CDK6 is Essential for Mesenchymal Stem Cell Proliferation and Adipocyte Differentiation

Overview

Journal Front Mol Biosci

Specialty Biology

Date 2023 Sep 4

PMID 37664186

Authors

Alexander J Hu

Wei Li

Apana Pathak

Guo-Fu Hu

Xiaoli Hou

Stephen R Farmer

Miaofen G Hu

Affiliations

Soon will be listed here.

Abstract

Overweight or obesity poses a significant risk of many obesity-related metabolic diseases. Among all the potential new therapies, stem cell-based treatments hold great promise for treating many obesity-related metabolic diseases. However, the mechanisms regulating adipocyte stem cells/progenitors (precursors) are unknown. The aim of this study is to investigate if CDK6 is required for mesenchymal stem cell proliferation and adipocyte differentiation. Cyclin-dependent kinase 6 () mouse models together with stem cells derived from stromal vascular fraction (SVF) or mouse embryonic fibroblasts (MEFs) of mutant mice were used to determine if CDK6 is required for mesenchymal stem cell proliferation and adipocyte differentiation. We found that mice with a kinase inactive CDK6 mutants () had fewer precursor residents in the SVF of adult white adipose tissue (WAT). Stem cells from the SVF or MEFs of mice had defects in proliferation and differentiation into the functional fat cells. In contrast, mice with a constitutively active kinase CDK6 mutant () had the opposite traits. Ablation of RUNX1 in both mature and precursor cells, reversed the phenotypes. These results represent a novel role of CDK6 in regulating precursor numbers, proliferation, and differentiation, suggesting a potential pharmacological intervention for using CDK6 inhibitors in the treatment of obesity-related metabolic diseases.

Citing Articles

Cyclin-dependent kinases (CDKs) are key genes regulating early development of Neptunea arthritica cumingii: evidence from comparative transcriptome and proteome analyses.

Lv F, Ge X, Chang Y, Hao Z BMC Genomics. 2024; 25(1):1221.

PMID: 39701993 PMC: 11660575. DOI: 10.1186/s12864-024-10970-3.

References

Brooks A, Futrega K, Liang X, Hu X, Liu X, Crawford D . Concise Review: Quantitative Detection and Modeling the In Vivo Kinetics of Therapeutic Mesenchymal Stem/Stromal Cells. Stem Cells Transl Med. 2017; 7(1):78-86. PMC: 5746161. DOI: 10.1002/sctm.17-0209. View

Gounari F, Aifantis I, Martin C, Fehling H, Hoeflinger S, Leder P . Tracing lymphopoiesis with the aid of a pTalpha-controlled reporter gene. Nat Immunol. 2002; 3(5):489-96. DOI: 10.1038/ni778. View

Hansen J, Jorgensen C, Petersen R, Hallenborg P, De Matteis R, Boye H . Retinoblastoma protein functions as a molecular switch determining white versus brown adipocyte differentiation. Proc Natl Acad Sci U S A. 2004; 101(12):4112-7. PMC: 384703. DOI: 10.1073/pnas.0301964101. View

Fujimoto T, Anderson K, Jacobsen S, Nishikawa S, Nerlov C . Cdk6 blocks myeloid differentiation by interfering with Runx1 DNA binding and Runx1-C/EBPalpha interaction. EMBO J. 2007; 26(9):2361-70. PMC: 1864973. DOI: 10.1038/sj.emboj.7601675. View

Zhang Y, Li Y, Niepel M, Kawano Y, Han S, Liu S . Targeted deletion of thioesterase superfamily member 1 promotes energy expenditure and protects against obesity and insulin resistance. Proc Natl Acad Sci U S A. 2012; 109(14):5417-22. PMC: 3325675. DOI: 10.1073/pnas.1116011109. View

Biggs J, Peterson L, Zhang Y, Kraft A, Zhang D . AML1/RUNX1 phosphorylation by cyclin-dependent kinases regulates the degradation of AML1/RUNX1 by the anaphase-promoting complex. Mol Cell Biol. 2006; 26(20):7420-9. PMC: 1636878. DOI: 10.1128/MCB.00597-06. View

Walz C, Ahmed W, Lazarides K, Betancur M, Patel N, Hennighausen L . Essential role for Stat5a/b in myeloproliferative neoplasms induced by BCR-ABL1 and JAK2(V617F) in mice. Blood. 2012; 119(15):3550-60. PMC: 3325042. DOI: 10.1182/blood-2011-12-397554. View

