TY - JOUR
T1 - Dissecting engineered cell types and enhancing cell fate conversion via Cellnet
AU - Morris, Samantha A.
AU - Cahan, Patrick
AU - Li, Hu
AU - Zhao, Anna M.
AU - San Roman, Adrianna K.
AU - Shivdasani, Ramesh A.
AU - Collins, James J.
AU - Daley, George Q.
N1 - Funding Information:
We would like to thank members of the Daley laboratory for critical discussion, the Dana Farber Cancer Institute Hematological Neoplasia flow facility for assistance with cell sorting, and Thomas Graf for the C10 and RAW264.7 cells. G.Q.D. is supported by grants from the NIH (Progenitor Cell Biology Consortium UO1-HL100001 and R24DK092760), and the Boston Children's Hospital Stem Cell Program. G.Q.D. is an affiliate member of the Broad Institute, and an investigator of the Howard Hughes Medical Institute and the Manton Center for Orphan Disease Research. S.A.M. is supported by a Young Investigator Award from Alex’s Lemonade Stand Foundation and P50HG005550. P.C is supported by 1K01DK096013, 2T32HL066987, and 5T32HL007623. H.L. is supported by Mayo Clinic Center for Individualized Medicine and Mayo Clinic Center for Regenerative Medicine. J.J.C. is supported by NIH grant R24DK092760 and the HHMI. R.A.S. is supported by NIH grant R01DK082889.
PY - 2014/8/14
Y1 - 2014/8/14
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cell.2014.07.021
DO - 10.1016/j.cell.2014.07.021
M3 - Article
C2 - 25126792
AN - SCOPUS:84908431507
SN - 0092-8674
VL - 158
SP - 889
EP - 902
JO - Cell
JF - Cell
IS - 4
ER -