Institute of Physiological Chemistry and Pathobiochemistry, University of Muenster, Germany; Cells-in-Motion Cluster of Excellence, University of Muenster, Germany.
Institute of Physiological Chemistry and Pathobiochemistry, University of Muenster, Germany; Cells-in-Motion Cluster of Excellence, University of Muenster, Germany; Experimental Immunology Branch, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA.
Matrix Biol. 2018 Apr;67:47-62. doi: 10.1016/j.matbio.2018.01.007. Epub 2018 Jan 31.
Hematopoietic stem and progenitor cell (HSPC) functions are regulated by a specialized microenvironment in the bone marrow - the hematopoietic stem cell niche - of which the extracellular matrix (ECM) is an integral component. We describe here the localization of ECM molecules, in particular the laminin α4, α3 and α5 containing isoforms in the bone marrow. Laminin 421 (composed of laminin α4, β2, γ1 chains) is identified as a major component of the bone marrow ECM, occurring abundantly surrounding venous sinuses and in a specialized reticular fiber network of the intersinusoidal spaces of murine bone marrow (BM) in close association with HSPC. Bone marrow from Lama4 mice is significantly less efficient in reconstituting the hematopoietic system of irradiated wildtype (WT) recipients in competitive bone marrow transplantation assays and shows reduced colony formation in vitro. This is partially due to retention of Linc-kitSca-1CD48 long-term and short-term hematopoietic stem cells (LT-HSC/ST-HSC) in the G0 phase of the cell cycle in Lama4 bone marrow and hence a more quiescent phenotype. In addition, the extravasation of WT BM cells into Lama4 bone marrow is impaired, influencing the recirculation of HSPC. Our data suggest that these effects are mediated by a compensatory expression of laminin α5 containing isoforms (laminin 521/522) in Lama4 bone marrow. Collectively, these intrinsic and extrinsic effects lead to reduced HSPC numbers in Lama4 bone marrow and reduced hematopoietic potential.
造血干细胞和祖细胞 (HSPC) 的功能受到骨髓中造血干细胞龛的特殊微环境的调节，其中细胞外基质 (ECM) 是一个组成部分。我们在这里描述 ECM 分子的定位，特别是在骨髓中的层粘连蛋白 α4、α3 和 α5 包含的同种型。层粘连蛋白 421（由层粘连蛋白 α4、β2、γ1 链组成）被鉴定为骨髓 ECM 的主要成分，大量存在于静脉窦周围，并存在于鼠骨髓 (BM) 窦间空间的特殊网状纤维网络中，与 HSPC 密切相关。在竞争骨髓移植实验中，Lama4 小鼠的骨髓在重建照射野生型 (WT) 受体造血系统方面的效率明显较低，并且在体外集落形成能力降低。这部分是由于 Lama4 骨髓中 Linc-kitSca-1CD48 长期和短期造血干细胞 (LT-HSC/ST-HSC) 在细胞周期的 G0 期滞留，从而表现出更静止的表型。此外，WT BM 细胞进入 Lama4 骨髓的外渗受损，影响 HSPC 的再循环。我们的数据表明，这些效应是由 Lama4 骨髓中层粘连蛋白 α5 包含同种型（层粘连蛋白 521/522）的代偿性表达介导的。总的来说，这些内在和外在的影响导致 Lama4 骨髓中 HSPC 数量减少和造血潜力降低。