Zhang X, Sun Y, Cheng S, Yao Y, Hua X, Shi Y . CDK6 increases glycolysis and suppresses autophagy by mTORC1-HK2 pathway activation in cervical cancer cells. Cell Cycle. 2022; 21(9):984-1002. PMC: 9037534. DOI: 10.1080/15384101.2022.2039981. View

Permana P, Nair S, Lee Y, Luczy-Bachman G, Vozarova de Courten B, Tataranni P . Subcutaneous abdominal preadipocyte differentiation in vitro inversely correlates with central obesity. Am J Physiol Endocrinol Metab. 2004; 286(6):E958-62. DOI: 10.1152/ajpendo.00544.2003. View

10.

Hu M, Deshpande A, Enos M, Mao D, Hinds E, Hu G . A requirement for cyclin-dependent kinase 6 in thymocyte development and tumorigenesis. Cancer Res. 2009; 69(3):810-8. PMC: 2636510. DOI: 10.1158/0008-5472.CAN-08-2473. View

11.

Holmes C, Stanford W . Concise review: stem cell antigen-1: expression, function, and enigma. Stem Cells. 2007; 25(6):1339-47. DOI: 10.1634/stemcells.2006-0644. View

12.

Brown N, Jeselsohn R, Bihani T, Hu M, Foltopoulou P, Kuperwasser C . Cyclin D1 activity regulates autophagy and senescence in the mammary epithelium. Cancer Res. 2012; 72(24):6477-89. PMC: 3525807. DOI: 10.1158/0008-5472.CAN-11-4139. View

13.

Jena N, Sheng J, Hu J, Li W, Zhou W, Lee G . CDK6-mediated repression of CD25 is required for induction and maintenance of Notch1-induced T-cell acute lymphoblastic leukemia. Leukemia. 2015; 30(5):1033-43. PMC: 4856559. DOI: 10.1038/leu.2015.353. View

14.

Oguri Y, Shinoda K, Kim H, Alba D, Bolus W, Wang Q . CD81 Controls Beige Fat Progenitor Cell Growth and Energy Balance via FAK Signaling. Cell. 2020; 182(3):563-577.e20. PMC: 7415677. DOI: 10.1016/j.cell.2020.06.021. View

15.

Velickovic K, Wayne D, Leija H, Bloor I, Morris D, Law J . Caffeine exposure induces browning features in adipose tissue in vitro and in vivo. Sci Rep. 2019; 9(1):9104. PMC: 6591281. DOI: 10.1038/s41598-019-45540-1. View

16.

Bhansali S, Dutta P, Kumar V, Yadav M, Jain A, Mudaliar S . Efficacy of Autologous Bone Marrow-Derived Mesenchymal Stem Cell and Mononuclear Cell Transplantation in Type 2 Diabetes Mellitus: A Randomized, Placebo-Controlled Comparative Study. Stem Cells Dev. 2016; 26(7):471-481. DOI: 10.1089/scd.2016.0275. View

17.

Kollmann K, Heller G, Schneckenleithner C, Warsch W, Scheicher R, Ott R . A Kinase-Independent Function of CDK6 Links the Cell Cycle to Tumor Angiogenesis. Cancer Cell. 2016; 30(2):359-360. PMC: 5637299. DOI: 10.1016/j.ccell.2016.07.003. View

18.

Hansen J, Petersen R, Larsen B, Bartkova J, Alsner J, Kristiansen K . Activation of peroxisome proliferator-activated receptor gamma bypasses the function of the retinoblastoma protein in adipocyte differentiation. J Biol Chem. 1999; 274(4):2386-93. DOI: 10.1074/jbc.274.4.2386. View

19.

Abella A, Dubus P, Malumbres M, Rane S, Kiyokawa H, Sicard A . Cdk4 promotes adipogenesis through PPARgamma activation. Cell Metab. 2005; 2(4):239-49. DOI: 10.1016/j.cmet.2005.09.003. View

20.

Reschly E, Spaulding C, Vilimas T, Graham W, Brumbaugh R, Aifantis I . Notch1 promotes survival of E2A-deficient T cell lymphomas through pre-T cell receptor-dependent and -independent mechanisms. Blood. 2006; 107(10):4115-21. PMC: 1895288. DOI: 10.1182/blood-2005-09-3551. View