Bone Mesenchymal Stem Cells Promote Extracellular Matrix Remodeling of Degenerated Nucleus Pulposus Cells via the miR-101-3p/EIF4G2 Axis

Abstract

The etiology of lumbocrural pain is tightly concerned with intervertebral disk degeneration (IDD). Bone mesenchymal stem cell (BMSC)-based therapy bears potentials for IDD treatment. The properties of microRNA (miRNA)-modified BMSCs may be altered. This study investigated the role and mechanism of BMSCs promoting extracellular matrix (ECM) remodeling of degenerated nucleus pulposus cells (NPCs) via the miR-101-3p/EIF4G2 axis. NPCs were collected from patients with IDD and lumbar vertebral fracture (LVF). The expressions of miR-101-3p and ECM-related proteins, Collagen-I (Col-I) and Collagen-II (Col-II), were detected using the reverse transcription-quantitative polymerase chain reaction. The expressions of Col-I and Col-II, major non-collagenous component Aggrecan, and major catabolic factor Matrix metalloproteinase-13 (MMP-13) were detected using Western blotting. BMSCs were cocultured with degenerated NPCs from patients with IDD. Viability and apoptosis of NPCs were measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and flow cytometry. After the degenerated NPCs were transfected with the miR-101-3p inhibitor, the expressions of ECM-related proteins, cell viability, and apoptosis were detected. The targeting relationship between miR-101-3p and EIF4G2 was verified. Functional rescue experiments verified the effects of miR-101-3p and EIF4G2 on ECM remodeling of NPCs. Compared with the NPCs of patients with LVF, the degenerated NPCs of patients with IDD showed downregulated miR-101-3p, Col-II, and Aggrecan expressions and upregulated MMP-13 and Col-I expressions. BMSCs increased the expressions of miR-101-3p, Aggrecan, and Col-II, and decreased the expressions of MMP-13 and Col-I in degenerated NPCs. BMSCs enhanced NPC viability and repressed apoptosis. Downregulation of miR-101-3p suppressed the promoting effect of BMSCs on ECM remodeling. miR-101-3p targeted EIF4G2. Downregulation of EIF4G2 reversed the inhibiting effect of the miR-101-3p inhibitor on ECM remodeling. In conclusion, BMSCs increased the miR-101-3p expression in degenerated NPCs to target EIF4G2, thus promoting the ECM remodeling of NPCs.

The Proteolysis of ECM in Intervertebral Disc Degeneration

“…Yi et al used human tissue inhibitor of metalloproteinase 1 (TIMP-1) overexpression modified BMSCs to treat degenerated discs by directly targeting the ECM anabolic catabolic homeostasis [111]. In addition, Wang et al found that BMSCs promoted ECM regeneration in degenerated NP cells via the miR-101-3p/EIF4G2 axis [130]. However, stem cell injections or transplants alone often fail to achieve the desired effect due to their lack of protection and support by the ECM.…”

Neochlorogenic Acid Combined with Bone Marrow Mesenchymal Stem Cells Encapsulated into GelMA Hydrogel for Transplantation to Repair Intervertebral Disk Degeneration

“…Wang et al found that MSCs could improve disk degeneration by promoting the remodeling of the extracellular matrix in the nucleus pulposus tissue. 34 Centeno et al found that transplantation of autologous MSCs into patients with disk degeneration caused a significant improvement in the prolapse of the nucleus pulposus tissue, and a significant reduction in pain. 35 However, stem cell transplantation techniques still have several limitations.…”

“…The ability of BMSCs to differentiate into chondrocytes was verified by differentiation experiments. Wang et al found that MSCs could improve disk degeneration by promoting the remodeling of the extracellular matrix in the nucleus pulposus tissue . Centeno et al found that transplantation of autologous MSCs into patients with disk degeneration caused a significant improvement in the prolapse of the nucleus pulposus tissue, and a significant reduction in pain …”

Metformin Treatment Modulates Long Non-Coding RNA Isoforms Expression in Human Cells

“…EIF4G2 is related to the alternative scanning of the translation start site by the 40S ribosomal subunit, translation associated with alternative ORFs, and translation under stress [ 51 , 52 ]. EIF4G2 differential expression was previously related to extracellular matrix remodeling [ 53 ]. However, most of the literature regarding this gene explores its interaction with microRNAs, and no metformin effect on EIF4G2 expression has been previously reported.…”