Interplay between BMP4 and IL-7 in human intrathymic precursor cells.
Bone morphogenetic proteins (BMPs) play a pivotal role during vertebrate embryogenesis and organogenesis, and have also been described to function in regulating cell fate and determination in self-renewing tissues in adults. Recent results have demonstrated that the different components of the BMP2/4 signaling pathway are expressed in the human thymus. In this study, we provide evidence that BMP4 and IL-7 interplay is important in the maintenance of the human thymic progenitor population. Intrathymic CD34(+) cells express BMP receptors (BMPRIA, BMPRIB, ActRIA, BMPRII), signal transduction molecules (Smad1, 5, 8 and 4), and produce BMP4. Neutralization of endogenous BMP4 by treatment with the antagonist Noggin reduces thymic precursor cell survival, and the addition of exogenous BMP4 decreases their proliferation. The treatment of chimeric human-mouse fetal thymus organ cultures with BMP4 inhibits cell expansion, arrests thymocyte differentiation, and leads to the accumulation of human CD34(+) precursor cells. This effect is mainly attributed to the ability of BMP4 to counteract the IL-7-induced proliferation and differentiation of CD34(+) cells. BMP4 downregulates in the precursor cell population the expression of CD127 and inhibits the IL-7-dependent STAT5 phosphorylation. In addition, BMP signaling is promoted by IL-7. Our results also demonstrate that in thymic progenitors BMPs act downstream of Sonic Hedgehog, previously described to function as a maintenance factor for human intrathymic CD34(+) precursor cells.
Varas
Alberto
A
Department of Cell Biology, Faculty of Medicine, Complutense University, Madrid, Spain. avaras@bio.ucm.es
Sacedón
Rosa
R
Hidalgo
Laura
L
Martínez
Víctor G
VG
Valencia
Jaris
J
Cejalvo
Teresa
T
Zapata
Agustín
A
Hernández-López
Carmen
C
Vicente
Angeles
A
D018952:Antigens, CD34 / Q000378:metabolism; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism*; D052004:Bone Morphogenetic Protein Receptors / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism / Q000494:pharmacology; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002675:Child, Preschool; D002678:Chimera; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D015851:Interleukin-7 / Q000235:genetics / Q000378:metabolism*; D053699:Interleukin-7 Receptor alpha Subunit / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism*; D000099176:Noggin Protein
D018952:Antigens, CD34; D055415:Bone Morphogenetic Protein 4; D052004:Bone Morphogenetic Protein Receptors; D002352:Carrier Proteins; D053823:Hedgehog Proteins; D015851:Interleukin-7; D053699:Interleukin-7 Receptor alpha Subunit; D050799:STAT5 Transcription Factor; D051785:Smad Proteins; D000099176:Noggin Protein; C525809:BMP4 protein, human; C508605:IL7 protein, human