Abstract
The application of extracellular vesicles (EVs) as natural delivery vehicles capable of enhancing tissue regeneration could represent an exciting new phase in medicine. We sought to define the capacity of EVs derived from mineralising osteoblasts (MO-EVs) to induce mineralisation in mesenchymal stem cell (MSC) cultures and delineate the underlying biochemical mechanisms involved. Strikingly, we show that the addition of MO-EVs to MSC cultures significantly (P < 0.05) enhanced the expression of alkaline phosphatase, as well as the rate and volume of mineralisation beyond the current gold-standard, BMP-2. Intriguingly, these effects were only observed in the presence of an exogenous phosphate source. EVs derived from non-mineralising osteoblasts (NMO-EVs) were not found to enhance mineralisation beyond the control. Comparative label-free LC-MS/MS profiling of EVs indicated that enhanced mineralisation could be attributed to the delivery of bridging collagens, primarily associated with osteoblast communication, and other non-collagenous proteins to the developing extracellular matrix. In particular, EV-associated annexin calcium channelling proteins, which form a nucleational core with the phospholipid-rich membrane and support the formation of a pre-apatitic mineral phase, which was identified using infrared spectroscopy. These findings support the role of EVs as early sites of mineral nucleation and demonstrate their value for promoting hard tissue regeneration.
Highlights
Bone fractures present a growing worldwide medical and socioeconomic burden, with 8.9 million reported annually solely as a result of osteoporosis[1]
The fact that mineralising osteoblasts (MO)-extracellular vesicles (EVs) only enhanced matrix mineralisation in the presence of MM led to the hypothesis that small extracellular vesicles (sEVs) continued to accumulate calcium and phosphorus ions required for mineralisation within the developing ECM
It is hypothesised that a large subsection of these unbound vesicles continue to accumulate ions extracellularly and that this is critical for the sEV-induced mineralisation of human bone marrow stem cell (hBMSC) cultures
Summary
Bone fractures present a growing worldwide medical and socioeconomic burden, with 8.9 million reported annually solely as a result of osteoporosis[1]. ® with hyper-concentrated growth factors, such as bone morphogenetic proteins (BMPs) – for example INFUSE grafts[3] These methods are used in clinical practice with positive results, each suffers from significant limitations and even promising osteoinductive approaches utilising the growth factor BMP-2 have been subject to controversy and serious negative outcomes[4]. This means that current interventions offer a valuable method to facilitate bone repair, none of these approaches can be considered optimal and potent methods of inducing osteogenesis that are able to rapidly generate bone without associated patient morbidity are required[5]. We propose that there is considerable utility in the application of osteoblast-derived EVs as a source of osteoinductive components that can promote osteogenesis for hard tissue regeneration
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