Stromal cell–derived factor-1 and hematopoietic cell homing in an adult zebrafish model of hematopoietic cell transplantation

Abstract

In mammals, stromal cell-derived factor-1 (SDF-1) promotes hematopoietic cell mobilization and migration. Although the zebrafish, Danio rerio, is an emerging model for studying hematopoietic cell transplantation (HCT), the role of SDF-1 in the adult zebrafish has yet to be determined. We sought to characterize sdf-1 expression and function in the adult zebrafish in the context of HCT. In situ hybridization of adult zebrafish organs shows sdf-1 expression in kidney tubules, gills, and skin. Radiation up-regulates sdf-1 expression in kidney to nearly 4-fold after 40 Gy. Assays indicate that zebrafish hematopoietic cells migrate toward sdf-1, with a migration ratio approaching 1.5 in vitro. A sdf-1a:DsRed2 transgenic zebrafish allows in vivo detection of sdf-1a expression in the adult zebrafish. Matings with transgenic reporters localized sdf-1a expression to the putative hematopoietic cell niche in proximal and distal renal tubules and collecting ducts. Importantly, transplant of hematopoietic cells into myelosuppressed recipients indicated migration of hematopoietic cells to sdf-1a-expressing sites in the kidney and skin. We conclude that sdf-1 expression and function in the adult zebrafish have important similarities to mammals, and this sdf-1 transgenic vertebrate will be useful in characterizing the hematopoietic cell niche and its interactions with hematopoietic cells. (Blood. 2011;118(3):766-774) IntroductionThe zebrafish, Danio rerio, is emerging as a useful model organism for the study of hematopoietic cell transplantation (HCT). 1,2 Its fecundity makes high experimental sample numbers logistically feasible, it is amenable to high-throughput chemical screens for hematopoietic effects of drugs and small molecules, 3 and its optical transparency offers excellent opportunities for direct visualization of cell migration events and in vivo fluorescence detection of donor-derived hematopoietic reconstitution. The true extent to which the zebrafish will prove useful for experimental HCT studies, however, will ultimately depend on the degree to which the mechanisms that result in HCT success in mammals are conserved in the zebrafish.In mammals, the chemokine stromal cell-derived factor-1 (SDF-1; CXCL12) and its cognate receptor CXCR4 have been strongly implicated in the homing and reconstitution that that occurs during HCT. 4-6 SDF-1 is expressed in many organs throughout the body, including the spleen, thymus, skin, heart, lung, kidney, and bone marrow. 7,8 The widespread anatomic distribution of SDF-1 expression has been shown to play roles in diverse migration and retention events of a wide array of hematopoietic cells, including migration of mast cell precursors in the skin, 9 retention of myeloid cells in extramedullary locations, 10 migration of megakaryocytes in the bone marrow after radiation, 11 migration of hematopoietic stem cells (HSCs) to regions of injury, 12 and HSC migration to bone marrow both during homeostasis as well as during HCT. 13,14 In the bone marrow cavity, cells expressing high levels o...

Hematopoietic Stem Cell Arrival Triggers Dynamic Remodeling of the Perivascular Niche

“…To further understand the interaction of HSPCs with the perivascular niche, we identified a cxcl12a:DsRed2 transgenic line that allowed us to observe mesenchymal stromal cells in the CHT (Glass et al, 2011). These are likely the “fibroblastic reticular cells” that were previously described in the CHT (Murayama et al, 2006) and similar to the “CXCL12-abundant reticular” cells in the perivascular bone marrow niche (Sugiyama et al, 2006).…”

Migration of cardiomyocytes is essential for heart regeneration in zebrafish

“…S3A-CЈ), which is expressed in the epicardial cells (Perner et al, 2007). We did not detect expression of the cxcl12a-DsRed2 reporter (Glass et al, 2011) in MHCpositive CMs (supplementary material Fig. S3D-F) or in fli1-EGFP-positive endothelial cells (supplementary material Fig.…”

“…We first tested whether FC131, a recently developed selective CXCR4 antagonist (Narumi et al, 2010), can block zebrafish Cxcr4 function. AMD3100, a widely used CXCR4 antagonist, was not used because our previous studies indicated that it did not efficiently block Cxcr4 function, either in the adult zebrafish hematopoietic system in vivo (Glass et al, 2011) or in the migration of primordial germ cells in zebrafish embryos (data not shown). Treating zebrafish embryos with FC131 significantly impaired directed migration of primordial germ cells into the gonad-forming region (supplementary material Fig.…”

Cancer Cell Dissemination and Homing to the Bone Marrow in a Zebrafish Model

“…There is recent evidence that many cytokines and chemokines are similar between zebrafish and that of mammals such as CXCL12, and that the hematopoietic role of the CXCR4-CXCL12 axis in zebrafish mirrors the functional role of CXCR4-CXCL12 in mammals (17). We therefore sought to develop a zebrafish model for assessment of tumor cell homing and metastasis to the BM by injecting either MM cell lines or patient-derived MM cells into zebrafish embryos and demonstrating their homing to the caudal hematopoietic tissue (CHT) where the HSCs migrate after their emergence from the ventral wall of the dorsal aorta: (18) This posterior/caudal area is considered an early site of definitive hematopoiesis analogous to the mammalian fetal liver (19).…”