A systems biology pipeline identifies regulatory networks for stem cell engineering

Melissa A. Kinney, Linda T. Vo, Jenna M. Frame, Jessica Barragan, Ashlee J. Conway, Shuai Li, Kwok Kin Wong, James J. Collins, Patrick Cahan, Trista E. North, Douglas A. Lauffenburger, George Q. Daley

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)810-818
Number of pages9
JournalNature biotechnology
Volume37
Issue number7
DOIs
StatePublished - Jul 1 2019

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Applied Microbiology and Biotechnology
  • Molecular Medicine
  • Biomedical Engineering

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