Regulation of osteogenesis via miR-101-3p in mesenchymal stem cells by human gingival fibroblasts

Abstract

Introduction

Mesenchymal stem cells (MSCs) can differentiate into various types of cells and can thus be used for periodontal regenerative therapy. However, the mechanism of differentiation is still unclear. Transplanted MSCs are, via their transcription factors or microRNAs (miRNAs), affected by periodontal cells with direct contact or secretion of humoral factors. Therefore, transplanted MSCs are regulated by humoral factors from human gingival fibroblasts (HGF). Moreover, insulin-like growth factor (IGF)-1 is secreted from HGF and regulates periodontal regeneration. To clarify the regulatory mechanism for MSC differentiation by humoral factors from HGF, we identified key genes, specifically miRNAs, involved in this process, and determined their function in MSC differentiation.

Materials and Methods

Mesenchymal stem cells were indirectly co-cultured with HGF in osteogenic or growth conditions and then evaluated for osteogenesis, undifferentiated MSC markers, and characteristic miRNAs. MSCs had their miRNA expression levels adjusted or were challenged with IGF-1 during osteogenesis, or both of which were performed, and then, MSCs were evaluated for osteogenesis or undifferentiated MSC markers.

Results

Mesenchymal stem cells co-cultured with HGF showed suppression of osteogenesis and characteristic expression of ETV1, an undifferentiated MSC marker, as well as miR-101-3p. Over-expression of miR-101-3p regulated osteogenesis and ETV1 expression as well as indirect co-culture with HGF. IGF-1 induced miR-101-3p and ETV1 expression. However, IGF-1 did not suppress osteogenesis.

Conclusions

Humoral factors from HGF suppressed osteogenesis in MSCs. The effect was regulated by miRNAs and undifferentiated MSC markers. miR-101-3p and ETV1 were the key factors and were regulated by IGF-1.

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Acknowledgements

A portion of this work was carried out at the Analysis Center of Life Science, Natural Science Center for Basic Research and Development, Hiroshima University.

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Authors

Contributions

EK-I: designed and performed the experiments; collected, analyzed, and interpreted the data; and wrote the manuscript; TI: designed the experiments with EK-I: analyzed the data, and edited the manuscript; NM, TN, MK, KO, MY, and SI: contributed to the experiments; HK: contributed to the experimental design; HK: supervised all the aspects of the study as the senior investigator and director of the laboratory.

Corresponding author

Correspondence to Tomoyuki Iwata.

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The authors declare no competing financial interests.

Ethical approval

This study was approved by the Ethics Committee of Hiroshima University Faculty of Dentistry (Hiroshima, Japan: approval no. E-D47-4).

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Informed consent was obtained from all HGF donor in this study.

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Fig. S1 IGF-1 induced various miRNAs and regulated markers of undifferentiated hMSCs or other osteogenic regulatory genes. hMSCs were cultured with IGF-1 (50 ng/mL) for 7 days (a), or hMSCs were transfected with the miR-101-3p mimic or the corresponding non-targeting miRNA. Cells were then cultured for 14 days in osteogenic induction medium with or without IGF-1 (50 ng/mL) (b). miR-101-3p expression on day 7 (a) and mRNAs for Smad7 and TWIST1 on day 14 (b) were determined with real-time PCR. The values represent miRNA expression levels normalized to U6 snRNA expression relative to the control and mRNA expression levels normalized to -actin mRNA expression relative to the control (Mean ± SD; **p < 0.01, *p < 0.05; Mann–Whitney U test; n = 4). (PDF 335 kb)

Fig. S2 miR-101-3p was changed in osteogenesis conditions and targeted Ezh2. hMSCs were cultured in growth medium or osteogenic induction medium for 14 days (a). hMSCs were transfected with the miR-101-3p mimic (b), miR-101-3p inhibitor (c), or the corresponding non-targeting miRNA, and then cultured for 14 days in osteogenic induction medium. miR-101-3p expression (a) and Ezh2 mRNA expression (b, c) were determined with real-time PCR. The values represent miRNA expression levels normalized to U6 snRNA expression relative to the control and mRNA expression levels normalized to -actin mRNA expression relative to the control (Mean ± SD; **p < 0.01, *p < 0.05; Mann–Whitney U test; n = 4). (PDF 536 kb)

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Kaneda-Ikeda, E., Iwata, T., Mizuno, N. et al. Regulation of osteogenesis via miR-101-3p in mesenchymal stem cells by human gingival fibroblasts. J Bone Miner Metab 38, 442–455 (2020). https://doi.org/10.1007/s00774-019-01080-2

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Keywords

  • Mesenchymal stem cell
  • Gingival fibroblast
  • MicroRNA
  • miR-101-3p
  • ETV1