Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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Overexpression of COMP-Angiopoietin-1 in K14-Expressing Cells Impairs Hematopoiesis and Disturbs Erythrocyte Maturation

  • Sim, Hyun-Jaung (Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences and School of Dentistry, Jeonbuk National University) ;
  • Kim, Min-Hye (Department of Bioactive Material Sciences, Research Center of Bioactive Materials, Jeonbuk National University) ;
  • Bhattarai, Govinda (Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences and School of Dentistry, Jeonbuk National University) ;
  • Hwang, Jae-Won (Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences and School of Dentistry, Jeonbuk National University) ;
  • So, Han-Sol (Department of Bioactive Material Sciences, Research Center of Bioactive Materials, Jeonbuk National University) ;
  • Poudel, Sher Bahadur (Department of Basic Science & Craniofacial Biology, College of Dentistry, New York University) ;
  • Cho, Eui-Sic (Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences and School of Dentistry, Jeonbuk National University) ;
  • Kook, Sung-Ho (Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences and School of Dentistry, Jeonbuk National University) ;
  • Lee, Jeong-Chae (Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences and School of Dentistry, Jeonbuk National University)
  • Received : 2020.07.19
  • Accepted : 2021.04.05
  • Published : 2021.04.30
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Abstract

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 K14-Cre;inducible-COMP-Ang1-transgenic 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 rhCOMP-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.

Keywords

Acknowledgement

This research was supported by Basic Science Research Program through the National Research Foundation (NRF) funded by the Ministry of Science, Information and Communications Technology and Future Planning (2018R1A2A3074639, 2019R1A2C2084453, 2020R1C1C1004968, and 2021R1A2C2006032) and by Ministry of Education (2018R1D1A1B07047162), South Korea. We also thank Dr. G.Y. Koh for providing IND-COMP-Ang1-Tg mice and B.-C. Lee for advising in manuscript preparation.

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