JHDM1d调控ERK信号通路在牙髓干细胞成骨分化及骨修复过程中的作用研究

Cranial neural crest cells (CNCCs) contribute to the formation of most soft and hard tissues constituting craniofacial structures after its migration and differentiation. Dental pulp stem cells, originated from CNCCs, may share the same genetic and molecular regulation with lip and palate morphogenesis. We isolated dental pulp stem cells from non-syndromic cleft lip/palate patients derived-exfoliated deciduous teeth (SHED-CLP) and previous studies found: 1) The proliferation and osteogenic differentiation capacity of SHED-CLP was defect; 2) ERK1/2 was abnormally up regulated and Runx2 level was decreased in SHED-CLP while blocking ERK1/2 expression rescued Runx2 activity; 3) Histone demethylase JHDM1d was abnormally activated in SHED-CLP. Based on these results, we are going to elucidate the regulation of ERK signaling and the role of JHDM1d through ERK pathway in osteogenesis of SHED-CLP, which could generate bone formation in bone defect model. Our research will not only help to understand the osteogenesis imperfect mechanism of NSCL/P, but also provide a new strategy for clinically developing new methods of bone regeneration.

颅神经嵴细胞迁移分化构成了组成颅颌面的大部分软硬结缔组织，而牙髓干细胞正来源于颅神经嵴细胞，提示唇腭部组织发育与牙髓干细胞可能接受相同的基因分子调控。本课题从非综合征型唇腭裂患儿脱落乳牙中分离培养牙髓干细胞(SHED-CLP)，近期预实验发现：1)SHED-CLP增殖和成骨分化能力受损；2)ERK1/2在SHED-CLP中异常活化，Runx2在SHED-CLP中表达降低，而阻断ERK1/2表达后Runx２活性上调；3)组蛋白去甲基化酶JHDM1D在SHED-CLP中异常上调。我们将在前期研究基础上, 进一步阐明ERK信号通路在SHED-CLP成骨能力的关键作用，揭示JHDM1D通过调控ERK信号通路调节干细胞成骨分化，并利用骨缺损模型证明其可促进骨再生。对此机制的研究不仅有助于理解非综合征型唇腭裂成骨不全发病机制，也为临床开发新的骨组织再生方法提供思路。