Overexpression of COMP-Angiopoietin-1 in K14 -Expressing Cells Impairs Hematopoiesis and Disturbs Erythrocyte Maturation

• Published in: Molecules and cells 2021, 44(4), , pp.254-266
• Main Authors: Sim, Hyun-Jaung, Kim, Min-Hye, Bhattarai, Govinda, Hwang, Jae-Won, So, Han-Sol, Poudel, Sher Bahadur, Cho, Eui-Sic, Kook, Sung-Ho, Lee, Jeong-Chae
• Format: Article
• Language: English
• Subjects: Angiopoietin-1 - metabolism; Animals; Cell Differentiation; Erythrocytes - metabolism; Hematopoiesis - genetics; Humans; Mice; Mice, Transgenic; 생물학
• ISSN: 1016-8478; 0219-1032
• DOI: 10.14348/molcells.2021.2155

Numerous studies highlight the potential benefits potentials of supplemental cartilage oligomeric matrix protein-angiopoietin-1 (COMP-Ang1) through improved angiogenic effects. However, our recent findings show that excessive overexpression of COMP-Ang1 induces an impaired bone marrow (BM) microenvironment and senescence of hematopoietic stem cells (HSCs). Here, we investigated the underlying mechanisms of how excessive COMP-Ang1 affects the function of BM-conserved stem cells and hematopoiesis using mice. Excessive COMP-Ang1 induced peripheral egression and senescence of BM HSCs and mesenchymal stem cells (MSCs). Excessive COMP-Ang1 also caused abnormal hematopoiesis along with skewed differentiation of HSCs toward myeloid lineage rather than lymphoid lineage. Especially, excessive COMP-Ang1 disturbed late-stage erythroblast maturation, followed by decreased expression of stromal cell-derived factor 1 (SDF-1) and globin transcription factor 1 (GATA-1) and increased levels of superoxide anion and p-p38 kinase. However, transplantation with the mutant-derived BM cells or treatment with COMP-Ang1 protein did not alter the frequency or GATA-1 expression of erythroblasts in recipient mice or in cultured BM cells. Together, our findings suggest that excessive COMP-Ang1 impairs the functions of BM HSCs and MSCs and hematopoietic processes, eventually leading to abnormal erythropoiesis via imbalanced SDF-1/CXCR4 axis and GATA-1 expression rather than Ang1/Tie2 signaling axis alterations.