Demethylation of IGFBP5 by Histone Demethylase KDM6B Promotes Mesenchymal Stem Cell-Mediated Periodontal Tissue Regeneration by Enhancing Osteogenic Differentiation and Anti-Inflammation Potentials

Abstract

Mesenchymal stem cell (MSC)-mediated periodontal tissue regeneration is considered a promising method for periodontitis treatment. The molecular mechanism underlying directed differentiation and anti-inflammatory actions remains unclear, thus limiting potential MSC application. We previously found that insulin-like growth factor binding protein 5 (IGFBP5) is highly expressed in dental tissue-derived MSCs compared with in non-dental tissue-derived MSCs. IGFBP5 is mainly involved in regulating biological activity of insulin-like growth factors, and its functions in human MSCs and tissue regeneration are unclear. In this study, we performed gainand loss-of-function assays to test whether IGFBP5 could regulate the osteogenic differentiation and anti-inflammatory potential in MSCs. We found that IGFBP5 expression was upregulated upon osteogenic induction, and that IGFBP5 enhanced osteogenic differentiation in MSCs. We further showed that IGFBP5 prompted the anti-inflammation effect of MSCs via negative regulation of NFjB signaling. Depletion of the histone demethylase lysine (K)-specific demethylase 6B (KDM6B) downregulated IGFBP5 expression by increasing histone K27 methylation in the IGFBP5 promoter. Moreover, IGFBP5 expression in periodontal tissues was downregulated in individuals with periodontitis compared with in healthy people, and IGFBP5 enhanced MSC-mediated periodontal tissue regeneration and alleviated local inflammation in a swine model of periodontitis. In conclusion, our present results reveal a new function for IGFBP5, provide insight into the mechanism underlying the directed differentiation and anti-inflammation capacities of MSCs, and identify a potential target mediator for improving tissue regeneration. STEM CELLS 2015;33:2523-2536

CB1 enhanced the osteo/dentinogenic differentiation ability of periodontal ligament stem cells via p38 MAPK and JNK in an inflammatory environment

“…Mesenchymal stem cells (MSCs) are reported to be excellent seed cells for regeneration treatments due to their multidirectional differentiation capability. In‐depth studies on the utility of MSCs in periodontal tissue regeneration have reported that using MSCs as seed cells implanted into periodontal lesion areas via cell sheet or local injection can enhance periodontal tissue regeneration . Periodontal ligament stem cells (PDLSCs) are a type of tissue‐specific MSC and behave according to the prevailing MSC speciality, such as in the expression of key markers, self‐renewal, multipotency, and immune suppression responses, and they can differentiate into mesenchymal cell lineages in vitro and in vivo .…”

“…In-depth studies on the utility of MSCs in periodontal tissue regeneration have reported that using MSCs as seed cells implanted into periodontal lesion areas via cell sheet or local injection can enhance periodontal tissue regeneration. [5][6][7][8] Periodontal ligament stem cells (PDLSCs) are a type of tissue-specific MSC and behave according to the prevailing MSC speciality, such as in the expression of key markers, self-renewal, multipotency, and immune suppression responses, and they can differentiate into mesenchymal cell lineages in vitro and in vivo. 4,[9][10][11] However, several key PDLSC surface markers, including STRO-1, CD90, OCT-4 and CD146, are significantly abnormally expressed in inflamed tissues compared with healthy PDLSCs.…”

IGF-1/IGF-1R/hsa-let-7c axis regulates the committed differentiation of stem cells from apical papilla

“…Various growth factors can mediate the osteo/dentinogenic differentiation of MSCs2345, including stem cells from apical papilla (SCAPs)6. These SCAPs can differentiate into odontoblasts or osteoblasts in vitro , and form dentin-like tissues along with tooth root-like structures in vivo 137.…”

Leptin Overexpression in Bone Marrow Stromal Cells Promotes Periodontal Regeneration in a Rat Model of Osteoporosis

“…On the other hand, it was reported that LEP increased messenger RNA expression of IGF‐binding protein (IGFBP)‐2 and ‐5, 46 which are mainly involved in regulating biologic activity of IGF. Recently, a new function of IGFBP‐5 was found: that it could enhance MSC‐mediated periodontal tissue regeneration and alleviate local inflammation in a swine model of periodontitis 47 . These underlying mechanisms may give clues to the potential function of LEP in periodontal regeneration.…”