A dual involvement of Protocadherin 18a in stromal cell development guides the formation of a functional hematopoietic niche

Abstract

Hematopoietic stem and progenitor cells (HSPCs) 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 HSPCs. 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 vs. perivascular fate of SCPs. Thus, Pcdh18a expression in SCPs is essential for the proper development of the hematopoietic niche.

Single-cell analysis reveals distinct fibroblast plasticity during tenocyte regeneration in zebrafish

“…1E, S4A, S4C). Previous studies have shown that stromal reticular cells arise from the sclerotome and become closely associated with the vasculature in the caudal vein plexus (CVP), where they play a critical role in the hematopoietic stem cell (HSC) development ( 20 , 21 , 30 , 34 ). Consistent with this, we identified a ‘stromal reticular cell’ (SRC) cluster within our dataset, with high-level marker expression ( clec19a , sfrp1a , ccl25b ) in CVP-associated fibroblasts (Figs.…”

“…A few studies have characterized individual fibroblast populaKons in the trunks of zebrafish embryos. For instance, fibroblasts along the horizontal myosepta 19 and stromal reKcular cells in the caudal venous plexus 20,21 have been shown to regulate lymphangiogenesis and hematopoiesis during zebrafish development, respecKvely. Similarly, tenocytes .…”

“…A few studies have characterized individual fibroblast populaLons in the trunks of zebrafish embryos. For instance, fibroblasts along the horizontal myosepta (19) and stromal reLcular cells in the caudal vein plexus (20,21) have been shown to regulate lymphangiogenesis and hematopoiesis during zebrafish development, respecLvely. Similarly, tenocytes along the myotendinous juncLon (MTJ) (22)(23)(24)(25), fin mesenchymal cells in the fin folds (26), and perivascular fibroblasts along intersegmental vessels (ISVs) (27) are known to provide structural support to their respecLve Lssues of residence by deposiLng ECM.…”

Single-cell analysis reveals distinct fibroblast plasticity during tenocyte regeneration in zebrafish

“…S4, A and C). Previous studies have shown that SRCs arise from the sclerotome and become closely associated with the vasculature in the caudal vein plexus (CVP), where they play a critical role in the hematopoietic stem cell development ( 20 , 21 , 30 , 34 ). Consistent with this, we identified an SRC cluster within our dataset, with high-level marker expression ( clec19a , sfrp1a , and ccl25b ) in CVP-associated fibroblasts (Fig.…”

“…A few studies have characterized individual fibroblast populations in the trunks of zebrafish embryos. For instance, fibroblasts along the horizontal myosepta (19) and stromal reticular cells (SRCs) in the caudal vein plexus (20,21) have been shown to regulate lymphangiogenesis and hematopoiesis during zebrafish development, respectively. Similarly, tenocytes along the myotendinous junction (MTJ) (22)(23)(24)(25), fin mesenchymal cells in the fin folds (26), and perivascular fibroblasts along intersegmental vessels (ISVs) (27) are known to provide structural support to their respective tissues of residence by depositing ECM.…”