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J Exp Med. 2016 Mar 7;213(3):433-49. doi: 10.1084/jem.20150806. Epub 2016 Feb 15.

Functional screen identifies regulators of murine hematopoietic stem cell repopulation.

Author information

1
Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105.
2
Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa City, IA 52242.
3
Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN 38105.
4
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105.
5
Department of Internal Medicine, University of Iowa, Iowa City, IA 52242.
6
Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105 shannon.mckinney-freeman@stjude.org.

Abstract

Understanding the molecular regulation of hematopoietic stem and progenitor cell (HSPC) engraftment is paramount to improving transplant outcomes. To discover novel regulators of HSPC repopulation, we transplanted >1,300 mice with shRNA-transduced HSPCs within 24 h of isolation and transduction to focus on detecting genes regulating repopulation. We identified 17 regulators of HSPC repopulation: Arhgef5, Armcx1, Cadps2, Crispld1, Emcn, Foxa3, Fstl1, Glis2, Gprasp2, Gpr56, Myct1, Nbea, P2ry14, Smarca2, Sox4, Stat4, and Zfp251. Knockdown of each of these genes yielded a loss of function, except in the cases of Armcx1 and Gprasp2, whose loss enhanced hematopoietic stem cell (HSC) repopulation. The discovery of multiple genes regulating vesicular trafficking, cell surface receptor turnover, and secretion of extracellular matrix components suggests active cross talk between HSCs and the niche and that HSCs may actively condition the niche to promote engraftment. We validated that Foxa3 is required for HSC repopulating activity, as Foxa3(-/-) HSC fails to repopulate ablated hosts efficiently, implicating for the first time Foxa genes as regulators of HSPCs. We further show that Foxa3 likely regulates the HSC response to hematologic stress. Each gene discovered here offers a window into the novel processes that regulate stable HSPC engraftment into an ablated host.

PMID:
26880577
PMCID:
PMC4813668
DOI:
10.1084/jem.20150806
[Indexed for MEDLINE]
Free PMC Article

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