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Adipose-Derived Stem Cells (ASCs) and Ceiling Culture-Derived Preadipocytes (ccdPAs) Cultured from Subcutaneous Fat Tissue Differ in their Epigenetic Characteristics and Osteogenic Potential

Sasahara, Yoshitaro M.D., Ph. D.1; Kubota, Yoshitaka M.D., Ph. D.1; Kosaka, Kentaro M.D., Ph. D.1; Adachi, Naoki M.D., Ph. D.2; Yamaji, Yoshihisa M.D., Ph. D.1; Nagano, Hidekazu M.D., Ph. D.3; Akita, Shinsuke M.D., Ph. D.1; Kuroda, Masayuki Ph. D.4; Tanaka, Tomoaki M. D., Ph. D.3; Bujo, Hideaki M.D., Ph. D.5; Mitsukawa, Nobuyuki M.D., Ph. D.1

Plastic and Reconstructive Surgery: June 6, 2019 - Volume PRS Online First - Issue - p
doi: 10.1097/PRS.0000000000005913
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Background: Adipose-derived stem cells (ASCs) and ceiling culture-derived preadipocytes (ccdPAs) can be harvested from subcutaneous adipose tissue. Little is known about the epigenetic differences, which may contribute to differences in osteogenic potential, between these cell types.

Purpose: The purpose of this study was to address the osteogenic potential and underlying epigenetic status of ASCs and ccdPAs.

Materials and Methods: ASCs and ccdPAs were cultured from abdominal subcutaneous fat tissues of four metabolically healthy, lean females. After seven weeks of culture, cellular responses to osteogenic differentiation media were examined. To evaluate the osteogenic potentials of undifferentiated ASCs and ccdPAs, two types of epigenetic assessment were performed using next generation sequencing: DNA methylation assays with a 450K BeadChip; and chromatin immunoprecipitation assays (ChIP-Seq) for trimethylation of histone H3 at lysine 4 (H3K4me3).

Results: Human ccdPAs showed greater osteogenic differentiation ability than did ASCs. In an epigenetic survey of the promoters of four osteogenic regulator genes (RUNX2, SP7, ATF4, and BGLAP), we found a general trend toward decreased CpG methylation and increased H3K4me3 levels in ccdPAs as compared to ASCs, indicating that these genes were more likely to be highly expressed in ccdPAs.

Conclusion: The surveyed epigenetic differences between ASCs and ccdPAs were consistent with the observed differences in osteogenic potential. These results enhance our understanding of these cells and will facilitate their further application in regenerative medicine.

1 Department of Plastic Surgery, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba-city, Chiba, #260-8677, Japan.

2 Department of General Surgery, National Organization Hospital Mito Medical Center, 280, Sakuranogo, Ibarakimachi, Higashiibarakigun, Ibaraki, #311-3193, Japan

3 Department of Molecular Diagnosis, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba-city, Chiba, #260-8677, Japan.

4 Center for Advanced Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba-city, Chiba, #260-8677, Japan.

5 Department of Research and Development, Toho University, 564-1, Shimoshizu, Sakura-city, Chiba, #285-8741, Japan

Ethics: This study was conducted in accordance with the ethical committee of Chiba University School of Medicine (approval number 1510). Written informed consent was obtained from all participants. All studies were performed according to the guidelines of the Declaration of Helsinki.

Financial Disclosure Statement: None of the authors have a financial interest in any of the products, devices, or drugs mentioned in this manuscript.

Acknowledgements: This work was supported by Grant-in-Aid for Scientific Research (KAKENHI) from Japan Society for Promotion of Science (JSPS): (Y.K.) JP15K10934, (N.M.) JP17K11531, and (Y.S.) JP26861491. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Corresponding author: Yoshitaka Kubota, M.D., Ph.D., Department of Plastic Surgery, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba City, Chiba, #260-8677, Japan. Phone & Fax: +81-43-226-2316, E-mail: kubota-cbu@umin.ac.jp

©2019American Society of Plastic Surgeons