Zebrafish models of inflammation in hematopoietic development and disease

Abstract

Zebrafish offer an excellent tool for studying the vertebrate hematopoietic system thanks to a highly conserved and rapidly developing hematopoietic program, genetic amenability, optical transparency, and experimental accessibility. Zebrafish studies have contributed to our understanding of hematopoiesis, a complex process regulated by signaling cues, inflammation being crucial among them. Hematopoietic stem cells (HSCs) are multipotent cells producing all the functional blood cells, including immune cells. HSCs respond to inflammation during infection and malignancy by proliferating and producing the blood cells in demand for a specific scenario. We first focus on how inflammation plays a crucial part in steady-state HSC development and describe the critical role of the inflammasome complex in regulating HSC expansion and balanced lineage production. Next, we review zebrafish studies of inflammatory innate immune mechanisms focusing on interferon signaling and the downstream JAK-STAT pathway. We also highlight insights gained from zebrafish models harbouring genetic perturbations in the role of inflammation in hematopoietic disorders such as bone marrow failure, myelodysplastic syndrome, and myeloid leukemia. Indeed, inflammation has been recently identified as a potential driver of clonal hematopoiesis and leukemogenesis, where cells acquire somatic mutations that provide a proliferative advantage in the presence of inflammation. Important insights in this area come from mutant zebrafish studies showing that hematopoietic differentiation can be compromised by epigenetic dysregulation and the aberrant induction of signaling pathways.

Stem Cell-Associated Signatures Help to Predict Diagnosis and Prognosis in Ovarian Serous Cystadenocarcinoma

“…MF is enriched during oxidoreductase activity and ferroxidase activity as well as when metal ions are oxidized and electrons are accepted by oxygen. Some studies have demonstrated the driving role of JAK-STAT signaling in the ability of cancer stem cells [ 19 , 20 ]. At the same time, some studies have indicated that the immune microenvironment, such as T cell activation, can be regulated via JAK/STAT molecular pathway, thereby regulating stem cell growth [ 21 , 22 ].…”

Inflammation in Development and Aging: Insights from the Zebrafish Model

“…The ontogeny of the hematopoietic system relies on a specific sequence of events and spatial and temporal cellular interactions throughout development, which control stem cell properties and balance self-renewal, quiescence, and lineage commitment [99,100]. As such, hematopoiesis is a complex and accurate developmental process that provides a good platform to identify the genetic requirements of specific critical stages and characterize the molecular mechanisms and cellular mediators of developmental inflammation [101][102][103].…”

“…Zebrafish are at the forefront of vertebrate model systems for studying vertebrate developmental hematopoiesis. The high homology of cellular components, core regulators of hematopoiesis, and conserved expression and function of genes for both myeloid/lymphoid fate determination and terminal differentiation between humans and zebrafish make them a powerful model for studying the developmental process of hematopoiesis [101,[106][107][108][109][110]. Moreover, defects in zebrafish hematopoiesis reliably phenocopy human blood disorders, including leukemia, making them an attractive model for defining critical regulators of these blood disorders [111,112].…”

“…These primitive myeloid cells can induce a hemogenic cell fate (runx1+; gata2+) in the vascular endothelium (kdrl+; fli1+) and are in close proximity to emerging HSPCs in the HE of zebrafish, mice, and humans [120][121][122]. Other sources of inflammatory signals in sterile setups have recently been summarized [101]. Among these, metabolic alterations due to glucose exposure are responsible for the activation of the NLRP3 inflammasome complex, which in turn elicits sterile inflammation and HSPC emergence [102].…”

“…Repetitive element transcripts and R-loops also participate in the induction of developmental inflammation [101]. Transposable elements expressed in the zebrafish hemogenic endothelium can induce NF-κB and IFN-mediated inflammatory pathways by activating retinoic acid-inducible gene 1-like receptors (RLRs).…”