Integrative genomic and functional analyses reveal neuronal subtype differentiation bias in human embryonic stem cell lines

Proceedings of the National Academy of Sciences of the United States of America - Tập 104 Số 34 - Trang 13821-13826 - 2007
Hao Wu1,2, Jun‐Wei Xu3,4, Zhiping P. Pang3, Weihong Ge5,1, Kevin J. Kim5,1, Bruno Blanchi5,1, Caifu Chen6, Thomas C. Südhof3,4, Yi Eve Sun5,1
1Departments of Psychiatry and Biobehavioral Sciences and Molecular and Medical Pharmacology, Neuropsychiatric Institute, David Geffen School of Medicine at University of California, Los Angeles, Neuroscience Research Building Room 351, 635 Charles E. Young Drive South, Los Angeles, CA 90095;
2Mental Retardation Research Center, David Geffen School of Medicine at University of California, Los Angeles, Neuroscience Research Building Room 351, 635 Charles E. Young Drive South, Los Angeles, CA 90095, USA.
3Departments of Neuroscience and Molecular Genetics and
4Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard NA4.118, Dallas, TX 75390; and
5*Mental Retardation Research Center and
6Applied Biosystems, Inc., Foster City, CA 94404

Tóm tắt

The self-renewal and differentiation potential of human embryonic stem cells (hESCs) suggests that hESCs could be used for regenerative medicine, especially for restoring neuronal functions in brain diseases. However, the functional properties of neurons derived from hESC are largely unknown. Moreover, because hESCs were derived under diverse conditions, the possibility arises that neurons derived from different hESC lines exhibit distinct properties, but this possibility remains unexplored. To address these issues, we developed a protocol that allows stepwise generation from hESCs of cultures composed of ≈70–80% human neurons that exhibit spontaneous synaptic network activity. Comparison of neurons derived from the well characterized HSF1 and HSF6 hESC lines revealed that HSF1- but not HSF6-derived neurons exhibit forebrain properties. Accordingly, HSF1-derived neurons initially form primarily GABAergic synaptic networks, whereas HSF6-derived neurons initially form glutamatergic networks. microRNA profiling revealed significant expression differences between the two hESC lines, suggesting that microRNAs may influence their distinct differentiation properties. These observations indicate that although both HSF1 and HSF6 hESCs differentiate into functional neurons, the two hESC lines exhibit distinct differentiation potentials, suggesting that they are preprogrammed. Information on hESC line-specific differentiation biases is crucial for neural stem cell therapy and establishment of novel disease models using hESCs.

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Tài liệu tham khảo

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Proceedings of the National Academy of Sciences of the United States of America

Tập 104 Số 34

13821-13826

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