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An orthogonal differentiation platform for genomically programming stem cells, organoids, and bioprinted tissues

Mark A. Skylar-Scott, Jeremy Y. Huang, Aric Lu, Alex H.M. Ng, Tomoya Duenki, Lucy L. Nam, Sarita Damaraju, George M. Church, Jennifer A. Lewis
doi: https://doi.org/10.1101/2020.07.11.198671
Mark A. Skylar-Scott
1Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA
2Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA
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  • For correspondence: skyscott@stanford.edu jalewis@seas.harvard.edu
Jeremy Y. Huang
1Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA
2Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA
3Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
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Aric Lu
1Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA
2Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA
4Biological Engineering Division, Draper Laboratory, Cambridge, MA, USA
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Alex H.M. Ng
1Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA
3Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
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Tomoya Duenki
1Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA
2Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA
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Lucy L. Nam
1Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA
2Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA
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Sarita Damaraju
1Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA
2Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA
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George M. Church
1Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA
3Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
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Jennifer A. Lewis
1Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA
2Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA
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  • For correspondence: skyscott@stanford.edu jalewis@seas.harvard.edu
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Abstract

Simultaneous differentiation of human induced pluripotent stem cells (hiPSCs) into divergent cell types offers a pathway to achieving tailorable cellular complexity, patterned architecture, and function in engineered human organoids and tissues. Recent transcription factor (TF) overexpression protocols typically produce only one cell type of interest rather than the multitude of cell types and structural organization found in native human tissues. Here, we report an orthogonal differentiation platform for genomically programming stem cells, organoids and bioprinted tissues with controlled composition and organization. To demonstrate this platform, we orthogonally differentiated endothelial cells and neurons from hiPSCs in a one-pot system containing neural stem cell-specifying media. By aggregating inducible-TF and wildtype hiPSCs into pooled and multicore-shell embryoid bodies, we produced vascularized and patterned cortical organoids within days. Using multimaterial 3D bioprinting, we patterned 3D neural tissues from densely cellular, matrix-free stem cell inks that were orthogonally differentiated on demand into distinct layered regions composed of neural stem cells, endothelium, and neurons, respectively. Given the high proliferative capacity and patient-specificity of hiPSCs, our platform provides a facile route for programming cells and multicellular tissues for drug screening and therapeutic applications.

Competing Interest Statement

Multiple patents have been filed on the research advances reported in this manuscript. A. Ng and G. Church have co-founded a startup company, GC Therapeutics.

Footnotes

  • ↵** M.A. Skylar-Scott is now on the faculty at Stanford University.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted July 12, 2020.
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An orthogonal differentiation platform for genomically programming stem cells, organoids, and bioprinted tissues
Mark A. Skylar-Scott, Jeremy Y. Huang, Aric Lu, Alex H.M. Ng, Tomoya Duenki, Lucy L. Nam, Sarita Damaraju, George M. Church, Jennifer A. Lewis
bioRxiv 2020.07.11.198671; doi: https://doi.org/10.1101/2020.07.11.198671
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An orthogonal differentiation platform for genomically programming stem cells, organoids, and bioprinted tissues
Mark A. Skylar-Scott, Jeremy Y. Huang, Aric Lu, Alex H.M. Ng, Tomoya Duenki, Lucy L. Nam, Sarita Damaraju, George M. Church, Jennifer A. Lewis
bioRxiv 2020.07.11.198671; doi: https://doi.org/10.1101/2020.07.11.198671

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