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

Abstract

Osteoarthritis (OA) has generally been introduced as a degenerative disease; however, it has recently been understood as a low-grade chronic inflammatory process that could promote symptoms and accelerate the progression of OA. Current treatment strategies, including corticosteroid injections, have no impact on the OA disease progression. Mesenchymal stem cells (MSCs) based therapy seem to be in the spotlight as a disease-modifying treatment because this strategy provides enlarged anti-inflammatory and chondroprotective effects. Currently, bone marrow, adipose derived, synovium-derived, and Wharton's jelly-derived MSCs are the most widely used types of MSCs in the cartilage engineering. MSCs exert immunomodulatory, immunosuppressive, antiapoptotic, and chondrogenic effects mainly by paracrine effect. Because MSCs disappear from the tissue quickly after administration, recently, MSCs-derived exosomes received the focus for the next-generation treatment strategy for OA. MSCs-derived exosomes contain a variety of miRNAs. Exosomal miRNAs have a critical role in cartilage regeneration by immunomodulatory function such as promoting chondrocyte proliferation, matrix secretion, and subsiding inflammation. In the future, a personalized exosome can be packaged with ideal miRNA and proteins for chondrogenesis by enriching techniques. In addition, the target specific exosomes could be a gamechanger for OA. However, we should consider the off-target side effects due to multiple gene targets of miRNA.

Keywords: antiinflammation; exosome; immunomodulation; mesenchymal stem cell; miRNA; osteoarthritis.

Figure 1

The “inflammatory” pathogenesis of osteoarthritis (OA). (a) OA is not only damage of cartilage, but also surrounding joint tissue including inflammation of the synovium, subchondral bone remodeling, bone erosion, and osteophyte formation were accompanied. (b) In addition, cells in the affected joint tissues actively participate in the OA initiation and progression. (c) Lots of regulatory pathways are related to OA onset and progression; however, not all are necessarily implicated in all phenotypes of the OA progression. (d) During OA progression, multiple inflammatory cytokines and proteins are involved in damaging cartilage and promote an endless cycle of inflammation. (e) Senescent chondrocytes themselves also trigger an inflammatory response to the surrounding area.

Figure 2

Schematic presentation of the mesenchymal stem cells (MSCs) in cartilage regeneration. MSCs can be recruited from bone marrow, adipose tissue, synovium, and umbilical cord blood. MSCs induce cartilage regeneration by various mechanisms. MSCs can proliferate and differentiate directly into chondrocytes to replace damaged cells. In addition, MSCs can secrete exosomes including cytokines and miRNA to maintain chondrocyte phenotypes and promote their proliferation and ECM composition as a paracrine effect. Furthermore, MSCs can exert immunomodulatory and anti-inflammatory functions on numerous immune cells through exosome secretion. The exosome signals prohibit the inflammatory pathway, prevent cartilage degradation, and promote cartilage regeneration.

Figure 3

The future paradigm of osteoarthritis (OA) treatment. (a,b) After analyzing the patient genome and joint synovial fluid, (c) we can find crucial factors including proinflammatory cytokine and miRNA for chondral damage of each patient based on big data and artificial intelligence (AI). (d) We can arrange a personalized ideal exosome to control the key OA pathway by applying enhancing miRNA and exosome packaging techniques. (e) Single or twice injection for local delivery and (f) promoting cartilage regeneration and recovery to normal joint conditions.