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Cell. 2014 Aug 14;158(4):889-902. doi: 10.1016/j.cell.2014.07.021.

Dissecting engineered cell types and enhancing cell fate conversion via CellNet.

Author information

1
Stem Cell Transplantation Program, Division of Pediatric Hematology and Oncology, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Boston Children's Hospital and Dana Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
2
Center for Individualized Medicine, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
3
Department of Medical Oncology Dana-Farber Cancer Institute, Boston, MA 02215, USA; Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA.
4
Department of Medical Oncology Dana-Farber Cancer Institute, Boston, MA 02215, USA; Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
5
Howard Hughes Medical Institute, Department of Biomedical Engineering and Center for BioDynamics, Boston University; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02215, USA.
6
Stem Cell Transplantation Program, Division of Pediatric Hematology and Oncology, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Boston Children's Hospital and Dana Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address: george.daley@childrens.harvard.edu.

Abstract

Engineering clinically relevant cells in vitro holds promise for regenerative medicine, but most protocols fail to faithfully recapitulate target cell properties. To address this, we developed CellNet, a network biology platform that determines whether engineered cells are equivalent to their target tissues, diagnoses aberrant gene regulatory networks, and prioritizes candidate transcriptional regulators to enhance engineered conversions. Using CellNet, we improved B cell to macrophage conversion, transcriptionally and functionally, by knocking down predicted B cell regulators. Analyzing conversion of fibroblasts to induced hepatocytes (iHeps), CellNet revealed an unexpected intestinal program regulated by the master regulator Cdx2. We observed long-term functional engraftment of mouse colon by iHeps, thereby establishing their broader potential as endoderm progenitors and demonstrating direct conversion of fibroblasts into intestinal epithelium. Our studies illustrate how CellNet can be employed to improve direct conversion and to uncover unappreciated properties of engineered cells.

PMID:
25126792
PMCID:
PMC4291075
DOI:
10.1016/j.cell.2014.07.021
[Indexed for MEDLINE]
Free PMC Article
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