title: Downregulated CXCL12 expression in mesenchymal stem cells associated with severe aplastic anemia in children.
abstract: 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.
authors.affiliation: Institute of Medicine, Chung Shan Medical University, No. 110, Sec. 1, Chien-Kuo N. Road, Taichung, 402, Taiwan.
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Chao
authors.forename: Kang-Hsi
authors.initials: KH
authors.lastname: Wu
authors.forename: Shiow-Her
authors.initials: SH
authors.lastname: Chiou
authors.forename: Shu-Fen
authors.initials: SF
authors.lastname: Chiang
authors.forename: Chih-Yang
authors.initials: CY
authors.lastname: Huang
authors.forename: Hsiu-Ching
authors.initials: HC
authors.lastname: Yang
authors.forename: Chin-Kan
authors.initials: CK
authors.lastname: Chan
authors.forename: Ching-Tien
authors.initials: CT
authors.lastname: Peng
authors.forename: Han-Ping
authors.initials: HP
authors.lastname: Wu
authors.forename: Kuan-Chih
authors.initials: KC
authors.lastname: Chow
authors.forename: Maw-Sheng
authors.initials: MS
authors.lastname: Lee
mesh_terms: D000293:Adolescent; D000741:Anemia, Aplastic / Q000175:diagnosis / Q000378:metabolism*; D054377:Chemokine CXCL12 / Q000096:biosynthesis*; D002648:Child; D002675:Child, Preschool; D015536:Down-Regulation / Q000502:physiology*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D012720:Severity of Illness Index
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12