Abstract
The enhanced osteogenesis of mesenchymal stem cells (MSCs) modified by expression of cytotoxic T lymphocyte-associated antigen 4 (CTLA4) has been shown in previous studies, but the mechanism remains unknown. Here we found that the bone repair effect of CTLA4-modified MSCs in demineralized bone matrix (DBM) in a rabbit radius defect model was significantly better than that observed for unmodified MSCs in DBM or DBM alone, and the periostin (POSTN) expression in CTLA4-modified MSCs was significantly higher than that in unmodified MSCs both in vivo and in vitro. In addition, we also found that treatment of CTLA4-modified MSCs with soluble POSTN could inhibit the glycogen synthase kinase-3β activity and increase β-catenin expression through up-regulation of lipoprotein-related protein-6 phosphorylation to promote osteogenic differentiation, but blocking of integrin αvβ3, a receptor of POSTN, could suppress these effects. Our data demonstrated that POSTN expressed in response to CTLA4 can promote the osteogenesis of xenotransplanted MSCs through interaction with Wnt/β-catenin pathway.
Highlights
Successful treatment of a large bone defect using a tissue engineering strategy has been achieved in clinical practice[1,2]
We further demonstrated that the immune activation microenvironment reduced the expression of osteogenic markers in mesenchymal stem cells (MSCs) but not in the Cytotoxic T lymphocyte antigen 4 (CTLA4)-modified MSCs10, which indicated that the presence of CTLA4 maintained the osteogenic differentiation of MSCs in immune activation conditions; the underlying mechanisms are not clear
At 8 weeks, plain X-ray examination showed that osteoid tissues were presented in all implantation areas, but a better bone union was observed for the demineralized bone matrix (DBM) with CTLA4-modified MSCs compared to the DBM with control MSCs or DBM alone (Fig. 2)
Summary
Successful treatment of a large bone defect using a tissue engineering strategy has been achieved in clinical practice[1,2]. Animal studies showed that POSTN-deficient mice exhibit disrupted collagen fibrillogenesis in the periosteum, low bone mass, reduced cortical bone volume, and increased bone damage in response to fatigue loading injury[19,20]. These results suggest that POSTN is a structural protein of the ECM, and plays a key role in bone formation and metabolism in morphogenesis and postnatal development. We examined the ability of CTLA4-modified MSCs to promote the repair of a critical-sized segmental radius defects in vivo through bone tissue engineering and investigated the underlying mechanism, the involvement of the Wnt/β-catenin pathway. Our results may elucidate an exact mechanism for an allogenic human MSC-based bone tissue engineering strategy for the repair of large bone defects and provide a new theoretical basis for clinical treatment
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