ABSTRACT
Adipose tissues (ATs) are innervated by sympathetic nerves, which drive reduction of fat mass via lipolysis and thermogenesis. Here, we report a population of immunomodulatory leptin receptor-positive (LepR+) sympathetic perineurial barrier cells (SPCs) present in mice and humans, which uniquely co-express Lepr and interleukin-33 (Il33) and ensheath AT sympathetic axon bundles. Brown ATs (BATs) of mice lacking IL-33 in SPCs (SPCΔIl33) had fewer regulatory T (Treg) cells and eosinophils, resulting in increased BAT inflammation. SPCΔIl33 mice were more susceptible to diet-induced obesity, independently of food intake. Furthermore, SPCΔIl33 mice had impaired adaptive thermogenesis and were unresponsive to leptin-induced rescue of metabolic adaptation. We therefore identify LepR+ SPCs as a source of IL-33, which orchestrate an anti-inflammatory BAT environment, preserving sympathetic-mediated thermogenesis and body weight homeostasis. LepR+IL-33+ SPCs provide a cellular link between leptin and immune regulation of body weight, unifying neuroendocrinology and immunometabolism as previously disconnected fields of obesity research.
Subject(s)
Adipose Tissue, Brown , Leptin , Animals , Humans , Mice , Adipose Tissue, Brown/innervation , Adipose Tissue, Brown/metabolism , Body Weight , Energy Metabolism/physiology , Interleukin-33/genetics , Interleukin-33/metabolism , Obesity/metabolism , Receptors, Leptin/genetics , Receptors, Leptin/metabolism , Thermogenesis/physiologyABSTRACT
Haematopoietic stem and progenitor cells emerge from specialized haemogenic endothelial cells in select vascular beds during embryonic development. Specification and commitment to the blood lineage, however, occur before endothelial cells are endowed with haemogenic competence, at the time of mesoderm patterning and production of endothelial cell progenitors (angioblasts). Whilst early blood cell fate specification has long been recognized, very little is known about the mechanisms that induce endothelial cell diversification and progressive acquisition of a blood identity by a subset of these cells. Here, we review the endothelial origin of the haematopoietic system and the complex developmental journey of blood-fated angioblasts. We discuss how recent technological advances will be instrumental to examine the diversity of the embryonic anatomical niches, signaling pathways and downstream epigenetic and transcriptional processes controlling endothelial cell heterogeneity and blood cell fate specification. Ultimately, this will give essential insights into the ontogeny of the cells giving rise to haematopoietic stem cells, that may aid in the development of novel strategies for their in vitro production for clinical purposes.
Subject(s)
Hemangioblasts , Cell Differentiation , Cell Lineage , Endothelium , Female , Hemangioblasts/metabolism , Hematopoietic Stem Cells , Humans , Mesoderm/metabolism , PregnancyABSTRACT
Growth Factor Independence 1 (GFI1) is a transcriptional repressor that plays a critical role during both myeloid and lymphoid haematopoietic lineage commitment. Several studies have demonstrated the involvement of GFI1 in haematological malignancies and have suggested that low expression of GFI1 is a negative indicator of disease progression for both myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). In this study, we have stratified AML patients into those defined as having a normal karyotype (CN-AML). Unlike the overall pattern in AML, those patients with CN-AML have a poorer survival rate when GFI1 expression is high. In this group, high GFI1 expression is paralleled by higher FLT3 expression, and, even when the FLT3 gene is not mutated, exhibit a FLT3-ITD signature of gene expression. Knock-down of GFI1 expression in the human AML Fujioka cell line led to a decrease in the level of FLT3 RNA and protein and to the down regulation of FLT3-ITD signature genes, thus linking two major prognostic indicators for AML.