Genetic overexpression of COMP-Ang1 impairs BM microenvironment and induces senescence of BM HSCs

Supplemental Angiopoietin 1 (Ang1) exerts its therapeutic potential on microvascular regression-associated diseases, and this potential is linked with the function of hematopoietic stem cells (HSCs). However, the underlying mechanisms of the effect of enhanced angiogenesis on the modulation of HSCs...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2018-05, Vol.499 (3), p.669-674
Main Authors: Kook, Sung-Ho, Sim, Hyun-Jaung, Hwang, Jae-Won, Baek, Young-Hyun, Kim, Chun-Chu, Lee, Jeong-Hoon, Cho, Eui-Sic, Lee, Jeong-Chae
Format: Article
Language:English
Subjects:
Angiogenesis
Bone marrow
COMP-Ang1
Hematopoietic stem cells
Senescence
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Summary:Supplemental Angiopoietin 1 (Ang1) exerts its therapeutic potential on microvascular regression-associated diseases, and this potential is linked with the function of hematopoietic stem cells (HSCs). However, the underlying mechanisms of the effect of enhanced angiogenesis on the modulation of HSCs are not yet defined. Here, we generated transgenic mice expressing Cartilage Oligomeric Matrix Protein (COMP)-Ang1 in keratin 14-expressing cells. The mutant animals expressed excessive angiogenic characteristics in the skin and bone marrow (BM) along with redder skin with more numerous and branched vessels compared with their wild-type (WT) littermates. The mutants displayed reduced long bone formation and osteoclast activity than did WT littermates and had fewer CD150+CD48−Lineage−Sca-1+c-Kit+ (LSK) cells in the BM. The mutants also exhibited greater senescence-associated (SA) β-gal activity, p16INK4a protein expression, and superoxide anion levels in CD150+CD48−LSK cells in the BM. Furthermore, transplantation assay revealed that the mutant-derived LSK cells were inferior to the cells derived from WT littermate in inducing competitive repopulating capacity in the recipients. Collectively, our results demonstrate that persistent and prolonged administration of COMP-Ang1 by inducible transgenic expression mediates excessive angiogenesis in the body and impairs BM microenvironment, eventually leading to senescence of BM HSCs. •Transgenic mice expressing COMP-Ang1 in keratin 14-expressing cells were generated.•The mutant expressed excessive angiogenic characteristics in the skin and BM.•The mutants displayed impaired BM microenvironment with low osteoclast activity.•Collectively, genetic COMP-Ang1 overexpression induces senescence of BM HSCs.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2018.03.210