CDR1as regulated by hnRNPM maintains stemness of periodontal ligament stem cells via miR‐7/KLF4

Abstract

Periodontal ligament stem cells (PDLSCs) are undifferentiated mesenchymal stem cells present in the periodontal ligament (PDL) that have the capacity to self-renew and generate differentiated cells.Human PDLSCs have been successfully isolated in vitro, and their stem cell properties have been identified. 1 They are considered the main candidate stem cells for developing periodontal tissue regeneration techniques. 2 Recently, PDLSC-based periodontal regeneration was successfully established in dogs, rats and sheep. 3 Furthermore, PDLSCs were successfully used to treat periodontal intrabony defects in a randomized clinical trial. 4 Our previous studies have shown that PDLSC sheets can regenerate PDL-like tissue in nude mice and miniature pigs. 5,6 A key step in tissue regeneration is the self-renewal of stem cells.The evaluation of cell's self-renewal capacity is the most direct way to measure 'stemness' of stem cells. 7 Studies have demonstrated that stemness is modulated by the microenvironment, which includes small molecules, biologics, biomaterials and/or mechanical forces. 8 Besides these external factors, stemness has been demonstrated to be regulated by complex genetic networks, including bone morphogenetic protein (BMP), Janus kinase/signal transducers and activators of transcription, Wnt and Notch signalling. [9][10][11][12] The exploration of stemness regulatory genes might provide a foundation for a more detailed understanding of stem cell biology, but the stemness regulatory mechanisms of PDLSCs have not yet been fully elucidated.Circular RNA (circRNA) is a type of endogenous, non-coding RNA with a covalently closed-loop structure. 13 Thanks to their

Identification of potentially functional circRNAs and prediction of circRNA‐miRNA‐mRNA regulatory network in periodontitis: Bridging the gap between bioinformatics and clinical needs

“…CircRNA CDR1as was downregulated in periodontitis as the sponge of miR‐7. The function of CDR1as was validated to promote osteogenic differentiation of hPDLSCs, promote cell proliferation and maintain stemness, including expression levels of stemness‐associated genes (SOX2, OCT4, and Nanog), osteogenic differentiation, adipogenic differentiation, and migration capability 14,17,20 …”

“…One recent study profiled circRNA expression in exosomes that were derived from hPDLSCs, whose results indicated that extracellular vesicles could act as a source of circRNA to regulate hPDLSCs osteogenic differentiation 16 . In addition to the regulation of osteogenic differentiation, other functional validation studies suggested that circRNAs are also involved in the regulation of hPDLSCs cell viability, apoptosis, proliferation, migration, response to inflammation and oxidative stress, and the maintenance of stemness 17–21 . Some recent studies have used human gingival tissue samples to profile circRNA expression, including studies that profiled circRNA expression in human gingival tissues from patients with periodontitis and loss‐of‐function studies that presented circRNA as a promising therapeutical target for periodontitis using human gingival fibroblasts derived from human gingival tissues 22–25 …”

Progress in the Study of Non-Coding RNAs in Multidifferentiation Potential of Dental-Derived Mesenchymal Stem Cells

“…Antisense to the cerebellar degeneration-related protein 1 transcript (CDR1as), also known as CIRS-7, has approximately 70 conserved miR-7 binding sites and could therefore act as a miR-7 “sponge”. ( Gu et al, 2021 ) demonstrated that CDR1as promotes the pluripotent state of PDLSCs by inhibiting miR-7-mediated suppression of KLF4 expression, and hnRNPM can promote the expression of CDR1as in PDLSCs. CDR1as was also reported ( Li X. et al, 2018 ) to regulate the osteoblastic differentiation of PDLSCs by triggering the activation of Smad and p38 MAPK signaling pathway, as well as upregulation of GDF5.…”

CircRNA–miRNA networks in regulating bone disease

“…It turned out that there are a huge number of circRNAs which showed miRNAs seed binding sequences distributed through the whole circRNA sequences and prove that the circularization of the linear transcript is miRNA dependent (Belter et al, 2020); CDR1as is one of the most classical circRNA, which has been proved to be positively correlated with circRNA by the sponging relationship. Therefore, CDR1as can upregulate the expression of miR‐7 to induce osteogenic differentiation of periodontal ligament stem cells (Gu et al, 2021) and influence OA progression (C. Jiang et al, 2020; X. Zhou et al, 2020). The complementarity of nucleotides 2–7 of the miRNA mediates the miRNA‐loaded RNA‐induced silencing complex targeting to an mRNA, which is regarded as the seed region, the canonical mode of miRNA‐mediated gene regulation.…”