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 Blood, 1 December 2003, Vol. 102, No. 12, pp. 3947-3953.
Prepublished online as a Blood First Edition Paper on August 14, 2003; DOI 10.1182/blood-2003-05-1657.

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HEMATOPOIESIS

BMP4 acts upstream of FGF in modulating thymic stroma and regulating thymopoiesis

Peter T. Tsai, Robert A. Lee, and Hong Wu

From the Molecular Biology Institute, the Department of Molecular and Medical Pharmacology, and the Howard Hughes Medical Institute, University of California, Los Angeles School of Medicine.

Thymocyte development is a non–cell-autonomous process that requires signals provided by the thymic stroma. Bone morphogenetic proteins (BMPs) and fibroblast growth factors (FGFs) derived from thymic stroma have been implicated as possible regulators of T-cell development. Using thymic organ culture, this study demonstrates that both BMP4 and FGF7/FGF10 arrest early T-cell development at the CD4-CD8-CD44+CD25- (double-negative 1 [DN1]) population and at the CD4-CD8- double-negative (DN) to CD4+CD8+ double-positive (DP) transition in a stromal compartment–dependent manner. Furthermore, BMP4 functions upstream of FGF7/FGF10, as the effects of BMP can be suppressed by cotreatment with an FGF receptor antagonist. BMP4 also acts directly on the thymic stroma to up-regulate the stroma-specific transcription factor Foxn1 and stroma-expressed chemokines. Taken together, the data in this report demonstrate that BMP acts upstream of FGF in the regulation of early T-cell development and that BMP4 acts primarily through the thymic stroma, thereby altering the thymic microenvironment and affecting thymopoiesis.


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