Cellular modeling of defective osteogenesis in Menkes disease-induced pluripopent stem cells = 멘케스병 특이적 역분화줄기세포를 이용한 골형성과정의 결함 연구

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Bone abnormalities, one of the primary manifestations of Menkes disease (MD), include a weakened bone matrix and low mineral density. However, the molecular and cellular mechanisms underlying these bone defects are poorly understood. Here, we present in vitro modeling for impaired osteogenesis in MD using human induced pluripotent stem cells (iPSCs) with a mutated ATP7A gene. MD-iPSC lines were generated from two patients harboring different mutations. The MD-iPSCs showed a remarkable retardation in CD105 expression with morphological anomalies during development to mesenchymal stem cells (MSCs) compared with wild type (WT)-iPSCs. Although prolonged culture enhanced CD105 expression, interestingly, mature MD-MSCs presented with low alkaline phosphatase activity, reduced calcium deposition in the extracellular matrix, and down-regulated osteoblast-specific genes during osteoblastic differentiation in vitro. Copper chelation in WT-MSCs recapitulated the aberrant phenotypes observed in MD-MSCs, but copper treatment in MD-MSCs did not rescue the impaired osteogenesis. Lysyl oxidase activity was also decreased in MD-MSCs during osteoblastic differentiation. Our findings indicate that ATP7A dysfunction contributes to retardation in MSC development and impairs osteogenesis.
Advisors
Han, Yong-Mahnresearcher한용만researcher
Description
한국과학기술원 :생명과학과,
Publisher
한국과학기술원
Issue Date
2015
Identifier
325007
Language
eng
Description

학위논문(박사) - 한국과학기술원 : 생명과학과, 2015.2 ,[x, 103 p. :]

Keywords

Menkes disease; ATP7A; Copper; Mesenchymal stem cells; Osteoblasts; 멘케스병; 구리; 중간엽줄기세포; 골세포

URI
http://hdl.handle.net/10203/222132
Link
http://library.kaist.ac.kr/search/detail/view.do?bibCtrlNo=657556&flag=dissertation
Appears in Collection
BS-Theses_Ph.D.(박사논문)
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