSC-derived EXs and AgNPs on burned animal models. Results showed that a large number of protein-coding genes (4578 genes) have been detected in UCMSC-derived EXs, among which 2004 genes are upregulated in exosomes while 2574 genes are downregulated compared to secreting cells. Interestingly, many genes enriched in exosomes were associated with the biology of the wound healing process. Gene ontology (GO) term and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analysis indicated the upregulated exosomal genes belonging to GO terms and KEGG pathways related to signaling pathways such as DNA replication, ribosome, cell cycle, and pyrimidine metabolism. Further investigations that aimed to test exosomes and AgNPs in wound healing stimulation confirmed the faster healing capacity belongs to all exosomes, AgNPs, and a combination of EXs and AgNPs in the early healing process. The exosomes also expressed their capacity to enhance the dermal fibroblast proliferation. Our findings indicated the selective sorting of mRNAs into EXs, the potential of EXs, and the combination of EXs with AgNPs in cutaneous wound healing. Extracellular vesicles (EVs) are on the edge of innovation aimed at regenerative and therapeutic applications, including wound healing, by containing therapeutic agents originating from secreting cells. Moreover, silver nanoparticles (AgNPs) play a role in wound healing because they have antiseptic activities. Therefore, in this study, we used sequencing technology to investigate the mRNA profile in UCMSC-derived exosomes (EXs). We also attempted to determine the role of the transcriptome, particularly in cutaneous wound healing, using bioinformatics analysis. Additionally, we investigated the efficacy of utilising a combination of UCMSC-derived EXs and AgNPs on burned animal models. Results showed that a large number of protein-coding genes (4578 genes) have been detected in UCMSC-derived EXs, among which 2004 genes are upregulated in exosomes while 2574 genes are downregulated compared to secreting cells. Interestingly, many genes enriched in exosomes were associated with the biology of the wound healing process. Gene ontology (GO) term and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analysis indicated the upregulated exosomal genes belonging to GO terms and KEGG pathways related to signaling pathways such as DNA replication, ribosome, cell cycle, and pyrimidine metabolism. Further investigations that aimed to test exosomes and AgNPs in wound healing stimulation confirmed the faster healing capacity belongs to all exosomes, AgNPs, and a combination of EXs and AgNPs in the early healing process. The exosomes also expressed their capacity to enhance the dermal fibroblast proliferation. Our findings indicated the selective sorting of mRNAs into EXs, the potential of EXs, and the combination of EXs with AgNPs in cutaneous wound healing. Extracellular vesicles (EVs) are on the edge of innovation aimed at regenerative and therapeutic applications, including wound healing, by containing therapeutic agents originating from secreting cells. Moreover, silver nanoparticles (AgNPs) play a role in wound healing because they have antiseptic activities. Therefore, in this study, we used sequencing technology to investigate the mRNA profile in UCMSC-derived exosomes (EXs). We also attempted to determine the role of the transcriptome, particularly in cutaneous wound healing, using bioinformatics analysis. Additionally, we investigated the efficacy of utilising a combination of UCMSC-derived EXs and AgNPs on burned animal models. Results showed that a large number of protein-coding genes (4578 genes) have been detected in UCMSC-derived EXs, among which 2004 genes are upregulated in exosomes while 2574 genes are downregulated compared to secreting cells. Interestingly, many genes enriched in exosomes were associated with the biology of the wound healing process. Gene ontology (GO) term and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analysis indicated the upregulated exosomal genes belonging to GO terms and KEGG pathways related to signaling pathways such as DNA replication, ribosome, cell cycle, and pyrimidine metabolism. Further investigations that aimed to test exosomes and AgNPs in wound healing stimulation confirmed the faster healing capacity belongs to all exosomes, AgNPs, and a combination of EXs and AgNPs in the early healing process. The exosomes also expressed their capacity to enhance the dermal fibroblast proliferation. Our findings indicated the selective sorting of mRNAs into EXs, the potential of EXs, and the combination of EXs with AgNPs in cutaneous wound healing.

Dataset Information

Local control of the host immune response performed with mesenchymal stem cells: perspectives for functional intracerebral xenotransplantation.

Publications

Local control of the host immune response performed with mesenchymal stem cells: perspectives for functional intracerebral xenotransplantation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets