Downregulated CXCL12 expression in mesenchymal stem cells associated with severe aplastic anemia in children
- 463 Downloads
The mechanisms of idiopathic severe aplastic anemia (SAA) in children are not completely understood. Insufficiency of the bone marrow microenvironment, in which mesenchymal stem cells (MSCs) are an important element, can be a potential factor associated with hematopoietic impairment. In the current study, we studied whether aberrant gene expression could be found in MSCs from children with SAA. Using microarray analysis, two different patterns of global gene expression were detected in the SAA MSCs. Fourteen genes (POLE2, HGF, KIF20A, TK1, IL18R1, KITLG, FGF18, RRM2, TTK, CXCL12, DLG7, TOP2A, NUF2, and TYMS), which are related to DNA synthesis, cytokines, or growth factors, were significantly downregulated. Further, knockdown of gene expression was performed using the small hairpin RNA (shRNA)-containing lentivirus method. We found that knockdown of CXCL12, HGF, IL-18R1, FGF18, or RRM2 expression compelled MSCs from the controls to behave like those from the SAA children, with decreased survival and differentiation potential. Among them, inhibition of CXCL12 gene expression had the most profound effects on the behavior of MSCs. Further experiments regarding re-introduction of the CXCL12 gene could largely recover the survival and differentiation potential in MSCs with inhibition of CXCL12 expression. Our findings suggest that MSCs from children with SAA exhibit aberrant gene expression profiles and downregulation of CXCL12 gene may be associated with alterations in the bone marrow microenvironment.
KeywordsAplastic anemia Bone marrow failure CXCL12 Gene expression Mesenchymal stem cells
The study was supported by grants from the Chung Shan Medical University Hospital (CSH-2013-A-006), the China Medical University Hospital (DMR-102-039), the Tao-Yuan General Hospital (PTH9909), and the National Research Program for Genomic Medicine (NSC 97-3112-B-001-016).
Conflict of interest
The authors declare that they have no conflict of interest.
- 11.Xu Y, Takahashi Y, Wang Y, Hama A, Nishio N, Muramatsu H, Tanaka M, Yoshida N, Villalobos IB, Yagasaki H, Kojima S, Xu Y, Takahashi Y, Wang Y, Hama A, Nishio N, Muramatsu H, Tanaka M, Yoshida N, Villalobos IB, Yagasaki H, Kojima S (2009) Downregulation of GATA-2 and overexpression of adipogenic gene-PPARgamma in mesenchymal stem cells from patients with aplastic anemia. Exp Hematol 37:1393–1399PubMedCrossRefGoogle Scholar
- 29.Lataillade JJ, Clay D, Bourin P, Herodin F, Dupuy C, Jasmin C, Le Bousse-Kerdiles MC (2002) Stromal cell-derived factor 1 regulates primitive hematopoiesis by suppressing apoptosis and by promoting G(0)/G(1) transition in CD34(+) cells: evidence for an autocrine/paracrine mechanism. Blood 99:1117–1129PubMedCrossRefGoogle Scholar
- 30.Broxmeyer HE, Kohli L, Kim CH, Lee Y, Mantel C, Cooper S, Hangoc G, Shaheen M, Li X, Clapp DW (2003) Stromal cell-derived factor-1/CXCL12 directly enhances survival/antiapoptosis of myeloid progenitor cells through CXCR4 and G(alpha)i proteins and enhances engraftment of competitive, repopulating stem cells. J Leukocyte Biol 73:630–638PubMedCrossRefGoogle Scholar
- 37.Petit I, Szyper-Kravitz M, Nagler A, Lahav M, Peled A, Habler L, Ponomaryov T, Taichman RS, Arenzana-Seisdedos F, Fujii N, Sandbank J, Zipori D, Lapidot T (2002) G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4. Nat Immunol 3:687–694PubMedCrossRefGoogle Scholar
- 39.Schajnovitz A, Itkin T, D'Uva G, Kalinkovich A, Golan K, Ludin A, Cohen D, Shulman Z, Avigdor A, Nagler A, Kollet O, Seger R, Lapidot T (2011) CXCL12 secretion by bone marrow stromal cells is dependent on cell contact and mediated by connexin-43 and connexin-45 gap junctions. Nat Immunol 12:391–398PubMedCrossRefGoogle Scholar
- 41.Bobis-Wozowicz S, Miekus K, Wybieralska E, Jarocha D, Zawisz A, Madeja Z, Majka M (2011) Genetically modified adipose tissue-derived mesenchymal stem cells overexpressing CXCR4 display increased motility, invasiveness, and homing to bone marrow of NOD/SCID mice. Exp Hematol 39:686–696PubMedCrossRefGoogle Scholar