Inflammatory signaling regulates embryonic hematopoietic stem and progenitor cell production.
Identifying signaling pathways that regulate hematopoietic stem and progenitor cell (HSPC) formation in the embryo will guide efforts to produce and expand HSPCs ex vivo. Here we show that sterile tonic inflammatory signaling regulates embryonic HSPC formation. Expression profiling of progenitors with lymphoid potential and hematopoietic stem cells (HSCs) from aorta/gonad/mesonephros (AGM) regions of midgestation mouse embryos revealed a robust innate immune/inflammatory signature. Mouse embryos lacking interferon γ (IFN-γ) or IFN-α signaling and zebrafish morphants lacking IFN-γ and IFN-ϕ activity had significantly fewer AGM HSPCs. Conversely, knockdown of IFN regulatory factor 2 (IRF2), a negative regulator of IFN signaling, increased expression of IFN target genes and HSPC production in zebrafish. Chromatin immunoprecipitation (ChIP) combined with sequencing (ChIP-seq) and expression analyses demonstrated that IRF2-occupied genes identified in human fetal liver CD34(+) HSPCs are actively transcribed in human and mouse HSPCs. Furthermore, we demonstrate that the primitive myeloid population contributes to the local inflammatory response to impact the scale of HSPC production in the AGM region. Thus, sterile inflammatory signaling is an evolutionarily conserved pathway regulating the production of HSPCs during embryonic development.
Abramson Family Cancer Research Institute, Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19014, USA;
Yan
Y
Li
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA;
Virginie
V
Esain
Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52242, USA;
Li
L
Teng
Howard Hughes Medical Institute, Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts 02115, USA;
Jian
J
Xu
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA;
Wanda
W
Kwan
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA;
Isaura M
IM
Frost
Abramson Family Cancer Research Institute, Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19014, USA;
Amanda D
AD
Yzaguirre
Abramson Family Cancer Research Institute, Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19014, USA;
Xiongwei
X
Cai
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA;
Mauricio
M
Cortes
Abramson Family Cancer Research Institute, Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19014, USA;
Marijke W
MW
Maijenburg
Abramson Family Cancer Research Institute, Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19014, USA;
Joanna
J
Tober
The University of Edinburgh, Edinburgh EH8 9YL, United Kingdom;
Elaine
E
Dzierzak
Howard Hughes Medical Institute, Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA;
Stuart H
SH
Orkin
Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52242, USA; Department of Bioengineering, University of Iowa, Iowa City, Iowa 52242, USA.
Kai
K
Tan
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA; nancyas@exchange.upenn.edu tnorth@bidmc.harvard.edu.
Trista E
TE
North
Abramson Family Cancer Research Institute, Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19014, USA;
Nancy A
NA
Speck
D000818:Animals; D000950:Antigens, Ly / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D004622:Embryo, Mammalian; D004625:Embryo, Nonmammalian; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics* / Q000276:immunology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D007372:Interferons / Q000235:genetics / Q000378:metabolism; D051379:Mice; D015398:Signal Transduction; D015027:Zebrafish / Q000196:embryology
D000950:Antigens, Ly; D016207:Cytokines; D007372:Interferons
hematopoiesis; hematopoietic stem cell; interferon; lymphoid progenitor; mouse; zebrafish