Inhibition of KDM2/7 Promotes Notochordal Differentiation of hiPSCs

被引:0
作者
Diaz-Hernandez, Martha E. [1 ,2 ]
Murakami, Kimihide [1 ,3 ]
Murata, Shizumasa [1 ,3 ]
Khan, Nazir M. [1 ]
Shenoy, Sreekala P. V. [1 ]
Henke, Katrin [1 ]
Yamada, Hiroshi [3 ]
Drissi, Hicham [1 ,2 ]
机构
[1] Emory Univ, Dept Orthopaed, Atlanta, GA 30329 USA
[2] Atlanta VA Med Ctr, Decatur, GA 30033 USA
[3] Wakayama Med Univ, Dept Orthopaed Surg, Wakayama 6418510, Japan
关键词
human iPSC; notochordal cells; intervertebral disc degeneration; epigenetics; bulk RNA transcriptomics; differentiation; KDM; STEM-CELLS; DEMETHYLASES; PHYSIOLOGY; NETWORKS; ROLES; GENE;
D O I
10.3390/cells13171482
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Intervertebral disc disease (IDD) is a debilitating spine condition that can be caused by intervertebral disc (IVD) damage which progresses towards IVD degeneration and dysfunction. Recently, human pluripotent stem cells (hPSCs) were recognized as a valuable resource for cell-based regenerative medicine in skeletal diseases. Therefore, adult somatic cells reprogrammed into human induced pluripotent stem cells (hiPSCs) represent an attractive cell source for the derivation of notochordal-like cells (NCs) as a first step towards the development of a regenerative therapy for IDD. Utilizing a differentiation method involving treatment with a four-factor cocktail targeting the BMP, FGF, retinoic acid, and Wnt signaling pathways, we differentiate CRISPR/Cas9-generated mCherry-reporter knock-in hiPSCs into notochordal-like cells. Comprehensive analysis of transcriptomic changes throughout the differentiation process identified regulation of histone methylation as a pivotal driver facilitating the differentiation of hiPSCs into notochordal-like cells. We further provide evidence that specific inhibition of histone demethylases KDM2A and KDM7A/B enhanced the lineage commitment of hiPSCs towards notochordal-like cells. Our results suggest that inhibition of KDMs could be leveraged to alter the epigenetic landscape of hiPSCs to control notochord-specific gene expression. Thus, our study highlights the importance of epigenetic regulators in stem cell-based regenerative approaches for the treatment of disc degeneration.
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页数:14
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