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Stem Cell Transplant Down to a T - Mesenchymal stem cell–based tissue regeneration is governed by recipient T lymphocytes via IFNγ and TNFα

From Nature Medicine
By Stuart P. Atkinson

Bone marrow mesenchymal stem cells (BMMSCs) are multipotent adult stem cells which are capable of differentiating into various cell types (osteoblasts, adipocytes and chondrocytes (Friedenstein et al, Pittinger et al and Prockop)) and their regenerative capabilities shown to be of clinical importance in the treatment of bone and bone-associated tissue disease (Caplan, García-Gómez et al, Tasso et al and Bueno and Glowacki). Further, BMMSCs have been shown to interact with immune cells to aid bone regeneration but the specific function of recipient immune cells has not been assessed. Now, researchers from the laboratory of Songtao Shi at the University of Southern California, USA, have found that recipient immune cells, specifically T cells, govern BMMSC-based tissue regeneration using an established in vivo BMMSC implantation system (Liu et al).

Initial analysis using the in vivo BMMSC implantation system found that autologous BMMSCs did not generate bone in C57BL/6 mice, but when BMMSCs were implanted into T cell–deficient nude mice, they formed bone and bone-associated hematopoietic marrows.  However infusion of T-cells not enriched for a specific population before BMMSC implantation completely blocked bone formation. Analysis of specific T-cell populations found that CD4+ or CD4+CD25 T cell infusion totally blocked BMMSC-mediated bone formation in nude mice and CD4+CD25+Foxp3+ regulatory T cells (Treg cells) improved the formation of bone marrow elements. Systemic infusion of CD4+ T-cells led to the appearance of these cells at the BMMSC implant, and bone formation was observed at 14 days. To assess the mechanism of T cell–regulated BMMSC-based bone formation, cytokines which could be released by the T-cells were assessed in the BMMSC implant model and, notably, high concentrations of IFN-γ and TNF-α were found to be correlated with a lack of new bone formation. In contrast, antibody-mediated neutralisation of IFNγ and TNFα significantly improved BMMSC-mediated bone formation. Treg cells, which were shown to improve bone formation, are reported to inhibit T-cell activation and reduce IFNγ and TNFα production (Lourenco and La Cava, Zhou et al) and in the BMMSC implant model, Treg cell infusion 2 days before BMMSC implantation led to an increased amount of bone formation, associated with a reduced level of IFNγ and TNF-α.

Ifng−/− T-cells did not block BMMSC-mediated bone formation and analysis found that IFNγ inhibited the osteogenic differentiation of BMMSCs, associated with an upregulation of the osteogenesis inhibitor Smad6 and downregulation of the osteogenic genes Runx2, Ocn and Alp. IFNγ was also found to synergistically enhance BMMSC apoptosis with TNF-α; BMMSCs implanted with TNFα showed a significant reduction in the number of surviving cells compared to the untreated control, with further addition of IFNγ leading to total cell death. This was associated with Fas internalization and clustering, leading to the activation of Caspase 3 and 8 mediated by the reduction in concentration of TNFR2 and that TNFR2’s -anti-apoptotic effect caused by IFNγ and TNF-α. Therefore the Treg cells may limit the effect of IFNγ and TNFα, inhibiting BMMSC apoptosis and promoting bone formation.

These studies also indicated the Treg cells may improve cell-based tissue engineering, and this was further demonstrated through the complete repair of a critical-sized calvarial (cranial) bone defect in wild type mice following infusion of Treg cells into recipients 2 days before BMMSC implantation, with BMMSC and gelfoam implantation only leading to moderate bone repair. Aspirin has been reported to inhibit the function of TNFα and IFNγ (Kwon et al), and was found to increase survival of BMMSCs in the implantation model and increase BMMSC-mediated bone for­mation compared to the untreated group. Aspirin also restored the bone formation that was sup­pressed by IFNγ or TNFα treatment of BMMSCs. Aspirin also resulted in a dose-dependent improvement of BMMSC-mediated bone regeneration in the calvarial defect area compared to the control BMMSC group.

Collectively these data show that both IFNγ and TNFα have key roles in governing BMMSC-based bone formation, through the mediation of BMMSC apoptosis requiring Fas signalling and subsequent activation of Caspase 8 or 3. Most importantly, these data find that Treg cells improves BMMSC-mediated bone repair as does Aspirin, through the downregulation of TNFα and IFNγ. This demonstrates that analysis of the basic biology of tissue rejection can lead to a simple pharmacological answer to a trying problem in transplantation.



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