The epigenetic promotion of osteogenic differentiation of human adipose-derived stem cells by the genetic and chemical blockade of histone demethylase LSD1
The epigenetic promotion of osteogenic differentiation of human adipose-derived stem cells by the genetic and chemical blockade of histone demethylase LSD1
复制标题
通过组蛋白去甲基化酶LSD1的遗传和化学阻断对人类脂肪干细胞成骨分化的表观遗传促进
DOI：
10.1016/j.biomaterials.2014.04.055
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发表时间：
2014-07-01
期刊：
影响因子：
14
通讯作者：
Zhou, Yongsheng
中科院分区：
文献类型：
--
作者：
Ge, Wenshu;Liu, Yunsong;Zhou, Yongsheng
人脂肪源性干细胞（hASCs）是骨组织工程中极具吸引力的来源。人们越来越清楚，染色质调节因子在细胞命运决定中发挥着重要作用。然而，hASCs的成骨分化是如何受表观遗传机制控制的还不完全清楚。在这里，我们使用遗传工具和化学抑制剂来修改hASC的表观遗传程序，并鉴定赖氨酸特异性脱甲基酶1（LSD 1），一种特异性催化二甲基和单甲基组蛋白H3赖氨酸4（H3 K4 me 2/1）脱甲基化的组蛋白脱甲基酶，作为hASC成骨分化的关键调节因子。具体地说，我们通过细胞研究和异种移植试验证明，用慢病毒基因敲减策略消除LSD 1基因可促进hASC的成骨分化。在分子水平上，我们发现LSD 1通过其组蛋白去甲基化酶活性调节成骨相关基因的表达。值得注意的是，我们证明了LSD 1去甲基化酶抑制剂可以有效地阻断其催化活性，并在表观遗传学上促进hASC的成骨分化。总之，我们的研究确定了LSD 1的功能和生物学作用，并广泛探讨了其酶活性在hASCs成骨分化中的作用。更好地了解LSD 1如何影响成骨相关的表观遗传事件将为基于hASC的细胞治疗的调节提供新的见解，并通过表观遗传干预促进骨组织工程的发展。(C)2014爱思唯尔有限公司版权所有。
Human adipose-derived stem cells (hASCs) are a highly attractive source in bone tissue engineering. It has become increasingly clear that chromatin regulators play an important role in cell fate determination. However, how osteogenic differentiation of hASCs is controlled by epigenetic mechanisms is not fully understood. Here we use genetic tools and chemical inhibitors to modify the epigenetic program of hASCs and identify lysine-specific demethylase 1 (LSD1), a histone demethylase that specifically catalyzes demethylation of di- and mono- methyl histone H3 lysine 4 (H3K4me2/1), as a key regulator in osteogenic differentiation of hASCs. Specifically, we demonstrated that genetic depletion of LSD1 with lentiviral strategy for gene knockdown promoted osteogenic differentiation of hASCs by cell studies and xenograft assays. At the molecular level, we found that LSD1 regulates osteogenesis-associated genes expression through its histone demethylase activity. Significantly, we demonstrated LSD1 demethylase inhibitors could efficiently block its catalytic activity and epigenetically boost osteogenic differentiation of hASCs. Altogether, our study defined the functional and biological roles of LSD1 and extensively explored the effects of its enzymatic activity in osteogenic differentiation of hASCs. A better understanding of how LSD1 influences on osteogenesis associated epigenetic events will provide new insights into the modulation of hASCs based cell therapy and improve the development of bone tissue engineering with epigenetic intervention. (C) 2014 Elsevier Ltd. All rights reserved.