Use of Extracellular Vesicles for Cell-Free Regenerative Medicine in Osteochondral and Bone-Related Therapies

Abstract

The tissue engineering paradigm considers cells, signals and scaffolds as the major elements of tissue engineering approaches to repair and/or regenerate tissues [1]. Unexpectedly, a paradigm shift is taking place in this field by the only use of extracellular vesicles (EVs) to deliver the right signals to the damaged tissue. In recent years, EVs role in intercellular signalling has begun to emerge [2]. EVs range in size from 30 to 1000 nm and can be derived from the endosomal system (exosomes, 70-150 nm) or produced by outward budding of the plasma membrane (micro vesicles, 100-1000 nm) [3,4]. All EVs are enriched in proteins, lipids, and nucleic acids (DNA, mRNA, miRNA, tRNA) that can be delivered to recipient cells for cell- to-cell communication [5]. In fact, EVs have recently evolved to be vital components of cell-based therapies based on the observations that the beneficial effects of cell therapies could not be attributed to cell survival and differentiation, leading to the thought that cell therapies act in a paracrine rather than in a cellular manner [6]. This shift was based on in vivo data showing that stem cell engraftment and differentiation at injury sites was very low and transient [7-11]. And on the observation that conditioned media from cultured stem cells reproduces some of the beneficial effects of intact cells [12,13]. This paracrine effect exerted by stem cells would depend on their capacity to secrete soluble factors [14], but also, by the release of EVs [15]. In particular, preclinical models studying graft versus host disease, acute kidney failure and ischemic stroke suggest that EVs exert the stem cells' therapeutic effects