Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences and School of Dentistry, Jeonbuk National University, Jeonju 54896, Korea.
Department of Bioactive Material Sciences, Research Center of Bioactive Materials, Jeonbuk National University, Jeonju 54896, Korea.
Mol Cells. 2021 Apr 30;44(4):254-266. 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.
大量研究强调了补充软骨寡聚基质蛋白-血管生成素-1（COMP-Ang1）的潜在益处，其通过改善血管生成作用。然而，我们最近的研究结果表明，COMP-Ang1 的过度过表达会导致骨髓（BM）微环境受损和造血干细胞（HSCs）衰老。在这里，我们使用 小鼠研究了 COMP-Ang1 如何通过过度表达影响 BM 中保留的干细胞功能和造血作用的潜在机制。过多的 COMP-Ang1 诱导 BM HSCs 和间充质干细胞（MSCs）的外周排斥和衰老。过多的 COMP-Ang1 还导致异常造血，同时 HSCs 向髓系而不是淋巴系分化偏斜。特别是，过多的 COMP-Ang1 干扰晚期红系母细胞成熟，随后基质细胞衍生因子 1（SDF-1）和珠蛋白转录因子 1（GATA-1）的表达下调，而过氧化物阴离子和 p-p38 激酶水平升高。然而，用突变衍生的 BM 细胞移植或用 COMP-Ang1 蛋白处理并没有改变受者小鼠或培养的 BM 细胞中红系母细胞的频率或 GATA-1 表达。总之，我们的研究结果表明，过多的 COMP-Ang1 会损害 BM HSCs 和 MSCs 的功能和造血过程，最终通过失衡的 SDF-1/CXCR4 轴和 GATA-1 表达而不是 Ang1/Tie2 信号轴改变导致异常红细胞生成。
