Protective effects of PDGF-AB/BB against cellular senescence in human intervertebral disc.

Autor:	Zhang C; Department of Orthopaedics, Emory University School of Medicine, Atlanta, GA, USA.; Atlanta VA Medical Center, Decatur, GA, USA., Diaz-Hernandez ME; Department of Orthopaedics, Emory University School of Medicine, Atlanta, GA, USA.; Atlanta VA Medical Center, Decatur, GA, USA., Fukunaga T; Department of Orthopaedics, Emory University School of Medicine, Atlanta, GA, USA.; Atlanta VA Medical Center, Decatur, GA, USA., Sreekala S; Department of Orthopaedics, Emory University School of Medicine, Atlanta, GA, USA.; Atlanta VA Medical Center, Decatur, GA, USA., Yoon ST; Emory Orthopaedics & Spine Center, Atlanta, GA, USA., Haglund L; Department of Surgery, McGill University, Montreal, Qc., Canada., Drissi H; Department of Orthopaedics, Emory University School of Medicine, Atlanta, GA, USA.; Atlanta VA Medical Center, Decatur, GA, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Oct 13. Date of Electronic Publication: 2024 Oct 13.
DOI:	10.1101/2024.10.11.617862
Abstrakt:	Cellular senescence, characterized by a permanent state of cell cycle arrest and a secretory phenotype contributing to inflammation and tissue deterioration, has emerged as a target for age-related interventions. Accumulation of senescent cells is closely linked with intervertebral disc (IVD) degeneration, a prevalent age-dependent chronic disorder causing low back pain. Previous studies have highlighted that platelet-derived growth factor (PDGF) mitigated IVD degeneration through anti-apoptosis, anti-inflammation, and pro-anabolism. However, its impact on IVD cell senescence remains elusive. In this study, human NP and AF cells derived from aged, degenerated IVDs were treated with recombinant human (rh) PDGF-AB/BB for 5 days and changes of transcriptome profiling were examined through mRNA sequencing. NP and AF cells demonstrated similar but distinct responses to the treatment. However, the effects of PDGF-AB and BB on human IVD cells were comparable. Specifically, PDGF-AB/BB treatment resulted in downregulation of gene clusters related to neurogenesis and response to mechanical stimulus in AF cells while the downregulated genes in NP cells were mainly associated with metabolic pathways. In both NP and AF cells, PDGF-AB and BB treatment upregulated the expression of genes involved in cell cycle regulation, mesenchymal cell differentiation, and response to reduced oxygen levels, while downregulating the expression of genes related to senescence associated phenotype, including oxidative stress, reactive oxygen species (ROS), and mitochondria dysfunction. Network analysis revealed that PDGFRA and IL6 were the top hub genes in treated NP cells. Furthermore, in irradiation-induced senescent NP cells, PDGFRA gene expression was significantly reduced compared to non-irradiated cells. However, rhPDGF-AB/BB treatment increased PDGFRA expression and mitigated the senescence progression through increased cell population in the S phase, reduced SA-β-Gal activity, and decreased expression of senescence related regulators including P21, P16, IL6, and NF-κB. Our findings reveal a novel anti-senescence role of PDGF in the IVD, demonstrating its ability to alleviate the senescent phenotype and protect against the progression of senescence. This makes it a promising candidate for preventing or treating IVD degeneration by targeting cellular senescence. Competing Interests: Conflict of interest: The authors have no conflict of interest associated with this work.
Databáze:	MEDLINE
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