Inducible and Deterministic Forward Programming of Human Pluripotent Stem Cells into Neurons, Skeletal Myocytes, and Oligodendrocytes

The isolation or in vitro derivation of many human cell types remains challenging and inefficient. Direct conversion of human pluripotent stem cells (hPSCs) by forced expression of transcription factors provides a potential alternative. However, deficient inducible gene expression in hPSCs has compr...

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Published in:Stem cell reports 2017-04, Vol.8 (4), p.803-812
Main Authors: Pawlowski, Matthias, Ortmann, Daniel, Bertero, Alessandro, Tavares, Joana M., Pedersen, Roger A., Vallier, Ludovic, Kotter, Mark R.N.
Format: Article
Language:English
Subjects:
Cell Differentiation
Cell Line
Cellular Reprogramming
Gene Expression
Gene Targeting - methods
human pluripotent stem cells
Humans
Muscle Development
Muscle Fibers, Skeletal - cytology
Muscle Fibers, Skeletal - metabolism
Neurogenesis
neurons
Neurons - cytology
Neurons - metabolism
oligodendrocyte progenitor cells
Oligodendroglia - cytology
Oligodendroglia - metabolism
Pluripotent Stem Cells - cytology
Pluripotent Stem Cells - metabolism
reprogramming
skeletal myocytes
Transgenes
Up-Regulation
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Summary:The isolation or in vitro derivation of many human cell types remains challenging and inefficient. Direct conversion of human pluripotent stem cells (hPSCs) by forced expression of transcription factors provides a potential alternative. However, deficient inducible gene expression in hPSCs has compromised efficiencies of forward programming approaches. We have systematically optimized inducible gene expression in hPSCs using a dual genomic safe harbor gene-targeting strategy. This approach provides a powerful platform for the generation of human cell types by forward programming. We report robust and deterministic reprogramming of hPSCs into neurons and functional skeletal myocytes. Finally, we present a forward programming strategy for rapid and highly efficient generation of human oligodendrocytes. [Display omitted] •Dual genomic safe harbor targeting of the Tet-ON system•Optimized inducible transgene expression in human pluripotent stem cells•Deterministic forward programming into neurons, myocytes, and oligodendrocytes In this article, Pawlowski and colleagues report a dual genomic safe harbor targeting approach for optimized inducible transgene expression in human pluripotent stem cells (hPSCs). The optimized inducible expression of reprogramming factors in hPSCs enables deterministic forward programming into mature cell types. This is exemplified by the rapid, single-step generation of neurons, skeletal myocytes, and oligodendrocytes.
ISSN:2213-6711
2213-6711
DOI:10.1016/j.stemcr.2017.02.016