Abstract
Stromal cell-derived factor-1 (SDF-1) and Exendin-4 (EX-4) play beneficial roles in promoting periodontal ligament stem cells (PDLSCs) osteogenic differentiation, while the detailed mechanism has not been clarified. In this study, we aimed to evaluate the biological mechanism of SDF-1 and EX-4 alone or synergistic application in regulating PDLSCs differentiation by RNA-sequencing (RNA-seq). A total of 110, 116 and 109 differentially expressed genes (DEGs) were generated in osteogenic medium induced PDLSCs treated by SDF-1, EX-4, and SDF-1+EX-4, respectively. The DEGs in SDF-1 group were enriched in signal transduction related signaling pathways; the DEGs in EX-4 group were enriched in metabolism and biosynthesis-related pathways; and the DEGs generated in SDF-1+EX-4 group were mainly enriched in RNA polymerase II transcription, cell differentiation, chromatin organization, protein phosphorylation pathways. Based on Venn analysis, a total of 37 specific DEGs were identified in SDF-1+EX-4 group, which were mainly enriched in negative regulation of autophagy and cellular component disassembly signaling pathways. Short time-series expression miner (STEM) analysis grouped all expressed genes of PDLSCs into 49 clusters according to the dynamic expression patterns and 25 genes, including NRSN2, CHD9, TUBA1A, distributed in 10 gene clusters in SDF-1+EX-4 treated PDLSCs were significantly up-regulated compared with the SDF-1 and EX-4 alone groups. The gene set enrichment analysis indicated that SDF-1 could amplify the role of EX-4 in regulating varied signaling pathways, such as type II diabetes mellitus and insulin signaling pathways; while EX-4 could aggravate the effect of SDF-1 on PDLSCs biological roles via regulating primary immunodeficiency, tight junction signaling pathways. In summary, our study confirmed that SDF-1 and EX-4 combined application could enhance PDLSCs biological activity and promote PDLSCs osteogenic differentiation by regulating the metabolism, biosynthesis and immune-related signaling pathways.
Highlights
Periodontal disease-induced tooth loss has become a global public health challenge that greatly affects people’s quality of life (Peres et al, 2019)
The thresh old value of |fold change (FC)|>1 and FDR ≤ 0.05 was used to identify differentially expressed genes (DEGs) between two different groups, and the results indicated that 110, 116, 109, 125, 103 and 100 DEGs were generated in different comparison groups Stromal cell-derived factor-1 (SDF-1) vs negative control (NC), EX-4 vs NC, SDF-1+EX-4 vs NC, SDF-1+EX-4 vs EX-4, SDF-1+EX-4 vs SDF-1, EX-4 vs SDF-1 (Fig. 1)
We identified that the DEGs generated by SDF-1+EX-4 was mainly enriched in RNA polymerase II transcription, cell differentiation, chromatin organization, and protein phosphorylation pathways according to the Gene ontology (GO) analysis results (Fig. 2E and Table S1)
Summary
Periodontal disease-induced tooth loss has become a global public health challenge that greatly affects people’s quality of life (Peres et al, 2019). An increasing number of researchers have focused on the recruitment of endogenous PDLSCs to the injury site to enhance healing by harnessing the innate regenerative potential of the body (Lee et al, 2017a). Chemokines, and adhesion molecules have been used to enhance cell migration, maintain tissue homeostasis, regulate immune responses, promote wound healing and facilitate periodontal tissue regeneration (Lee et al, 2017b; Onizuka & Iwata, 2019; Wang et al, 2013). Our previous study demonstrated that topical application of SDF-1 could significantly recruit MSCs to the wound area and promote local vascular regeneration in a rat model (Wang, Du & Ge, 2016). SDF-1 possesses great potential in promoting MSC migration and growth; the compromised osteogenic differentiation of these cells could not be induced by SDF-1. The application of SDF-1 alone is insufficient for favorable bone regeneration, and the optimal method for potentiating periodontal bone regeneration is to combine SDF-1 with other osteogenic factors
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