PLGA–collagen–ECM hybrid scaffolds functionalized with biomimetic extracellular matrices secreted by mesenchymal stem cells during stepwise osteogenesis-co-adipogenesis

Abstract

A shift in osteogenesis toward adipogenesis of human bone marrow-derived mesenchymal stem cells (hMSCs) is a crucial pathological factor in the progression of osteoporosis. The development of an in vitro three-dimensional (3D) model that reflects the dynamic remodeling of extracellular matrices (ECMs) during simultaneous osteogenesis and adipogenesis of hMSCs can provide a useful tool to mimic the process and to investigate how 3D ECMs balance the osteogenic and adipogenic differentiation of hMSCs. In this study, ECMs secreted by hMSCs during their stepwise osteogenesis-co-adipogenesis were deposited on hybrid meshes of poly(lactide-co-glycolide) (PLGA) and collagen to prepare biomimetic PLGA–collagen–ECM hybrid scaffolds. Four types of stepwise differentiation ECMs were prepared: ECMs secreted by hMSCs at early stages of osteogenesis and adipogenesis (EOEA–ECMs), hMSCs at early stages of osteogenesis and late stages of adipogenesis (EOLA–ECMs), hMSCs at late stages of osteogenesis and early stages of adipogenesis (LOEA–ECMs) and hMSCs at late stages of osteogenesis and late stages of adipogenesis (LOLA–ECMs). The deposited ECMs had different compositions that were dependent on the different stages of osteogenesis and adipogenesis. They also showed different effects on balancing the adipogenic and osteogenic differentiation of hMSCs. The EOEA–ECM scaffold had a promotive effect on adipogenesis and a suppressive effect on the osteogenesis of hMSCs. The LOEA–ECM and LOLA–ECM scaffolds showed a promotive effect on osteogenesis and a moderate effect on the adipogenic differentiation of hMSCs. The EOLA–ECM scaffold exhibited a suppressive effect on both osteogenesis and adipogenesis of hMSCs. However, the EOLA–ECM scaffold promoted hMSC proliferation more strongly than the other ECM scaffolds. The results indicated that dynamically remodeling ECM scaffolds could affect the osteogenic and adipogenic differentiation of hMSCs and should provide a useful 3D cell culture model for the investigation of ECM–cell interactions.