GATA2 regulates differentiation of bone marrow-derived mesenchymal stem cells

• Published in: Haematologica (Roma) 2014-11, Vol.99 (11), p.1686-1696
• Main Authors: Kamata, Mayumi, Okitsu, Yoko, Fujiwara, Tohru, Kanehira, Masahiko, Nakajima, Shinji, Takahashi, Taro, Inoue, Ai, Fukuhara, Noriko, Onishi, Yasushi, Ishizawa, Kenichi, Shimizu, Ritsuko, Yamamoto, Masayuki, Harigae, Hideo
• Format: Article
• Language: English
• Subjects: Adipocytes - cytology; Adipocytes - metabolism; Animals; Bone Marrow; Cell Cycle Proteins - genetics; Cell Differentiation - genetics; Cellular Microenvironment - genetics; GATA2 Transcription Factor - genetics; GATA2 Transcription Factor - metabolism; Gene Expression; Gene Expression Profiling; Gene Expression Regulation, Developmental; Humans; Mesenchymal Stromal Cells - cytology; Mesenchymal Stromal Cells - metabolism; Mice; Mice, Knockout; RNA Interference; RNA, Small Interfering - genetics
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2014.105692

The bone marrow microenvironment comprises multiple cell niches derived from bone marrow mesenchymal stem cells. However, the molecular mechanism of bone marrow mesenchymal stem cell differentiation is poorly understood. The transcription factor GATA2 is indispensable for hematopoietic stem cell function as well as other hematopoietic lineages, suggesting that it may maintain bone marrow mesenchymal stem cells in an immature state and also contribute to their differentiation. To explore this possibility, we established bone marrow mesenchymal stem cells from GATA2 conditional knockout mice. Differentiation of GATA2-deficient bone marrow mesenchymal stem cells into adipocytes induced accelerated oil-drop formation. Further, GATA2 loss- and gain-of-function analyses based on human bone marrow mesenchymal stem cells confirmed that decreased and increased GATA2 expression accelerated and suppressed bone marrow mesenchymal stem cell differentiation to adipocytes, respectively. Microarray analysis of GATA2 knockdowned human bone marrow mesenchymal stem cells revealed that 90 and 189 genes were upregulated or downregulated by a factor of 2, respectively. Moreover, gene ontology analysis revealed significant enrichment of genes involved in cell cycle regulation, and the number of G1/G0 cells increased after GATA2 knockdown. Concomitantly, cell proliferation was decreased by GATA2 knockdown. When GATA2 knockdowned bone marrow mesenchymal stem cells as well as adipocytes were cocultured with CD34-positive cells, hematopoietic stem cell frequency and colony formation decreased. We confirmed the existence of pathological signals that decrease and increase hematopoietic cell and adipocyte numbers, respectively, characteristic of aplastic anemia, and that suppress GATA2 expression in hematopoietic stem cells and bone marrow mesenchymal stem cells.