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Bone Morphogenetic Protein Signaling and Olig1/2 Interact to Regulate the Differentiation and Maturation of Adult Oligodendrocyte Precursor Cells
Xiaoxin Chenga,b, Yaping Wanga,b,d, Qian Hea,b, Mengsheng Qiua,c, Scott R. Whittemorea,b,c, Qilin Caoa,b
aKentucky Spinal Cord Injury Research Center and
Departments of bNeurological Surgery and
cAnatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, Kentucky, USA;
dDepartment of Anesthesiology, Second Xian-Ya Hospital of South Central University, Changsha, Hunan, People's Republic of China
Key Words. Adult oligodendrocyte precursor cell • Spinal cord • Bone morphogenetic protein • Transcription factor • Differentiation • Remyelination
Correspondence: Qilin Cao, M.D., Kentucky Spinal Cord Injury Research Center, Department of Neurological Surgery, MDR 616, 511 South Floyd Street, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA. Telephone: 502-852-0284; Fax: 502-852-5148; e-mail: Received April 18, 2007; accepted for publication August 31, 2007.
First published online in STEM CELLS EXPRESS September 13, 2007.
Promotion of remyelination is an important therapeutic strategy for the treatment of the demyelinating neurological disorders. Adult oligodendrocyte precursor cells (OPCs), which normally reside quiescently in the adult central nervous system (CNS), become activated and proliferative after demyelinating lesions. However, the extent of endogenous remyelination is limited because of the failure of adult OPCs to mature into myelinating oligodendrocytes (OLs) in the demyelinated CNS. Understanding the molecular mechanisms that regulate the differentiation of adult OPCs could lead to new therapeutic strategies to treat these disorders. In this study, we established a stable culture of adult spinal cord OPCs and developed a reliable in vitro protocol to induce their sequential differentiation. Adult OPCs expressed bone morphogenetic protein (BMP) type Ia, Ib, and II receptor subunits, which are required for BMP signal transduction. BMP2 and 4 promoted dose-dependent astrocyte differentiation of adult OPCs with concurrent suppression of OL differentiation. Treatment of OPCs with BMP2 and 4 increased ID4 expression and decreased the expression of olig1 and olig2. Overexpression of olig1 or olig2 blocked the astrocyte differentiation of adult OPCs induced by BMP2 and 4. Furthermore, overexpression of both olig1 and olig2, but not olig1 or olig2 alone, rescued OL differentiation from inhibition by BMP2 and 4. Our results demonstrated that downregulation of olig1 and olig2 is an important mechanism by which BMP2 and 4 inhibit OL differentiation of adult OPCs. These data suggest that blocking BMP signaling combined with olig1/2 overexpression could be a useful therapeutic strategy to enhance endogenous remyelination and facilitate functional recovery in CNS demyelinated disorders.
Disclosure of potential conflicts of interest is found at the end of this article.
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中南大学湘雅二医院始建于1958年，隶属于国家教育部直管的中南大学，是国家卫生部直管的一所集医疗、教学、科研、康复、预防、保健于一体的大型三级甲等医院，也是中国大陆医疗机构中专科设置最为齐全的大型现代化医院之一。先后荣获卫生部文明医院、全国百佳医院、全国五一劳动奖状、全国抗击非典先进集体、全国行业作风建设先进集体、全国百姓放心示范医院、湖南省精神文明建设先进集体等荣誉称号。
