Insulin-like growth factor 2 modulates murine hematopoietic stem cell maintenance through upregulation of p57.
Insulin-like growth factor 2 modulates murine hematopoietic stem cell maintenance through upregulation of p57.
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DOI：
10.1016/j.exphem.2016.01.010
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发表时间：
2016-05
影响因子：
2.6
通讯作者：
Mostoslavsky G
中科院分区：
文献类型：
--
作者：
Thomas DD;Sommer AG;Balazs AB;Beerman I;Murphy GJ;Rossi D;Mostoslavsky G
Hematopoietic stem cells (HSC) rely on a highly regulated molecular network to balance self-renewal and lineage specification to sustain life-long hematopoiesis. Despite a plethora of studies aimed at identifying molecules governing HSC fate, our current knowledge of the genes responsible is limited. We have found Insulin-like growth factor 2 (IGF2) to be predominantly expressed within long-term HSC. This study examines IGF2 expression patterns and the effects of the gene in HSC. Through the overexpression and knockdown of IGF2 within purified HSC, we demonstrate that IGF2 expression increases HSC-derived multilineage colonies in vitro and enhances hematopoietic contribution in vivo upon competitive bone marrow transplantation. The effects of IGF2 are mediated by direct upregulation of the CDKi p57, exclusively within long-term HSC, via activation of the PI3K-Akt pathway. Increased expression of p57 resulted in a concomitant increase of HSC in the G0/G1 stage of the cell cycle. Analysis of genomic DNA methylation revealed that HSC exhibited a hypomethylated state within the promoter region of the CDKN1C (p57) gene, providing a potential mechanism for the exclusive effects of IGF2 within HSC. Our studies demonstrate a novel role for IGF2 in regulating HSC cell cycle and illustrate potential novel therapeutic targets for hematological diseases.
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