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Thrombopoietin induces hematopoiesis from mouse ES cells via HIF‐1α–dependent activation of a BMP4 autoregulatory loop
Author(s) -
Pramono Andri,
Zahabi Azadeh,
Morishima Tatsuya,
Lan Dan,
Welte Karl,
Skokowa Julia
Publication year - 2016
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/nyas.13138
Subject(s) - thrombopoietin , bone morphogenetic protein 4 , haematopoiesis , microbiology and biotechnology , biology , noggin , bmpr2 , bone morphogenetic protein , morphogen , stem cell factor , autocrine signalling , embryonic stem cell , bone morphogenetic protein receptor , stem cell , cancer research , immunology , receptor , genetics , gene
Understanding the molecular mechanisms underlying hematopoietic differentiation of embryonic stem (ES) cells may help to ascertain the conditions for the in vitro generation of hematopoietic cells. Previously, we found that patients with congenital amegakaryocytic thrombocytopenia (CAMT), who develop pancytopenia early after birth, harbor mutations within the thrombopoietin (TPO) receptor, c‐MPL. This knowledge, together with observations in vitro and in vivo , suggests that TPO/c‐MPL signaling promotes early hematopoiesis. However, the mechanisms underlying TPO signaling are not fully elucidated. Here, we describe a direct connection between TPO and bone morphogenetic protein 4 (BMP4) signaling pathways in determining the hematopoietic fate of ES cells. Morphogen BMP4 is known to induce early hematopoietic differentiation of ES cells. Treatment of ES cells with TPO induced the autocrine production of BMP4 with concomitant upregulation of the BMP receptor BMPR1A, phosphorylation of SMAD1, 5, 8, and activation of specific BMP4 target genes; this was mediated by TPO‐dependent binding of transcription factor HIF‐1α to the BMP4 gene promoter. Treatment of ES cells with the BMP antagonist noggin substantially reduced TPO‐dependent hematopoietic differentiation of ES cells. Thus, our findings contribute to the establishment of techniques for generating hematopoietic cells from ES cells.