Bone marrow-derived mesenchymal stem cells in three-dimensional co-culture attenuate degeneration of nucleus pulposus cells.

Xunlin Li,Zhiqian Chen,Chen Han,Xiao Yang,An Qin,Tangjun Zhou,Haijun Tian,Kai Zhang,Aimin Wu,Chen Chen,Jie Zhao

doi:10.18632/aging.102390

Abstract

Intervertebral disc degeneration (IDD) is an irreversible aging-associated clinical condition of unclear etiology. Mesenchymal stem cells (MSCs) have the potential to delay IDD, but the mechanisms by which MSCs attenuate senescence-related degeneration of nucleus pulposus cells (NPCs) remain uncertain. The present study employed a three-dimensional (3D) co-culture system to explore the influence of MSCs on NPC degeneration induced by TNF-α in rat cells. We found that co-culture with bone marrow-derived MSCs (BMSCs) reduced senescence-associated β-galactosidase expression, increased cell proliferation, decreased matrix metalloproteinase 9, increased Coll-IIa production, and reduced TGFβ/NF-κB signaling in senescent NPCs. In addition, expression of zinc metallopeptidase STE24 (ZMPSTE24), whose dysfunction is related to premature cell senescence and aging, was decreased in senescent NPCs but restored upon BMSC co-culture. Accordingly, ZMPSTE24 overexpression in NPCs inhibited the pro-senescence effects of TGFβ/NF-κB activation upon TNF-α stimulation, while both CRISPR/Cas9-mediated silencing and pharmacological ZMPSTE24 inhibition prevented those effects. Ex-vivo experiments on NP explants provided supporting evidence for the protective effect of MSCs against NPC senescence and IDD. Although further molecular studies are necessary, our results suggest that MSCs may attenuate or prevent NP fibrosis and restore the viability and functional status of NPCs through upregulation of ZMPSTE24.

Highlights

Intervertebral disc degeneration (IDD) is a widespread condition in the aging population, frequently triggered by premature senescence and dysfunction of intervertebral disc cells [1]
mesenchymal stem cells (MSCs) frequency correlates with intervertebral disc degeneration in humans Activation of resident or recruited stem cells characterize the regenerative response to tissue senescence or damage
Primary nucleus pulposus cells (NPCs) were extracted from grade III (G III) and G IV discs, cultured, and senescence-associated β-galactosidase (SA-β-Gal) staining was performed on passage 1 cells

Summary

Introduction

Intervertebral disc degeneration (IDD) is a widespread condition in the aging population, frequently triggered by premature senescence and dysfunction of intervertebral disc cells [1]. To address the high burden of IDD and related conditions, many studies have focused on maintaining the number of nucleus pulposus cells (NPCs) and enhancing the deposition of functional components of the extracellular matrix (ECM) [8]. To this end, the potential of mesenchymal stem cells (MSCs), represented as progenitor NPCs in the NP, has been intensively explored in the field of IDD research [9, 10, 20]. Investigations showed differential NP gene expression in IDD models in response to stress-related processes such as aging [18], oxidation [19], the unfolded protein response [20], and metabolism [21]

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