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Edited by Ben A. Barres, Stanford University School of Medicine, Stanford, CA, and approved June 3, 2014 (received for review May 9, 2014)
Significance
Transplantation of human myelinogenic cells represents a realizable strategy for treatment of congenital and acquired demyelinating diseases. Although generation of undifferentiated neural stem and progenitors is feasible, the induction of myelinogenic cell fate remains a significant challenge. In this paper, we describe, to our knowledge, the first comprehensive study of transcription factor expression and function by purified neural and oligodendrocyte progenitors obtained directly from human brain tissue. We have identified those transcription factors capable of regulating oligodendrocyte progenitor fate and establish that among these, only SOX10 was capable of comprehensively inducing oligodendrocyte fate both in vitro and following transplantation into a model of human leukodystrophy. Thus, viral and pharmacologic approaches to increasing SOX10 expression likely will improve the outcome of human transplant therapy.
Abstract
Human oligodendrocyte progenitor cell (OPC) specification and differentiation occurs slowly and limits the potential for cell-based treatment of demyelinating disease. In this study, using FACS-based isolation and microarray analysis, we identified a set of transcription factors expressed by human primary CD140a+O4+ OPCs relative to CD133+CD140a− neural stem/progenitor cells (NPCs). Among these, lentiviral overexpression of transcription factors ASCL1, SOX10, and NKX2.2 in NPCs was sufficient to induce Sox10 enhancer activity, OPC mRNA, and protein expression consistent with OPC fate; however, unlike ASCL1 and NKX2.2, only the transcriptome of SOX10-infected NPCs was induced to a human OPC gene expression signature. Furthermore, only SOX10 promoted oligodendrocyte commitment, and did so at quantitatively equivalent levels to native OPCs. In xenografts of shiverer/rag2 animals, SOX10 increased the rate of mature oligodendrocyte differentiation and axon ensheathment. Thus, SOX10 appears to be the principle and rate-limiting regulator of myelinogenic fate from human NPCs.
Footnotes
- ↵1To whom correspondence should be addressed. E-mail: fjsim{at}buffalo.edu.
Author contributions: J.W. and F.J.S. designed research; J.W., S.U.P., A.K.H., C.W., M.A.O., and F.J.S. performed research; J.W. and F.J.S. analyzed data; and J.W. and F.J.S. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1408295111/-/DCSupplemental.
- Jing Wang,
- Suyog U. Pol,
- Alexa K. Haberman,
- Chunming Wang,
- Melanie A. O’Bara, and
- Fraser J. Sim1
- Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14214
Edited by Ben A. Barres, Stanford University School of Medicine, Stanford, CA, and approved June 3, 2014 (received for review May 9, 2014)
Significance
Transplantation of human myelinogenic cells represents a realizable strategy for treatment of congenital and acquired demyelinating diseases. Although generation of undifferentiated neural stem and progenitors is feasible, the induction of myelinogenic cell fate remains a significant challenge. In this paper, we describe, to our knowledge, the first comprehensive study of transcription factor expression and function by purified neural and oligodendrocyte progenitors obtained directly from human brain tissue. We have identified those transcription factors capable of regulating oligodendrocyte progenitor fate and establish that among these, only SOX10 was capable of comprehensively inducing oligodendrocyte fate both in vitro and following transplantation into a model of human leukodystrophy. Thus, viral and pharmacologic approaches to increasing SOX10 expression likely will improve the outcome of human transplant therapy.
Abstract
Human oligodendrocyte progenitor cell (OPC) specification and differentiation occurs slowly and limits the potential for cell-based treatment of demyelinating disease. In this study, using FACS-based isolation and microarray analysis, we identified a set of transcription factors expressed by human primary CD140a+O4+ OPCs relative to CD133+CD140a− neural stem/progenitor cells (NPCs). Among these, lentiviral overexpression of transcription factors ASCL1, SOX10, and NKX2.2 in NPCs was sufficient to induce Sox10 enhancer activity, OPC mRNA, and protein expression consistent with OPC fate; however, unlike ASCL1 and NKX2.2, only the transcriptome of SOX10-infected NPCs was induced to a human OPC gene expression signature. Furthermore, only SOX10 promoted oligodendrocyte commitment, and did so at quantitatively equivalent levels to native OPCs. In xenografts of shiverer/rag2 animals, SOX10 increased the rate of mature oligodendrocyte differentiation and axon ensheathment. Thus, SOX10 appears to be the principle and rate-limiting regulator of myelinogenic fate from human NPCs.
- neural precursor cell
- transplantation
- reprogramming
Footnotes
- ↵1To whom correspondence should be addressed. E-mail: fjsim{at}buffalo.edu.
Author contributions: J.W. and F.J.S. designed research; J.W., S.U.P., A.K.H., C.W., M.A.O., and F.J.S. performed research; J.W. and F.J.S. analyzed data; and J.W. and F.J.S. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1408295111/-/DCSupplemental.
Transcriptional regulation of human OPC fate
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