A systems biology pipeline identifies regulatory networks for stem cell engineering
Authors: Douglas A Lauffenburger
Shuai Li
Linda T Vo
Jenna M Frame
Melissa A Kinney
Trista E North
Kwok-Kin Wong
Jessica Barragan
Ashlee J Conway
James J Collins
George Q Daley
Patrick Cahan
Journal: Nature Biotechnology (2019)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: stem cell engineering; molecular networks; cell differentiation; computational approach; gene expression analysis
Affiliations: Stem Cell Program, Boston Children's Hospital, Boston, MA, USA., Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Boston, MA, USA., Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA., Harvard Medical School, Boston, MA, USA., Department of Pathology, Beth Israel-Deaconess Medical Center, Boston, MA, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Laura & Isaac Perlmutter Cancer Center, NYU Langone Medical Center, New York, NY, USA., Institute for Medical Engineering & Science, Department of Biological Engineering, Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA, USA., Harvard-MIT Program in Health Sciences and Technology, Cambridge, MA, USA., Broad Institute of MIT and Harvard, Cambridge, MA, USA., Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA., Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA., Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. ., Stem Cell Program, Boston Children's Hospital, Boston, MA, USA. ., Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Boston, MA, USA. ., Harvard Medical School, Boston, MA, USA. ., Harvard Stem Cell Institute, Boston, MA, USA. .

Abstract:  A major challenge for stem cell engineering is achieving a holistic understanding of the molecular networks and biological processes governing cell differentiation. To address this challenge, we describe a computational approach that combines gene expression analysis, previous knowledge from proteomic pathway informatics and cell signaling models to delineate key transitional states of differentiating cells at high resolution. Our network models connect sparse gene signatures with corresponding, yet disparate, biological processes to uncover molecular mechanisms governing cell fate transitions. This approach builds on our earlier CellNet and recent trajectory-defining algorithms, as illustrated by our analysis of hematopoietic specification along the erythroid lineage, which reveals a role for the EGF receptor family member, ErbB4, as an important mediator of blood development. We experimentally validate this prediction and perturb the pathway to improve erythroid maturation from human pluripotent stem cells. These results exploit an integrative systems perspective to identify new regulatory processes and nodes useful in cell engineering. 

Retracted: No

PubPeer comments:
 Experiments in fig. 5c-e used only one cell line, MSC-iPS. According to the original reference (Park et al, 2008, Nature), MSC-iPS line was estalished with six factors. In addition to Yamanaka four factors, the MSC-iPS line has hTERT and SV40 large T. Other posts pointed that MSC-iPS line expresses transgenes OCT4, SOX2, and MYC. The data of hTERT and SV40 large T are not shown. Because silencing resistant pMIG vector was used, one could assume that hTERT and SV40 large T are still expressed. https: pubpeer.com publications A600E09BABFB5C7A28B86BBA6F8AD9#2 https: pubpeer.com publications A600E09BABFB5C7A28B86BBA6F8AD9#4 This concerns that - whether proliferative capacity of MSC-iPS derived cells is due to hTERT and SV40 large T (fig. 5c). - the validity of ErbB4-Wnt axis in MSC-iPS derived cells (fig. 5d-e). Indeed, the Artandi group has shown that telomerase induces Wnt signaling. https: www.nature.com articles nature08137 The authors could address if they have validated with other iPS lines. ![file] , 
 Erratum for A systems biology pipeline identifies regulatory networks for stem cell engineering. [Nat Biotechnol. 2019] In the version of this article initially published, the second NIH grant  R24-DK49216 to author George Q. Daley contained an error. The grant number should have read U54DK110805. The error has been corrected in the HTML and PDF versions of the article. https: www.ncbi.nlm.nih.gov pubmed 31312048 ,