Mechanism of Action of Mesenchymal Stem Cell-Derived Exosomes in the Intervertebral Disc Degeneration Treatment and Bone Repair and Regeneration

Abstract

Exosomes are extracellular vesicles formed by various donor cells that regulate gene expression and cellular function in recipient cells. Exosomes derived from mesenchymal stem cells (MSC-Exos) perform the regulatory function of stem cells by transporting proteins, nucleic acids, and lipids. Intervertebral disc degeneration (IDD) is one of the main causes of low back pain, and it is characterized by a decreased number of nucleus pulposus cells, extracellular matrix decomposition, aging of the annulus fibrosus, and cartilage endplate calcification. Besides, nutrient transport and structural repair of intervertebral discs depend on bone and cartilage and are closely related to the state of the bone. Trauma, disease and aging can all cause bone injury. However, there is a lack of effective drugs against IDD and bone injury. Recent MSC-Exos fine tuning has led to significant progress in the IDD treatment and bone repair and regeneration. In this review, we looked at the uniqueness of MSC-Exos, and the potential treatment mechanisms of MSC-Exos with respect to IDD, bone defects and injuries.

Keywords: bone repair and regeneration; exosomes; intervertebral disc degeneration (IDD); mechanism of action; mesenchymal stem cells (MeSH ID D059630).

FIGURE 1

Typical process of exosome generation, secretion, and transfer from the donor cells to the recipient cells, and the exosome structure is shown. Early endosomes containing ILVs are formed preliminarily and then developed into mature MVBs to release and form exosomes into the extracellular. The exosomes have a bilayered membrane structure containing functional proteins, nucleic acids (mRNA, miRNA, lncRNA, etc.), and lipids, some of which are released into recipient cells to regulate gene expression and cell function.

FIGURE 2

Potential mechanisms of MSC-Exos for treating IDD. (A) Inhibiting NPC apoptosis and promoting NPC proliferation. MSC-Exos alleviate NPC apoptosis induced by acidic pH through repressing caspase-3 expression and attenuating caspase-3 cleavage. BMSC-Exos can increase miR-155 expression to upregulate HO-1 expression and downregulate Bach1 expression, subsequently activating autophagy in NPCs to inhibit the cell apoptosis in the state of low blood supply. MSC-Exos can deliver miR-532-5p, which targets RASSF5, and eventually inhibit TNF-α-induced NPC apoptosis. By delivering miR-142-3p to target MLK3 in NPCs, MSC-Exos inhibit the activation of the MAPK pathway and alleviate IL-1β-induced apoptosis and inflammation in NPCs. MSC-Exos can transfer miR-21, which directly targets PTEN; the PTEN silencing actives PI3K/Akt pathway and suppresses activation of Bad, Bax, and caspase-3 and inhibits TNF-α-induced NPC apoptosis. (B) Inhibiting ECM degradation. BMSC-Exos suppress the levels of MMP-1, MMP-3, MMP-13 in degenerative NPCs to inhibit ECM decomposition metabolism and evaluate expression levels of aggrecan, collagen II, SOX9, further inhibiting the ECM degradation. (C) Inhibiting inflammation response. MSC-Exos can decrease inflammatory factor expression including IL-1α, IL-1β, IL-6, IL-17, NF-κB-p65 and TNF-α in NPCs. MSC-Exos can inactivate the NLRP3 and inhibit the expression of NT-GSDMD, IL-18 and IL-1β proteins in degenerative NPCs, therefore inhibiting the NLRP3-mediated inflammatory pyroptosis. (D) Inhibiting oxidative stress. MSC-Exos can reduce the ROS and MDA level and inhibit oxidative stress-induced NPC apoptosis. MSC-Exos can activate Akt/ERK pathway to decrease CHOP protein expression, therefore inhibiting the cleavage of caspase-3, caspase-12 to treat AGEs-related ER stress-induced IDD. (E) Promoting chondrogenic differentiation. MSC-Exo treatment can induce chondrogenesis in degenerative NPCs earlier by increased the aggrecan, collagen II and SOX9 expression. (F) Protective effect on endplate chondrocytes. MSC-Exos containing miR-31-5p could negatively regulate ER stress by targeting ATF6, and further reducing caspase-3, caspase-7 and caspase-9 expression to inhibit apoptosis and calcification of endplate chondrocytes. (G) Protective effect on annulus fibrosus of IDD. BMSC-Exos can suppress PI3K/Akt/mTOR signaling pathway-mediated autophagy and inhibit the IL-1β-induced inflammation and apoptosis in annulus fibrosus cells.

FIGURE 3

Potential mechanisms of MSC-Exos for promoting bone repair and regeneration. (A) Promoting osteogenic differentiation. MSC-Exos can activate the PI3K/Akt signaling pathway to promote osteogenic differentiation and proliferation of BMSCs. The Wnt/β-catenin signaling pathway activated by MSC-Exos with increased expression of β-catenin and Wnt3a can promote osteoblast proliferation and differentiation. Exosomes enriched with miR-375 inhibit the IGFBP3 expression to promote osteogenic differentiation of hBMSCs. (B) Promoting angiogenesis. BMSC-Exos activates the Akt/mTOR pathway to stimulate angiogenesis and further promotes bone regeneration. Exosomal miR-21 can upregulate the NOTCH1/DLL4 pathway and promote angiogenesis. (C) Immunoregulation. MSC-Exos can decrease the gene expression of IL-1β, IL-6, TNF-α, and iNOS in the inflammatory macrophages. (D) Inducing chondrogenesis. MSC-Exos increase the protein and mRNA expression of collagen II and SOX9 to improve cartilage regeneration. MSC-Exos can promote the macrophage’s polarization toward the M2 phenotype and further inhibit the inflammatory response to benefit chondrogenesis. BMSC-Exo treatment can decrease the c-MYC expression level, which indicates the chondrocyte’s maturation. (E) Improving osteoporosis. MALAT1 contained in BMC-Exos promotes alkaline phosphatase activity of osteoblasts and mineralizes nodules by increasing SATB2 expression. Activating MAPK signaling and increasing the P-p38 and P-JNK expression by MSC-Exos can promote osteoblast differentiation. BMSC-Exos enriched with miR-196a can inhibit Dkk1 expression to activate the Wnt/β-catenin pathway, thereby improving osteoporosis. Exosomes derived from human umbilical cord MSCs can inhibit BMSC apoptosis through the miR-1263/Mob1/Hippo signaling pathway to improve osteoporosis.