Date Published: February 15, 2018
Publisher: Public Library of Science
Author(s): Xiaoqin Wang, Omar Omar, Forugh Vazirisani, Peter Thomsen, Karin Ekström, Xing-Ming Shi.
Human mesenchymal stem cell (hMSC)-derived exosomes have shown regenerative effects, but their role in osteogenesis and the underlying mechanism are yet to be determined. In this study, we examined the time-course secretion of exosomes by hMSCs during the entire process of osteogenic differentiation. Exosomes derived from hMSCs in various stages of osteogenic differentiation committed homotypic cells to differentiate towards osteogenic lineage, but only exosomes from late stages of osteogenic differentiation induced extracellular matrix mineralisation. Exosomes from expansion and early and late stages of osteogenic differentiation were internalised by a subpopulation of hMSCs. MicroRNA profiling revealed a set of differentially expressed exosomal microRNAs from the late stage of osteogenic differentiation, which were osteogenesis related. Target prediction demonstrated that these microRNAs enriched pathways involved in regulation of osteogenic differentiation and general mechanisms how exosomes exert their functions, such as “Wnt signalling pathway” and “endocytosis”. Taken together, the results show that MSCs secrete exosomes with different biological properties depending on differentiation stage of their parent cells. The exosomal cargo transferred from MSCs in the late stage of differentiation induces osteogenic differentiation and mineralisation. Moreover, it is suggested that the regulatory effect on osteogenesis by exosomes is at least partly exerted by exosomal microRNA.
Exosomes, with a diameter of 30–150 nm , are the only subgroup of extracellular vesicles (EVs) known to be derived from endosomes and released into the extracellular milieu upon the fusion of multivesicular bodies with the plasma membrane [2, 3]. Exosomes are secreted by different cell types and exist in most body fluids. The contents of exosomes include lipids, proteins and nucleic acids, such as mRNAs, microRNAs and long non-coding RNA [1, 4–6]. The constituents are highly dependent on the cell type of origin and the microenvironment. Exosomes have attracted considerable attention in recent years due to their capacity to mediate intercellular communication via the transfer of biologically active components, thereby influencing the phenotype and function of target cells . Moreover, exosomes have been shown to be involved in both physiological and pathological processes [7, 8]. The multiple and comprehensive functions of exosomes have resulted in an accumulated interest in using exosomes as biomarkers for diseases or as vectors for cell-free therapy .
A growing body of studies have demonstrated therapeutic effects by MSC-derived exosomes on wound healing and tissue repair in various physiological systems , which has led to great interest in the utilisation of MSC-derived exosomes in tissue engineering and regenerative medicine . It has been suggested that MSC-derived exosomes mediate their functions on tissue repair/regeneration via the promotion of angiogenesis [34–36]. Moreover, MSC-derived exosomes possess immunomodulatory potential and are capable of attenuating inflammation [34, 37]. Overall, current studies indicate that MSC-derived exosomes at least partially mimic the properties and function of their parent cells.
In conclusion, the present study shows that exosomes derived from hMSCs at the late stages of osteogenic differentiation can induce the osteogenic differentiation and mineralisation of recipient homotypic MSCs. MSC-derived exosomes were internalized by a subpopulation of MSCs. Further, microRNA profiling revealed a change in the expression of microRNAs in exosomes and their parent cells. Differentially expressed exosomal microRNAs from the late stages of osteogenic differentiation are osteogenesis related and enriched pathways related to osteogenic differentiation and mechanisms by which exosomes exert their functions. These results will deepen our understanding of the functions of MSC-derived exosomes and further benefit the application of MSC-derived exosomes for bone regeneration.