MicroRNA-10A* and MicroRNA-21 modulate endothelial progenitor cell senescence via suppressing high-mobility group A2.
BACKGROUND
Endothelial progenitor cells (EPCs) contribute to the regeneration of endothelium. Aging-associated senescence results in reduced number and function of EPCs, potentially contributing to increased cardiac risk, reduced angiogenic capacity, and impaired cardiac repair effectiveness. The mechanisms underlying EPC senescence are unknown. Increasing evidence supports the role of microRNAs in regulating cellular senescence.


OBJECTIVE
We aimed to determine whether microRNAs regulated EPC senescence and, if so, what the underlying mechanisms are.


RESULTS
To map the microRNA/gene expression signatures of EPC senescence, we performed microRNA profiling and microarray analysis in lineage-negative bone marrow cells from young and aged wild-type and apolipoprotein E-deficient mice. We identified 2 microRNAs, microRNA-10A* (miR-10A*), and miR-21, and their common target gene Hmga2 as critical regulators for EPC senescence. Overexpression of miR-10A* and miR-21 in young EPCs suppressed Hmga2 expression, caused EPC senescence, as evidenced by senescence-associated β-galactosidase upregulation, decreased self-renewal potential, increased p16(Ink4a)/p19(Arf) expression, and resulted in impaired EPC angiogenesis in vitro and in vivo, resembling EPCs derived from aged mice. In contrast, suppression of miR-10A* and miR-21 in aged EPCs increased Hmga2 expression, rejuvenated EPCs, resulting in decreased senescence-associated β-galactosidase expression, increased self-renewal potential, decreased p16(Ink4a)/p19(Arf) expression, and improved EPC angiogenesis in vitro and in vivo. Importantly, these phenotypic changes were rescued by miRNA-resistant Hmga2 cDNA overexpression.


CONCLUSIONS
miR-10A* and miR-21 regulate EPC senescence via suppressing Hmga2 expression and modulation of microRNAs may represent a potential therapeutic intervention in improving EPC-mediated angiogenesis and vascular repair.
Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136, USA. szhu@med.miami.edu
Shoukang
S
Zhu
Shanming
S
Deng
Qi
Q
Ma
Taifang
T
Zhang
Chunling
C
Jia
Degen
D
Zhuo
Falin
F
Yang
Jianqin
J
Wei
Liyong
L
Wang
Derek M
DM
Dykxhoorn
Joshua M
JM
Hare
Pascal J
PJ
Goldschmidt-Clermont
Chunming
C
Dong
D000375:Aging / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D042783:Endothelial Cells / Q000378:metabolism*; D020869:Gene Expression Profiling / Q000379:methods; D005838:Genotype; D025765:HMGB3 Protein / Q000235:genetics / Q000378:metabolism*; D006614:Hindlimb; D007511:Ischemia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000098:blood supply; D018919:Neovascularization, Physiologic; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D013234:Stem Cells / Q000378:metabolism*; D014162:Transfection; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
D001057:Apolipoproteins E; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D025765:HMGB3 Protein; C569259:MIRN10 microRNA, mouse; C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; D001616:beta-Galactosidase