Abstract
The present study explored the effects of ascorbic-acid (AA)/retinol and timed inflammation on the stemness, the regenerative potential, and the transcriptomics profile of gingival mesenchymal stem/progenitor cells’ (G-MSCs). STRO-1 (mesenchymal stem cell marker) immuno-magnetically sorted G-MSCs were cultured in basic medium (control group), in basic medium with IL-1β (1 ng/mL), TNF-α (10 ng/mL) and IFN-γ (100 ng/mL, inflammatory-medium), in basic medium with AA (250 µmol/L) and retinol (20 µmol/L) (AA/retinol group) or in inflammatory medium with AA/retinol (inflammatory/AA/retinol group; n = 5/group). The intracellular levels of phosphorylated and total β-Catenin at 1 h, the expression of stemness genes over 7 days, the number of colony-forming units (CFUs) as well as the cellular proliferation aptitude over 14 days, and the G-MSCs’ multilineage differentiation potential were assessed. Next-generation sequencing was undertaken to elaborate on up-/downregulated genes and altered intracellular pathways. G-MSCs demonstrated all mesenchymal stem/progenitor cells characteristics. Controlled inflammation with AA/retinol significantly elevated NANOG (p < 0.05). The AA/retinol-mediated reduction in intracellular phosphorylated β-Catenin was restored through the effect of controlled inflammation (p < 0.05). Cellular proliferation was highest in the AA/retinol group (p < 0.05). AA/retinol counteracted the inflammation-mediated reduction in G-MSCs’ clonogenic ability and CFUs. Amplified chondrogenic differentiation was observed in the inflammatory/AA/retinol group. At 1 and 3 days, the differentially expressed genes were associated with development, proliferation, and migration (FOS, EGR1, SGK1, CXCL5, SIPA1L2, TFPI2, KRATP1-5), survival (EGR1, SGK1, TMEM132A), differentiation and mineral absorption (FOS, EGR1, MT1E, KRTAP1-5, ASNS, PSAT1), inflammation and MHC-II antigen processing (PER1, CTSS, CD74) and intracellular pathway activation (FKBP5, ZNF404). Less as well as more genes were activated the longer the G-MSCs remained in the inflammatory medium or AA/retinol, respectively. Combined, current results point at possibly interesting interactions between controlled inflammation or AA/retinol affecting stemness, proliferation, and differentiation attributes of G-MSCs.
Highlights
Initiation of periodontitis generally necessitates the stimulation of the periodontal immune system through a bacterial dysbiosis, setting complex inflammatory cascades in motion, characterized by the liberation of a variety of pro-inflammatory cytokines, mainly tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1 beta (IL-1β), IL-4, IL-6, IL-17 as well as interferon-gamma (IFN-γ) [1,2]
Periodontal reparative/regenerative approaches rely on the reiteration of developmental procedures, involving stem/progenitor cells’ proliferation, differentiation, and maturation [36]. These primary events occur under inflamed periodontal micro-environmental conditions, with inflammatory cytokines stage-managing the path of events [2,37,38]
AA and retinol at specific concentrations, which were employed in the current investigation, could drive cellular reprogramming/de-differentiation and pluripotency [19,20,47]
Summary
Initiation of periodontitis generally necessitates the stimulation of the periodontal immune system through a bacterial dysbiosis, setting complex inflammatory cascades in motion, characterized by the liberation of a variety of pro-inflammatory cytokines, mainly tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1 beta (IL-1β), IL-4, IL-6, IL-17 as well as interferon-gamma (IFN-γ) [1,2]. Such pro-inflammatory response is pivotal in combating the invading pathogens and in boosting subsequent periodontal stem/progenitor cells-mediated reparative/regenerative endeavors, a longlasting not adequately self-limiting pro-inflammatory insult could detrimentally affect the tooth-supporting and investing cellular components of the periodontium [3]. Chronic periodontitis was found to be associated with a lower retinol intake in young Korean women [9] and low serum levels of a variety of carotenoids, in particular beta-cryptoxanthin and beta-carotene, were demonstrated to be connected with an elevated periodontitis prevalence in a sample of 1258, 60–70-year-old
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