MicroRNA-138 Suppresses Adipogenic Differentiation in Human Adipose Tissue-Derived Mesenchymal Stem Cells by Targeting Lipoprotein Lipase

다국어 초록 (Multilingual Abstract)

Purpose: Adipogenic differentiation of adipose tissue-derived mesenchymal stem cells (AMSCs) is critical to many disease-relateddisorders, such as obesity and diabetes. Studies have demonstrated that miRNA-138 (miR-138) is closely involved in adipogenesis.
However, the mechanisms affected by miR-138 remain unclear. This work aimed to investigate interactions between miR-138and lipoprotein lipase (LPL), a key lipogenic enzyme, in AMSCs.
Materials and Methods: Human AMSCs (hAMSCs) isolated from human abdomen tissue were subjected to adipogenic differentiationmedium. Quantitative real-time polymerase chain reaction and Western blot assay were applied to measure the expressionsof miR-138, LPL, and the two adipogenic transcription factors cytidine-cytidine-adenosine-adenosine-thymidine enhancerbinding protein alpha (C/EBPα) and peroxisome proliferator-activated receptor gamma (PPARγ). The relationship between miR-138 and LPL was predicted utilizing the miRTarBase database and validated by dual luciferase reporter assay.
Results: Showing increases in C/EBPα and PPARγ expression levels, hAMSCs were induced into adipogenic differentiation. Duringadipogenesis of hAMSCs, miR-138 expression was significantly downregulated. Overexpression of miR-138 by transfection inhibitedhAMSCs adipogenic differentiation in vitro. Mechanically, LPL was a target of miR-138. LPL expression was upregulated duringadipogenesis of hAMSCs, and this upregulation was reversed by miR-138 overexpression. Functionally, silencing of LPL by transfectionexerted similar inhibition of the expressions of C/EBPα and PPARγ. Meanwhile, LPL ectopic expression was able to partlyabolish the suppressive effect of miR-138 overexpression on adipogenic differentiation of hAMSCs.
Conclusion: Upregulation of miR-138 inhibits adipogenic differentiation of hAMSCs by directly downregulating LPL.

참고문헌 (Reference)

1 Hamam D, "microRNAs as regulators of adipogenic differentiation of mesenchymal stem cells" 24 : 417-425, 2015

2 Karbiener M, "microRNA miR-27b impairs human adipocyte differentiation and targets PPARgamma" 390 : 247-251, 2009

3 Nardelli C, "miR-138/miR-222 overexpression characterizes the miRNome of amniotic mesenchymal stem cells in obesity" 26 : 4-14, 2017

4 Lee EK, "miR-130 suppresses adipogenesis by inhibiting peroxisome proliferator-activated receptor gamma expression" 31 : 626-638, 2011

5 Mota de Sá P, "Transcriptional regulation of adipogenesis" 7 : 635-674, 2017

6 Lee JE, "Transcriptional and epigenomic regulation of adipogenesis" 39 (39): e00601-00618, 2019

7 Moreira A, "Therapeutic potential of mesenchymal stem cells for diabetes" 59 : R109-R20, 2017

8 Yang HJ, "The stem cell potential and multipotency of human adipose tissue-derived stem cells vary by cell donor and are different from those of other types of stem cells" 199 : 373-383, 2014

9 Sha H, "The ER-associated degradation adaptor protein Sel1L regulates LPL secretion and lipid metabolism" 20 : 458-470, 2014

10 Pittenger MF, "Multilineage potential of adult human mesenchymal stem cells" 284 : 143-147, 1999

11 Esau C, "MicroRNA-143 regulates adipocyte differentiation" 279 : 52361-52365, 2004

12 Yang Z, "MicroRNA hsa-miR-138 inhibits adipogenic differentiation of human adipose tissue-derived mesenchymal stem cells through adenovirus EID-1" 20 : 259-267, 2011

13 Ortega FJ, "MiRNA expression profile of human subcutaneous adipose and during adipocyte differentiation" 5 : e9022-, 2010

14 Hu X, "MiR-27b impairs adipocyte differentiation of human adipose tissue-derived mesenchymal stem cells by targeting LPL" 47 : 545-555, 2018

15 Fitzsimmons REB, "Mesenchymal stromal/stem cells in regenerative medicine and tissue engineering" 2018 : 8031718-, 2018

16 Wang H, "Lipoprotein lipase : from gene to obesity" 297 : E271-88, 2009

17 Yu Y, "Knockdown of lncRNA KCNQ1OT1 suppresses the adipogenic and osteogenic differentiation of tendon stem cell via downregulating miR-138target genes PPARγ and RUNX2" 17 : 2374-2385, 2018

18 Almalki SG, "Key transcription factors in the differentiation of mesenchymal stem cells" 92 : 41-51, 2016

19 Takagi A, "Genetic diagnosis on hypertriglyceridemiaanalysis for LPL gene mutations" 71 : 1569-1576, 2013

20 Kim Y, "Direct comparison of human mesenchymal stem cells derived from adipose tissues and bone marrow in mediating neovascularization in response to vascular ischemia" 20 : 867-876, 2007

21 Goff LA, "Differentiating human multipotent mesenchymal stromal cells regulate microRNAs : prediction of microRNA regulation by PDGF during osteogenesis" 36 : 1354-1369, 2008

22 Bouvy-Liivrand M, "Combinatorial regulation of lipoprotein lipase by microRNAs during mouse adipogenesis" 11 : 76-91, 2014

23 Martin PJ, "Adipogenic RNAs are transferred in osteoblasts via bone marrow adipocytes-derived extracellular vesicles(EVs)" 16 : 10-, 2015

24 Skårn M, "Adipocyte differentiation of human bone marrowderived stromal cells is modulated by microRNA-155, microRNA-221, and microRNA-222" 21 : 873-883, 2012

25 Rosen ED, "Adipocyte differentiation from the inside out" 7 : 885-896, 2006

26 Kim D, "A nanoscale ridge/groove pattern arrayed surface enhances adipogenic differentiation of human supernumerary tooth-derived dental pulp stem cells in vitro" 59 : 765-774, 2014