Interplay between BMP4 and IL-7 in human intrathymic precursor cells

Cell Cycle. 2009 Dec 15;8(24):4119-26. doi: 10.4161/cc.8.24.10149. Epub 2009 Dec 21.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD34 / metabolism
  • Bone Morphogenetic Protein 4 / genetics
  • Bone Morphogenetic Protein 4 / metabolism*
  • Bone Morphogenetic Protein Receptors / metabolism
  • Carrier Proteins / metabolism
  • Carrier Proteins / pharmacology
  • Cell Differentiation / physiology
  • Cell Proliferation
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Cells, Cultured
  • Child, Preschool
  • Chimera
  • Hedgehog Proteins / metabolism
  • Humans
  • Infant
  • Infant, Newborn
  • Interleukin-7 / genetics
  • Interleukin-7 / metabolism*
  • Interleukin-7 Receptor alpha Subunit / metabolism
  • STAT5 Transcription Factor / metabolism
  • Signal Transduction / physiology
  • Smad Proteins / genetics
  • Smad Proteins / metabolism
  • Stem Cells / cytology
  • Stem Cells / metabolism*
  • T-Lymphocytes / cytology
  • T-Lymphocytes / metabolism
  • Thymus Gland / cytology
  • Thymus Gland / metabolism*

Substances

  • Antigens, CD34
  • BMP4 protein, human
  • Bone Morphogenetic Protein 4
  • Carrier Proteins
  • Hedgehog Proteins
  • IL7 protein, human
  • Interleukin-7
  • Interleukin-7 Receptor alpha Subunit
  • STAT5 Transcription Factor
  • Smad Proteins
  • noggin protein
  • Bone Morphogenetic Protein Receptors