Mesenchymal stem cells (MSCs) are a population of hierarchical postnatal stem cells with the potential to differentiate into mesodermal lineage-derived cells, including osteoblasts, chondrocytes, adipocytes, cardiomyocytes, myoblasts and non-mesodermal lineage-derived cells, such as neural cells.
They are a promising source for regenerative medicine in terms of forming mineralised tissue to replace damaged and diseased tissue, says Dr Songtao Shi from the US.
The orofacial region contains multiple lineage, including bone marrow-derived MSCs (BMMSCs), dental-pulp stem cells, periodontal ligament stem cells (PDLSCs), stem cells from human exfoliated deciduous teeth, stem cells from root apical papilla, and gingival stem/progenitor cells. Our team of researchers at the University of Southern California has identified that PDLSCs can be used successfully to treat periodontitis with regeneration of cementum and Sharpey’s fibres in swine and humans. More interestingly, we used orofacial MSCs to regenerate root/periodontal complexes that are capable of supporting artificial porcelain crowns, resulting in restoration of normal tooth function in swine. We were also able to generate jaw osteonecrosis in mice and employed BMMSC implantation to treat the necrosis, suggesting a novel therapeutic approach to treating jaw necrosis using new BMMSC-generated bone and bone marrow.
Although stem cell-based regenerative medicine is a promising approach for functional tissue reconstruction, the role of immune response in cell-based tissue regeneration remains unclear. We demonstrated that pro-inflammatory T cells in the recipients inhibited BMMSC-mediated bone formation via T helper 1 cytokine interferon (IFN)-γ-induced down-regulation of runt-related transcription factor 2 pathway and tumour necrosis factor (TNF)-α-regulated BMMSC apoptosis. We found that TNF-α converted IFN-γ-activated non-apoptotic Fas to a caspase 3/8-associated apoptotic signalling in BMMSCs through inhibition of nuclear factor kappa B, resulting in BMMSC apoptosis.
Conversely, reduction of IFN-γ and TNF-α levels at the implantation sites by systemic infusion of Foxp3+ regulatory T cells markedly improved BMMSC-based bone regeneration and calvarial defect repair in C57BL6 mice. For potential pharmacological intervention, we demonstrated that local administration of aspirin reduced levels of IFN-γ and TNF-α at the implantation site and significantly improved BMMSC-based calvarial defect repair.
These results collectively uncover a previously unrecognised role of recipient T cells in BMMSC-based tissue engineering and suggest a practical approach to enhancing bone regeneration by pharmacological control of local cytokines.
MSC-based immunotherapy has demonstrated successful outcomes in several human diseases and preclinical disease models, including acute graft-versus-host disease, systemic lupus erythematosus and SS, etc. The promising results of such therapeutic effects have led to exploration of the underlying mechanisms. It has been shown that MSCs, including orofacial tissue-derived MSCs, target lymphocytes through several soluble factors, such as nitric oxide, indoleamine 2,3-dioxygenase, and the Fas/FasL pathway. The immunomodulatory properties of MSCs also play an important role in treating immune-related oral diseases, such as bisphosphonate-related osteonecrosis of the jaw characterised by suppression of regulatory T cells and activation of T helper 17 cells.
Our and others’ studies indicate the great potential for using MSCs to treat a variety of disorders and to regenerate functional mineralised tissue.
Dr Songtao Shi is an associate professor at the University of Southern California’s Center for Craniofacial Molecular Biology in Los Angeles in the US. This afternoon, he will be presenting a paper on MSCs as part of the scientific programme at this year’s FDI Annual World Congress congress in Hall F of the Hong Kong Convention and Exhibition Centre.