Strategies in product engineering of mesenchymal stem cell-derived exosomes: unveiling the mechanisms underpinning the promotive effects of mesenchymal stem cell-derived exosomes

Abstract

Articular cartilage injuries present a significant global challenge, particularly in the aging population. These injuries not only restrict movement due to primary damage but also exacerbate elderly degenerative lesions, leading to secondary cartilage injury and osteoarthritis. Addressing osteoarthritis and cartilage damage involves overcoming several technical challenges in biological treatment. The use of induced mesenchymal stem cells (iMSCs) with functional gene modifications emerges as a solution, providing a more stable and controllable source of Mesenchymal Stem Cells (MSCs) with reduced heterogeneity. Furthermore, In addition, this review encompasses strategies aimed at enhancing exosome efficacy, comprising the cultivation of MSCs in three-dimensional matrices, augmentation of functional constituents within MSC-derived exosomes, and modification of their surface characteristics. Finally, we delve into the mechanisms through which MSC-exosomes, sourced from diverse tissues, thwart osteoarthritis (OA) progression and facilitate cartilage repair. This review lays a foundational framework for engineering iMSC-exosomes treatment of patients suffering from osteoarthritis and articular cartilage injuries, highlighting cutting-edge research and potential therapeutic pathways.

Keywords: 3D printed stent; cartilage damage; engineering; exosomes; induced mesenchymal stem cells; osteoarthritis.

FIGURE 1

Strategies for Enhancing Exosome Efficacy This figure presents three key strategies for boosting the performance of MSC-derived exosomes: 1) three-dimensional culture of MSCs to enhance exosome production and quality, 2) improving exosomal functional components through targeted pathways, and 3) surface modification of exosomes for better targeting and delivery. Additionally, it illustrates methods to increase the concentration of effective molecules (effectors) within the exosomes.

FIGURE 2

MCs of different shapes Spherical MCs like (A) Cytodex 1 and (B) Cytopore. (C) 2D microhex is an example of hexagon shape carriers produced by Nunc™. (D) Fibra-cel^® is a product of New Brunswick™ that has a disc shape. (E) Lens-shape MCs like Cytoline 1 and Cytoline 2 (F) are produced via GE Healthcare. (G) and (H) shows DE-52 and DE-53 as available cylindrical MCs in the market which are produced by Whatman™. In panel G, i and ii shows attachment of L-929, a corn-type fibroblastic and MDCK, a canine kidney cell line, Epithelial cells, respectively to DE-52. In panel H, i and ii shows attachment of the baby hamster kidney cell line (BHK, Fibroblastic type) and Primary chick embryo fibroblast, respectively to DE-53. (I) Morphology of human ESCs on (i) DE-53 (large aggregates), (ii) Cytodex-1 (thin aggregate layers) and (iii) Tosoh 65 PR (compact aggregates). Images adapted from Ref (Niet al., 2020).

FIGURE 3

Mechanisms of MSC-Exosome Action in Cartilage Homeostasis and Osteoarthritis Treatment This figure illustrates how MSC-exosomes, derived from different tissues, influence cartilage homeostasis and address osteoarthritis through multiple mechanisms: ① Delivery of miRNA, LncRNA, or proteins to chondrocytes suppresses NF-κB, mTOR, and pro-inflammatory factor release. While some MSC-exosomes may activate the Wnt/β-catenin signaling pathway, overexpression of certain miRNAs redirects these exosomes to inhibit this pathway; ②The suppression of MMP13, MMP3, RUNX2, and ADAMTS5 expression through various signaling pathways prevents ECM degradation; ③ Enhancement of COL2A1, Collagen II, aggrecan, and SOX9 expression via diverse signaling routes increases ECM synthesis; ④ Cartilage homeostasis is maintained by activating autophagy through multiple pathways; ⑤ Cartilage regeneration is promoted by stimulating chondrocyte proliferation and migration and reducing apoptosis via varied signaling mechanisms.