Summary
Tissue inhibitor of metalloprotease-1 (TIMP-1) is a tissue inhibitor of matrix metalloproteinases (MMPs). It however exerts multiple effects on biological processes, such as cell growth, proliferation, differentiation and apoptosis, in an MMP-independent manner. This study aimed to examine the role of TIMP-1 in adipogenesis of adipose-derived stem cells (ASCs) and the underlying mechanism. We knocked down the TIMP-1 gene in ASCs through lentiviral vectors encoding TIMP-1 small interfering RNA (siRNA), and then found that the knockdown of TIMP-1 in ASCs promoted the adipogenic differentiation of stem cells and inhibited the Wnt/β-catenin signaling pathway in ASCs. We also noted that mutant TIMP-1 without the inhibitory activity on MMPs promoted the activation of Wnt/β-catenin pathway as well as the recombinant wild type TIMP-1 did, which indicated that the effect of TIMP-1 on Wnt/β-catenin pathway was MMP-independent. Our study suggested that TIMP-1 negatively regulated the adipogenesis of ASCs via the Wnt/β-catenin signaling pathway in an MMP-independent manner.
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References
Patrick CW Jr. Tissue engineering strategies for adipose tissue repair. Anat Rec, 2001,263(4):361–366
Yamashita YM, Tumbar T. Stem cells and their niche in homeostasis/regeneration and disease. Mol Biol Cell, 2014,25(6):736
Bauer-Kreisel P, Goepferich A, Blunk T. Cell-delivery therapeutics for adipose tissue regeneration. Adv Drug Deliv Rev, 2010,62(7–8):798–813
Choi JH, Gimble JM, Lee K, et al. Adipose tissue engineering for soft tissue regeneration. Tissue Eng Part B Rev, 2010,16(4):413–26
Kvell K, Fejes AV, Parnell SM, et al. Active Wnt/beta-catenin signaling is required for embryonic thymic epithelial development and functionality ex vivo. Immunobiology, 2014,219(8):644–52
Logan CY, Nusse R.. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol, 2004,20:781–810
Yuan Z, Li Q, Luo S, et al. PPARy and Wnt Signaling in Adipogenic and Osteogenic Differentiation of Mesenchymal Stem Cells. Curr Stem Cell Res Ther, 2016,11(3):216–25
Im GI, Quan Z. The effects of Wnt inhibitors on the chondrogenesis of human mesenchymal stem cells. Tissue Eng Part A, 2010,16(7):2405–13
Bennett CN, Ross SE, Longo KA, et al. Regulation of Wnt signaling during adipogenesis. J Biol Chem, 2002,277(34):30998–1004
Hu L, Yang G, Hägg D, et al. IGF1 Promotes Adipogenesis by a Lineage Bias of Endogenous Adipose Stem/Progenitor Cells. Stem Cells, 2015,33(8):2483–95
Hu L, Hu J, Zhao J, et al.. Side-by-side comparison of the biological characteristics of human umbilical cord and adipose tissue-derived mesenchymal stem cells. Biomed Res Int, 2013,2013:438243
Nicaise AM, Johnson KM, Willis CM, et al. TIMP-1 Promotes Oligodendrocyte Differentiation Through Receptor-Mediated Signaling. Mol Neurobiol, 2019,56(5):3380–92
Moore CS, Crocker SJ. An alternate perspective on the roles of TIMPs and MMPs in pathology. Am J Pathol, 2012,180(1):12–6
Stetler-Stevenson WG. Tissue inhibitors of metalloproteinases in cell signaling: metalloproteinase-independent biological activities. Sci Signal, 2008,1(27):re6
Ries C. Cytokine functions of TIMP-1. Cell Mol Life Sci, 2014,71(4):659–72
Chirco R, Liu XW, Jung KK, et al. Novel functions of TIMPs in cell signaling. Cancer Metastasis Rev, 2006,25(1):99–113
Demeulemeester D, Scroyen I, Voros G, et al. Overexpression of tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) in mice does not affect adipogenesis or adipose tissue development. Thromb Haemost, 2006,95(6):1019–24
Scroyen I, Cosemans L, Lijnen HR. Effect of tissue inhibitor of matrix metalloproteinases-1 on in vitro and in vivo adipocyte differentiation. Thromb Res, 2009,124(5):578–83
Alexander CM, Selvarajan S, Mudgett J, et al. Stromelysin-1 Regulates Adipogenesis during Mammary Gland Involution. J Cell Biol, 2001,152(4):693–703
Chavey C, Mari B, Monthouel MN, et al. Matrix Metalloproteinases Are Differentially Expressed in Adipose Tissue during Obesity and Modulate Adipocyte Differentiation. J Biol Chem, 2003,278(14):11888–96
Meissburger B, Stachorski L, Röder E, et al. Tissue inhibitor of matrix metalloproteinase 1 (TIMP1) controls adipogenesis in obesity in mice and in humans. Diabetologia, 2011,54(6):1468–79
Christodoulides C, Lagathu C, Sethi JK, et al. Adipogenesis and WNT signalling. Trends Endocrinol Metab, 2009,20(1):16–24
Ross SE, Hemati N, Longo KA, et al. Inhibition of Adipogenesis by Wnt Signaling. Science, 2000,289(5481):950–3
Thevenard J, Verzeaux L, Devy J, et al. Low-density lipoprotein receptor-related protein-1 mediates endocytic clearance of tissue inhibitor of metalloproteinases-1 and promotes its cytokine-like activities. PLoS One, 2014,9(7):e103839
Jung YS, Liu XW, Chirco R, et al. TIMP-1 induces an EMT-like phenotypic conversion in MDCK cells independent of its MMP-inhibitory domain. PLoS One, 2012,7(6):e38773
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Wang, L., Zhang, Cg., Jia, Yl. et al. Tissue Inhibitor of Metalloprotease-1 (TIMP-1) Regulates Adipogenesis of Adipose-derived Stem Cells (ASCs) via the Wnt Signaling Pathway in an MMP-independent Manner. CURR MED SCI 40, 989–996 (2020). https://doi.org/10.1007/s11596-020-2265-2
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DOI: https://doi.org/10.1007/s11596-020-2265-2