Méndez-Olivos Emilio E, Kocha Katrinka M, Bloomekatz Joshua, Liao Shan, Huang Peng
Department of Biochemistry and Molecular Biology, Cumming School of Medicine, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada.
Department of Biology, University of Mississippi, University, Mississippi, United States of America.
PLoS Biol. 2025 Sep 2;23(9):e3003365. doi: 10.1371/journal.pbio.3003365. eCollection 2025 Sep.
In vertebrates, the sclerotome is a transient embryonic structure that gives rise to various tissue support cells, including fibroblasts. However, how fibroblast precursors are guided to diverse tissues remain poorly understood. Using zebrafish, our lab has previously shown that sclerotome-derived cells undergo extensive migration to generate distinct fibroblast subtypes, including tenocytes along the myotendinous junction and fin mesenchymal cells in the fin fold. The pan-fibroblast gene platelet-derived growth factor receptor a (pdgfra), which has been implicated in cell migration across various contexts, is specifically expressed in the sclerotome and its descendants. Loss of functional Pdgfra in a pdgfra gene-trap mutant results in severe defects in the migration of sclerotome-derived cells, leading to a dose-dependent loss of tenocytes and fin mesenchymal cells. By combining live imaging and mosaic labeling with a membrane-bound dominant-negative tool, we demonstrate that Pdgfra acts cell-autonomously to regulate the migration of sclerotome-derived cells. In the absence of ligand pdgfab, which is expressed in the medial somite, sclerotome-derived cells fail to migrate medially, resulting in a loss of tenocytes, although they can migrate normally toward the fin fold and generate fin mesenchymal cells. Strikingly, localized expression of Pdgfab in pdgfab mutants can direct the migration of sclerotome-derived cells to both normal and ectopic locations, suggesting a chemoattractive role for the Pdgfab ligand. Together, our results demonstrate that Pdgfab/Pdgfra-mediated chemoattraction guides the migration of sclerotome-derived fibroblast precursors to specific locations, where they diversify into distinct fibroblast subtypes.
在脊椎动物中，生骨节是一种短暂的胚胎结构，可产生包括成纤维细胞在内的各种组织支持细胞。然而，成纤维细胞前体如何被引导至不同组织仍知之甚少。利用斑马鱼，我们实验室之前已经表明，生骨节来源的细胞会进行广泛迁移，以产生不同的成纤维细胞亚型，包括沿肌腱连接的腱细胞和鳍褶中的鳍间充质细胞。泛成纤维细胞基因血小板衍生生长因子受体a（pdgfra）在各种情况下都与细胞迁移有关，它在生骨节及其后代中特异性表达。pdgfra基因陷阱突变体中功能性Pdgfra的缺失导致生骨节来源细胞迁移出现严重缺陷，导致腱细胞和鳍间充质细胞呈剂量依赖性减少。通过将实时成像和镶嵌标记与膜结合显性负性工具相结合，我们证明Pdgfra以细胞自主方式调节生骨节来源细胞的迁移。在内侧体节中表达的配体pdgfab缺失的情况下，生骨节来源的细胞无法向内侧迁移，导致腱细胞缺失，尽管它们可以正常向鳍褶迁移并产生鳍间充质细胞。引人注目的是，pdgfab突变体中Pdgfab的局部表达可以将生骨节来源的细胞引导至正常和异位位置，这表明Pdgfab配体具有趋化作用。总之，我们的结果表明，Pdgfab/Pdgfra介导的化学吸引引导生骨节来源的成纤维细胞前体迁移到特定位置，在那里它们分化为不同的成纤维细胞亚型。
