The epigenetic promotion of osteogenic differentiation of human adipose-derived stem cells by the genetic and chemical blockade of histone demethylase LSD1

Ge, Wenshu; Liu, Yunsong; Chen, Tong; Zhang, Xiao; Lv, Longwei; Jin, Chanyuan; Jiang, Yong; Shi, Lei; Zhou, Yongsheng

doi:10.1016/j.biomaterials.2014.04.055

Cited by 62 publications

(76 citation statements)

References 56 publications

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“…Further, KDM1A knockdown or pharmacological inhibition reduced the sphere formation ability and reduced the expression of nestin and sox2, and increased GFAP. Earlier studies demonstrated that inhibition of KDM1A promoted the osteogenic differentiation of human adipose-derived stem cells 52 and blockade of KDM1A induced the differentiation of leukemia stem cells, 53,54 further support the our conclusion that KDM1A blockade induces GSCs differentiation.…”

Section: Discussionsupporting

confidence: 84%

Novel KDM1A inhibitors induce differentiation and apoptosis of glioma stem cells via unfolded protein response pathway

et al. 2016

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Glioma stem cells (GSCs) have a central role in glioblastoma (GBM) development and chemo/radiation resistance, and their elimination is critical for the development of efficient therapeutic strategies. Recently, we showed that lysine demethylase KDM1A is overexpressed in GBM. In the present study, we determined whether KDM1A modulates GSCs stemness and differentiation and tested the utility of two novel KDM1A-specific inhibitors (NCL-1 and NCD-38) to promote differentiation and apoptosis of GSCs. The efficacy of KDM1A targeting drugs was tested on purified GSCs isolated from established and patient-derived GBMs using both in vitro assays and in vivo orthotopic preclinical models. Our results suggested that KDM1A is highly expressed in GSCs and knockdown of KDM1A using shRNA-reduced GSCs stemness and induced the differentiation. Pharmacological inhibition of KDM1A using NCL-1 and NCD-38 significantly reduced the cell viability, neurosphere formation and induced apoptosis of GSCs with little effect on differentiated cells. In preclinical studies using orthotopic models, NCL-1 and NCD-38 significantly reduced GSCs-driven tumor progression and improved mice survival. RNA-sequencing analysis showed that KDM1A inhibitors modulate several pathways related to stemness, differentiation and apoptosis. Mechanistic studies showed that KDM1A inhibitors induce activation of the unfolded protein response (UPR) pathway. These results strongly suggest that selective targeting of KDM1A using NCL-1 and NCD-38 is a promising therapeutic strategy for elimination of GSCs.

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Section: Discussionsupporting

confidence: 84%

Novel KDM1A inhibitors induce differentiation and apoptosis of glioma stem cells via unfolded protein response pathway

et al. 2016

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“…Our previous studies have demonstrated the epigenetic mechanism of osteogenic differentiation of human adipose-derived mesenchymal stem cells (hASCs). 26 The inhibition of the demethylase retinoblastoma binding protein 2 (RBP2) and lysine-specific demethylase 1 (LSD1) enhanced the osteogenic abilities of hASCs. However, to date, there has been no drug inhibitor of RBP2.…”

Section: Discussionmentioning

confidence: 99%

“…However, to date, there has been no drug inhibitor of RBP2. 26 Therefore, the inhibition of RBP2 could only be attained via small interfering RNA using vectors such as lentivirus, which has substantially hindered its clinical application. Fortunately, monoamine oxidase (MAO) inhibitors inhibit the activity of LSD1.…”

Section: Discussionmentioning

confidence: 99%

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Lysine-specific demethylase 1 inhibitor rescues the osteogenic ability of mesenchymal stem cells under osteoporotic conditions by modulating H3K4 methylation

Liu

et al. 2016

Bone Res

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Bone tissue engineering may be hindered by underlying osteoporosis because of a decreased osteogenic ability of autologous seed cells and an unfavorably changed microenvironment in these patients. Epigenetic regulation plays an important role in the developmental origins of osteoporosis; however, few studies have investigated the potential of epigenetic therapy to improve or rescue the osteogenic ability of bone marrow mesenchymal stem cells (BMMSCs) under osteoporotic conditions. Here, we investigated pargyline, an inhibitor of lysine-specific demethylase 1 (LSD1), which mainly catalyzes the demethylation of the di- and mono-methylation of H3K4. We demonstrated that 1.5 mmol·L−1 pargyline was the optimal concentration for the osteogenic differentiation of human BMMSCs. Pargyline rescued the osteogenic differentiation ability of mouse BMMSCs under osteoporotic conditions by enhancing the dimethylation level of H3K4 at the promoter regions of osteogenesis-related genes. Moreover, pargyline partially rescued or prevented the osteoporotic conditions in aged or ovariectomized mouse models, respectively. By introducing the concept of epigenetic therapy into the field of osteoporosis, this study demonstrated that LSD1 inhibitors could improve the clinical practice of MSC-based bone tissue engineering and proposes their novel use to treat osteoporosis.

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“…This is likely unrelated to the effects of CHD1 near the TSS as only low levels of CHD1 were detected at the TSS of the BGLAP or ALPL genes (data not shown). Interestingly, this inhibitory effect of CHD1 can be potentially explained by the recently discovered interaction of CHD1 with LSD1 (73), which was shown to repress osteoblast differentiation by silencing ALPL and BGLAP expression (74). In contrast to the higher expression of these early osteoblastic markers, CHD1 depletion led to impaired mineralization and decreased expression of extracellular matrix-associated genes.…”

Section: Discussionmentioning

confidence: 99%

CHD1 regulates cell fate determination by activation of differentiation-induced genes

Baumgart

Najafova

Hossan

et al. 2017

Nucleic Acids Research

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The coordinated temporal and spatial activation of gene expression is essential for proper stem cell differentiation. The Chromodomain Helicase DNA-binding protein 1 (CHD1) is a chromatin remodeler closely associated with transcription and nucleosome turnover downstream of the transcriptional start site (TSS). In this study, we show that CHD1 is required for the induction of osteoblast-specific gene expression, extracellular-matrix mineralization and ectopic bone formation in vivo. Genome-wide occupancy analyses revealed increased CHD1 occupancy around the TSS of differentiation-activated genes. Furthermore, we observed that CHD1-dependent genes are mainly induced during osteoblast differentiation and are characterized by higher levels of CHD1 occupancy around the TSS. Interestingly, CHD1 depletion resulted in increased pausing of RNA Polymerase II (RNAPII) and decreased H2A.Z occupancy close to the TSS, but not at enhancer regions. These findings reveal a novel role for CHD1 during osteoblast differentiation and provide further insights into the intricacies of epigenetic regulatory mechanisms controlling cell fate determination.

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The epigenetic promotion of osteogenic differentiation of human adipose-derived stem cells by the genetic and chemical blockade of histone demethylase LSD1

Cited by 62 publications

References 56 publications

Novel KDM1A inhibitors induce differentiation and apoptosis of glioma stem cells via unfolded protein response pathway

Novel KDM1A inhibitors induce differentiation and apoptosis of glioma stem cells via unfolded protein response pathway

Lysine-specific demethylase 1 inhibitor rescues the osteogenic ability of mesenchymal stem cells under osteoporotic conditions by modulating H3K4 methylation

CHD1 regulates cell fate determination by activation of differentiation-induced genes

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