Mesenchymal Stem Cell-Derived Exosomes and MicroRNAs in Cartilage Regeneration: Biogenesis, Efficacy, miRNA Enrichment and Delivery

Abstract

Exosomes are the small extracellular vesicles secreted by cells for intercellular communication. Exosomes are rich in therapeutic cargos such as microRNA (miRNA), long non-coding RNA (lncRNA), small interfering RNA (siRNA), DNA, protein, and lipids. Recently, many studies have focused on miRNAs as a promising therapeutic factor to support cartilage regeneration. Exosomes are known to contain a substantial amount of a variety of miRNAs. miRNAs regulate the post-transcriptional gene expression by base-pairing with the target messenger RNA (mRNA), leading to gene silencing. Several exosomal miRNAs have been found to play a role in cartilage regeneration by promoting chondrocyte proliferation and matrix secretion, reducing scar tissue formation, and subsiding inflammation. The exosomal miRNA cargo can be modulated using techniques such as cell transfection and priming as well as post-secretion modifications to upregulate specific miRNAs to enhance the therapeutic effect. Exosomes are delivered to the joints through direct injection or via encapsulation within a scaffold for sustained release. To date, exosome therapy for cartilage injuries has yet to be optimized as the ideal cell source for exosomes, and the dose and method of delivery have yet to be identified. More importantly, a deeper understanding of the role of exosomal miRNAs in cartilage repair is paramount for the development of more effective exosome therapy.

State of the Art: The Immunomodulatory Role of MSCs for Osteoarthritis

“…SASP is expressed by the overproduction of proteolytic and proinflammatory factors and reactive oxygen species (ROS) generation, which are harmful to the surrounding joint tissue, consequently joint destruction [43]. Premature chondrocyte senescence can be induced by repeated mechanical stress, traumatic injury, obesity, and finally leading to early OA [43,44].…”

“…Although lots of signaling pathways and the role of cytokines have been evaluated, OA subtypes exhibit variable pathologic pathways, making the development of effective therapies challenging [44].…”

“…Exosomes are the small extracellular vesicles (EVs) with a diameter range of 30-150 nm secreted by cells for intercellular communication [44]. MSC exosomes are derived from bone marrow, adipose tissue, synovimal tissue, fetal tissues, and the umbilical cord and embryo.…”

“…MSCs-derived exosomes provide a new paradigm for the development of cell-free and ready-to-use therapy for cartilage lesions and OA [39]. These exosomes do not have a nucleus structure; thus, they cannot replicate [44]. According to the latest update statement indicated in the Minimal Information for Studies of Extracellular Vesicles 2018 (MISEV2018) report [126], the terminologies of exosome and ectosome should only be used in an experimental research design with the subcellular origin of the EV subtype.…”

Modulation of Mesenchymal Stem Cells for Enhanced Therapeutic Utility in Ischemic Vascular Diseases

“…Agreeing with this finding, Brewster L et al, 2017, also demonstrated that MSCs expanded from CLI patients demonstrate the desired angiogenic activity compared with their healthy counterparts. In addition, MSCs from CLI patients can be sufficiently expanded with the novel culture media supplement, pooled human platelet lysate, to improve successful delivery of autologous MSCs to patients with CLI [ 188 ]. These controversial results may be due to the different MSCs sources, disease statuses, and/or angiogenic markers.…”