Mishra, R. | Search bioRxiv

bioRxiv2018

Drosophila Hox genes induce melanised pseudo-tumours when misexpressed in hemocytes

Homeotic genes are the key early determinants of cell identity along the anterior-posterior body axis across bilaterians. More recently, however, several late non-homeotic functions of hox genes have emerged in a variety of organogenesis processes, including in mammals. Being crucial factors in determining cell identity and organogenesis, the misregulation of hox genes is likely to be associated with defects in these processes. Several studies have reported misexpression of hox genes in a variety of malignancies including acute myeloid leukaemia. Considering that Drosophila is a well-established model for the study of haematopoiesis, we ectopically expressed the hox genes, Dfd, Ubx, abd-A and Abd-B, to ask if and how it will alter the process of haematopoiesis. We observed black melanised spots circulating in the viscera of the larvae and extensive lethality at during the pupal stage in these conditions. Such abnormalities are the hallmark of dysregulated haematopoiesis. We also observed an increase in blood cell number as well as their enhanced differentiation into lamellocytes. Our study opens a new possibility of addressing the function hox genes in normal and leukemogenic hematopoiesis with potential implications in downstream targets for diagnostic markers and therapy.\n\nSummaryDrosophila Hox genes, when expressed in blood cells, are leukemogenic, induce cell autonomous proliferation and differentiation. This reinforces previous studies in vertebrates and allows for Hox induced leukaemia to be studied in Drosophila.

cancer biology↗

bioRxiv2017

PDGFRα signaling in cardiac stem and stromal cells modulates quiescence, metabolism and self-renewal, and promotes anatomical and functional repair

The interstitial and perivascular spaces of the mammalian heart contain a highly interactive tissue community essential for cardiac homeostasis, repair and regeneration. Mesenchymal cells (fibroblasts) are one of the most abundant cell types, playing key roles as sentinels, tissue architects, paracrine signaling hubs and lineage precursors, and are linked to heart disease through their roles in inflammation and fibrosis. Platelet-derived growth factors (PDGFs) are secreted by several cell types involved in cardiac injury and repair, and are recognized mitogens for cardiac fibroblasts and mesenchymal stem cells. However, their roles are complex and investigations of their impact on heart repair have produced contrasting outcomes, leaving therapeutic potential uncertain. Here, we use new approaches and tools, including single cell RNA sequencing, to explore cardiac fibroblast heterogeneity and how PDGF receptor (PDGFR) signaling impacts fibroblasts during heart repair. Short-term systemic delivery of PDGF-AB to mice from the time of myocardial infarction (MI) led to enhanced anatomical and functional recovery. Underpinning these benefits was a priming effect, in which PDGF-AB accelerated exit of fibroblasts from quiescence and induced a higher translational biosynthetic capacity in both fibroblasts and macrophages without triggering fibrosis. Our study highlights the significant biosynthetic heterogeneity and plasticity in cardiac fibroblast populations, and suggests a rationale for a novel therapeutic approach to cardiac injury involving controlled stimulation of fibroblast activation.

cell biology↗