Osteoblast/fibroblast coculture derived bioactive ECM with unique matrisome profile facilitates bone regeneration

Extracellular matrix (ECM) with mimetic tissue niches was attractive to facilitate tissue regeneration in situ via recruitment of endogenous cells and stimulation of self-healing process. However, how to engineer the complicate tissue specific ECM with unique matrisome in vitro was a challenge of ECM-based biomaterials in tissue engineering and regenerative medicine. Here, we introduced coculture system to engineer bone mimetic ECM niche guided by cell-cell communication. In the cocultures, fibroblasts promoted osteogenic differentiation of osteoblasts via extracellular vesicles. The generated ECM (MN-ECM) displayed a unique appearance of morphology and biological components. The advantages of MN-ECM were demonstrated with promotion of multiple cellular behaviors (proliferation, adhesion and osteogenic mineralization) in vitro and bone regeneration in vivo. Moreover, proteomic analysis was used to clarify the molecular mechanism of MN-ECM, which revealed a specific matrisome signature. The present study provides a novel strategy to generate ECM with tissue mimetic niches via cell-cell communication in a coculture system, which forwards the development of tissue-bioactive ECM engineering along with deepening the understanding of ECM niches regulated by cells for bone tissue engineering.