Inhibition of erythropoiesis by Smad6 in human cord blood hematopoietic stem cells

Laboratory of Immunology, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea.
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 06/2012; 423(4):750-6. DOI: 10.1016/j.bbrc.2012.06.031
Source: PubMed


Bone morphogenetic proteins (BMPs) that belong to the transforming growth factor-β (TGF-β) superfamily cytokines, play crucial roles in hematopoiesis. However, roles of Smad6 in hematopoiesis remained unknown in contrast to the other inhibitory Smad (I-Smad), Smad7. Here we show that Smad6 inhibits erythropoiesis in human CD34(+) cord blood hematopoietic stem cells (HSCs). Smad6 was specifically expressed in CD34(+) cord blood HSCs, which was correlated with the expression of BMP2/4/6/7 and BMP type I receptor (BMPRI). BMP-specific receptor-regulated Smads (R-Smads), Smad1 and Smad5 in cooperation with Smad4 induced transcription of the Smad6 gene. Instead of affecting cell cycle, apoptosis, self-renewal, and stemness of CD34(+) cells, Smad6 knockdown enhanced, whereas Smad6 overexpression suppressed erythropoiesis in stem cell culture and colony formation assay. Consistently, Smad6 suppressed the expression of the genes essential for erythropoiesis, such as Kruppel-like factor 1 (erythroid) (KLF1/EKLF) and GATA binding protein 2 (GATA-2). Promoter analyses showed that Smad6 repressed Smad5/4-induced transcription of the Klf1 gene. Thus, our data suggest that Smad6 indirectly maintains stemness by preventing spontaneous erythropoiesis in HSCs.

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    • "In this context, and given the importance of EKLF in controlling a number of steps in the red cell heme biosynthetic pathway (Tallack et al., 2010) ( particularly the transferrin receptor and mitoferrin), it is tempting to speculate that EKLF may also play an analogous regulatory role for iron transfer in the macrophage. EKLF expression is regulated by the BMP4 pathway during early mammalian development, particularly via Smad5 (Adelman et al., 2002; Kang et al., 2012; Lohmann and Bieker, 2008). This same pathway plays a significant role in stress erythropoiesis (Porayette and Paulson, 2008). "
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