Institut Pasteur, Department of Developmental & Stem Cell Biology, Paris 75015, France.
CNRS, UMR3738, Paris 75015, France.
Development. 2022 Oct 1;149(19). doi: 10.1242/dev.200278. Epub 2022 Oct 3.
Hematopoietic stem and progenitor cells emerge from the aorta and migrate to the caudal hematopoietic tissue (CHT) of zebrafish larvae, the hematopoietic equivalent of the mammalian fetal liver, for their proliferation and differentiation. We previously reported that somite-derived stromal cells were a key component of the CHT niche. Here, we found that the cell adhesion protein Protocadherin 18a (Pcdh18a) is expressed in the stromal cell progenitors (SCPs) emigrating from somites toward the future CHT. Deletion of most of the Pcdh18a intracellular domain caused a decrease in the number of SCPs, the directionality of their migration, and the cell-contact mediated repulsion that normally occurs between migrating SCPs. These defects were followed by abnormal morphogenesis of the venous plexus that forms the CHT framework, and the inability of the CHT to function as a niche for hematopoietic stem and progenitor cells. Finally, we found that the extracellular domain of Pcdh18a mediates trans heterophilic adhesion of stromal cells to endothelial cells in vivo and thereby the reticular versus perivascular fate of SCPs. Thus, Pcdh18a expression in SCPs is essential for the proper development of the hematopoietic niche.
造血干细胞和祖细胞从主动脉中出现，并迁移到斑马鱼幼虫的尾侧造血组织 (CHT)，这是哺乳动物胎肝的造血等效物，用于增殖和分化。我们之前报道过，体节衍生的基质细胞是 CHT 龛位的关键组成部分。在这里，我们发现细胞黏附蛋白protocadherin 18a (Pcdh18a) 在从体节向未来 CHT 迁移的基质细胞祖细胞 (SCPs) 中表达。大部分 Pcdh18a 细胞内结构域的缺失导致 SCPs 的数量减少，其迁移的方向性，以及正常发生在迁移 SCPs 之间的细胞接触介导的排斥。这些缺陷之后是静脉丛的异常形态发生，静脉丛形成了 CHT 的框架，并且 CHT 无法作为造血干细胞和祖细胞的龛位发挥作用。最后，我们发现 Pcdh18a 的细胞外结构域在体内介导基质细胞与内皮细胞的同种嗜性黏附，从而决定 SCPs 的网状与血管周命运。因此，SCPs 中 Pcdh18a 的表达对于造血龛位的正常发育至关重要。
