Mechanical stimulation promotes MSCs healing the lesion of intervertebral disc annulus fibrosus

Abstract

Mesenchymal stem cells (MSCs) and scaffolds offer promising perspectives for annulus fibrosus (AF) repair. The repair effect was linked to features of the local mechanical environment related to the differentiation of MSCs. In this study, we established a Fibrinogen-Thrombin-Genipin (Fib-T-G) gel which is sticky and could transfer strain force from AF tissue to the human mesenchymal stem cells (hMSCs) embedded in the gel. After the Fib-T-G biological gel was injected into the AF fissures, the histology scores of intervertebral disc (IVD) and AF tissue showed that Fib-T-G gel could better repair the AF fissure in caudal IVD of rats, and increase the expression of AF-related proteins including Collagen 1 (COL1), Collagen 2 (COL2) as well as mechanotransduction-related proteins including RhoA and ROCK1. To clarify the mechanism that sticky Fib-T-G gel induces the healing of AF fissures and the differentiation of hMSCs, we further investigated the differentiation of hMSCs under mechanical strain in vitro. It was demonstrated that both AF-specific genes, including Mohawk and SOX-9, and ECM markers (COL1, COL2, aggrecan) of hMSCs were up-regulated in the environment of strain force. Moreover, RhoA/ROCK1 proteins were also found to be significantly up-regulated. In addition, we further -demonstrated that the fibrochondroinductive effect of the mechanical microenvironment process could be significantly blocked or up-regulated by inhibiting the RhoA/ROCK1 pathway or overexpressing RhoA in MSCs, respectively. Summarily, this study will provide a therapeutic alternative to repair AF tears and provide evidence that RhoA/ROCK1 is vital for hMSCs response to mechanical strain and AF-like differentiation.

How to enhance the ability of mesenchymal stem cells to alleviate intervertebral disc degeneration

“…Sustained mechanical stimulation is an innovative method of induced differentiation in MSCs, which can be continuously stimulated in a special microgel attached to them[ 46 ]. Repeated continuous stretching regulates transient receptor potential vanilloid 4 and Piezo1 channel proteins, regulates the value-added differentiation of MSCs into chondrocytes, regenerates the intercellular matrix, increases the water content in the IDs, and restores the normal structure of degenerated IDs[ 47 ].…”

“…Viscous fibrinogen-thrombin-genipin gels act specifically through the RhoA/LATS/YAP1 signaling pathway to direct differentiation of MSCs into nucleus pulposus cells or fibrous rings. This helps patients with IDD to reduce the number of nucleus pulposus cells and fibrous ring damage, which may provide a new direction for the treatment of IDD[ 46 , 48 ]. In the treatment of IDD and recovery of ID height by using bleomycin to induce MSCs fibrosis and by stimulating the TGFβ-SMAD2/3 signaling pathway, the gene expression of related collagen and ECM is maintained, thereby maintaining the height of the ID and increasing its ability to resist wear[ 49 ].…”

Stress stimulation maintaining by genipin crosslinked hydrogel promotes annulus fibrosus healing

“…Studies have shown that the RhoA/ROCK signaling pathway is the main pathway for mechanical stimulation to regulate MSCs differentiation [ 6 ]. In our previous study, we found that stress stimulation activated RhoA, which promoted MSCs differentiation to produce ordered collagen similar to AF tissue, and thus inferred that stress stimulation might regulate the differentiation of MSCs to AF-like cells through the RhoA/ROCK signaling pathway [ 7 ]. Therefore, choosing a suitable material that can adhere to the section tightly and provide a stable stress-stimulating environment for MSCs differentiation is an important direction for promoting AF regeneration.…”