Abstract
Bone defects are a common orthopaedic concern, and an increasing number of tissue-engineered bones (TEBs) are used to repair bone defects. Allogeneic mesenchymal stem cells (allo-MSCs) are used as seed cells in many approaches to develop TEB constructs, but the immune response caused by allogeneic transplantation may lead to transplant failure. V gamma 4 T (Vγ4T) cells play an important role in mediating the immune response in the early stage after transplantation; therefore, we wanted to verify whether suppressing Vγ4T cells by herpesvirus entry mediator (HVEM)/B and T lymphocyte attenuator (BTLA) signalling can promote MSCs osteogenesis in the transplanted area. In vitro experiments showed that the osteogenic differentiation of MSCs and Vγ4T cells was weakened after co-culture, and an increase in interleukin-17 (IL-17) and interferon-γ (IFN-γ) levels was detected in the culture supernatant. HVEM-transfected MSCs (MSCs-HVEM) still exhibited osteogenic differentiation activity after co-culture with Vγ4T cells, and the levels of IL-17 and IFN-γ in the co-culture supernatant were significantly reduced. In vivo experiments revealed that inflammation in the transplanted area was reduced and osteogenic repair was enhanced after Vγ4T cells were removed. MSCs-HVEM can also consistently contribute to reduced inflammation in the transplanted area and enhanced bone repair in wild-type (WT) mice. Therefore, our experiments verified that HVEM can promote the osteogenesis of allo-MSCs by inhibiting IL-17 and IFN-γ secretion from Vγ4T cells.
Highlights
Bone defects are common diseases treated in orthopaedic clinics, and most bone defects are caused by bone tuberculosis, osteoarthritis, bone tumour resection and severe fracture [1, 2]
As the osteogenic differentiation ability of allo-mesenchymal stem cells (MSCs) was inhibited by IL-17 and IFN-g [16, 21], the early source of IL-17 in the transplant area was identified as V gamma 4 T (Vg4T) cells [12]; we investigated whether herpesvirus entry mediator (HVEM)-B and T lymphocyte attenuator (BTLA) signalling could inhibit the function of Vg4T cells to promote allo-MSCbased tissueengineered bones (TEBs) repair of bone fractures
The methods of constructing TEB with MSCs were based on our previous studies [16], and TEB was transplanted into sites of femoral-amputated defects created by a high-speed motor
Summary
Bone defects are common diseases treated in orthopaedic clinics, and most bone defects are caused by bone tuberculosis, osteoarthritis, bone tumour resection and severe fracture [1, 2]. The development of tissue-engineered bone (TEB) derived from mesenchymal stem cells (MSCs) as seed cells have begun to emerge in the medical and scientific communities. Autologous bone marrow-derived MSCs (BMMSCs) were implanted into the scaffold material of TEB. This structure was found to actively assist in bone regeneration [2,3,4,5]. It takes too long to construct autologous TEB grafts in vitro, and it is difficult for autologous MSCs to meet the needs of individual and large-scale clinical applications. Allo-MSCs have been used as seed cells by many researches aiming to develop ideal TEB constructs [6]
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