The transcriptional landscape of hematopoietic stem cell ontogeny

Shannon McKinney-Freeman, Patrick Cahan, Hu Li, Scott A. Lacadie, Hsuan Ting Huang, Matthew Curran, Sabine Loewer, Olaia Naveiras, Katie L. Kathrein, Martina Konantz, Erin M. Langdon, Claudia Lengerke, Leonard I. Zon, James J. Collins, George Q. Daley

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100 Scopus citations

Abstract

Transcriptome analysis of adult hematopoietic stem cells (HSCs) and their progeny has revealed mechanisms of blood differentiation and leukemogenesis, but a similar analysis of HSC development is lacking. Here, we acquired the transcriptomes of developing HSCs purified from >2,500 murine embryos and adult mice. We found that embryonic hematopoietic elements clustered into three distinct transcriptional states characteristic of the definitive yolk sac, HSCs undergoing specification, and definitive HSCs. We applied a network-biology- based analysis to reconstruct the gene regulatory networks of sequential stages of HSC development and functionally validated candidate transcriptional regulators of HSC ontogeny by morpholino-mediated knockdown in zebrafish embryos. Moreover, we found that HSCs from in vitro differentiated embryonic stem cells closely resemble definitive HSCs, yet lack a Notch-signaling signature, likely accounting for their defective lymphopoiesis. Our analysis and web resource will enhance efforts to identify regulators of HSC ontogeny and facilitate the engineering of hematopoietic specification.

Original languageEnglish (US)
Pages (from-to)701-714
Number of pages14
JournalCell Stem Cell
Volume11
Issue number5
DOIs
StatePublished - Nov 2 2012
Externally publishedYes

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ASJC Scopus subject areas

  • Cell Biology
  • Molecular Medicine
  • Genetics

Cite this

McKinney-Freeman, S., Cahan, P., Li, H., Lacadie, S. A., Huang, H. T., Curran, M., Loewer, S., Naveiras, O., Kathrein, K. L., Konantz, M., Langdon, E. M., Lengerke, C., Zon, L. I., Collins, J. J., & Daley, G. Q. (2012). The transcriptional landscape of hematopoietic stem cell ontogeny. Cell Stem Cell, 11(5), 701-714. https://doi.org/10.1016/j.stem.2012.07.018