Autophagy regulates the maturation of hematopoietic precursors in the embryo.

An understanding of the mechanisms regulating embryonic hematopoietic stem cell (HSC) development would facilitate their regeneration. The aorta-gonad-mesonephros region is the site for HSC production from hemogenic endothelial cells (HEC). While several distinct regulators are involved in this process, it is not yet known whether macroautophagy (autophagy) plays a role in hematopoiesis in the pre-liver stage.

A life-time of hematopoietic cell function: ascent, stability, and decline.

Aging is a set of complex processes that occur temporally and continuously. It is generally a unidirectional progression of cellular and molecular changes occurring during the life stages of cells, tissues and ultimately the whole organism. In vertebrate organisms, this begins at conception from the first steps in blastocyst formation, gastrulation, germ layer differentiation, and organogenesis to a continuum of embryonic, fetal, adolescent, adult, and geriatric stages.

De novo hematopoietic (stem) cell generation - A differentiation or stochastic process?

The hematopoietic system is one of the earliest tissues to develop. De novo generation of hematopoietic progenitor and stem cells occurs through a transdifferentiation of (hemogenic) endothelial cells to hematopoietic identity, resulting in the formation of intra-aortic hematopoietic cluster (IAHC) cells. Heterogeneity of IAHC cell phenotypes and functions has stymied the field in its search for the transcriptional program of emerging hematopoietic stem cells (HSCs), given that an individual IAHC cannot be simultaneously examined for function and transcriptome.

Pain-induced autonomic dysreflexia secondary to spinal cord injury with significant improvement after spinal cord stimulator implantation.

Introduction: Spinal cord stimulation (SCS) has been established as a safe and effective alternative treatment for many conditions. This is a unique case involving SCS in spinal cord injury (SCI) patients with recurrent episodes of autonomic dysreflexia (AD). AD is a sympathetically driven reflexive hypertension in response to a noxious stimuli below the neurological level of spinal cord injury.

Spinal cord stimulator implantation with immediate post-operative paraplegia: Case report.

The most common complication of dorsal column spinal cord stimulator implantation is hardware migration. Spinal cord injury following paddle or percutaneous lead implant is rarely reported, with an overall incidence of 0.42%.

Gata2-regulated Gfi1b expression controls endothelial programming during endothelial-to-hematopoietic transition.

The first hematopoietic stem cells (HSCs) are formed through endothelial-to-hematopoietic transition (EHT) during embryonic development. The transcription factor GATA2 is a crucial regulator of EHT and HSC function throughout life. Because patients with GATA2 haploinsufficiency have inborn mutations, prenatal defects are likely to influence disease development.

The (intra-aortic) hematopoietic cluster cocktail: what is in the mix?

The adult-definitive hematopoietic hierarchy and hematopoietic stem cells (HSCs) residing in the bone marrow are established during embryonic development. In mouse, human, and many other mammals, it is the sudden formation of so-called intra-aortic/arterial hematopoietic clusters (IAHCs) that best signifies and visualizes this de novo generation of HSCs and hematopoietic progenitor cells (HPCs). Cluster cells arise through an endothelial-to-hematopoietic transition and, for some time, express markers/genes of both tissue types, whilst acquiring more hematopoietic features and losing endothelial ones.

Embryonic Origins of the Hematopoietic System: Hierarchies and Heterogeneity.

The hierarchical framework of the adult blood system as we know it from current medical and hematology textbooks, displays a linear branching network of dividing and differentiated cells essential for the growth and maintenance of the healthy organism. This view of the hierarchy has evolved over the last 75 years. An amazing increase in cellular complexity has been realized; however, innovative single-cell technologies continue to uncover essential cell types and functions in animal models and the human blood system.

Bioengineering Self-Organizing Signaling Centers to Control Embryoid Body Pattern Elaboration.

Multicellular systems possess an intrinsic capacity to autonomously generate nonrandom state distributions or morphologies in a process termed self-organization. Facets of self-organization, such as pattern formation, pattern elaboration, and symmetry breaking, are frequently observed in developing embryos. Artificial stem cell-derived structures including embryoid bodies (EBs), gastruloids, and organoids also demonstrate self-organization, but with a limited capacity compared to their developmental counterparts.

Unexpected redundancy of Gpr56 and Gpr97 during hematopoietic cell development and differentiation.

Integrated molecular signals regulate cell fate decisions in the embryonic aortic endothelium to drive hematopoietic stem cell (HSC) generation during development. The G-protein-coupled receptor 56 (Gpr56, also called Adgrg1) is the most highly upregulated receptor gene in cells that take on hematopoietic fate and is expressed by adult bone marrow HSCs. Despite the requirement for Gpr56 in hematopoietic stem/progenitor cell (HS/PC) generation in zebrafish embryos and the highly upregulated expression of GPR56 in treatment-resistant leukemic patients, its function in normal mammalian hematopoiesis remains unclear.

E-cadherin is regulated by GATA-2 and marks the early commitment of mouse hematopoietic progenitors to the basophil and mast cell fates.

E-cadherin is a calcium-dependent cell-cell adhesion molecule extensively studied for its involvement in tissue formation, epithelial cell behavior, and suppression of cancer. However, E-cadherin expression in the hematopoietic system has not been fully elucidated. Combining single-cell RNA-sequencing analyses and immunophenotyping, we revealed that progenitors expressing high levels of E-cadherin and contained within the granulocyte-monocyte progenitors (GMPs) fraction have an enriched capacity to differentiate into basophils and mast cells.

Iterative Single-Cell Analyses Define the Transcriptome of the First Functional Hematopoietic Stem Cells.

Whereas hundreds of cells in the mouse embryonic aorta transdifferentiate to hematopoietic cells, only very few establish hematopoietic stem cell (HSC) identity at a single time point. The Gata2 transcription factor is essential for HSC generation and function. In contrast to surface-marker-based cell isolation, Gata2-based enrichment provides a direct link to the internal HSC regulatory network.

Notch ligand Dll4 impairs cell recruitment to aortic clusters and limits blood stem cell generation.

Hematopoietic stem cells (HSCs) develop from the hemogenic endothelium in cluster structures that protrude into the embryonic aortic lumen. Although much is known about the molecular characteristics of the developing hematopoietic cells, we lack a complete understanding of their origin and the three-dimensional organization of the niche. Here, we use advanced live imaging techniques of organotypic slice cultures, clonal analysis, and mathematical modeling to show the two-step process of intra-aortic hematopoietic cluster (IACH) formation.

A role for macrophages in hematopoiesis in the embryonic head.

Along with the aorta-gonad-mesonephros region, the head is a site of hematopoietic stem and progenitor cell (HS/PC) development in the mouse embryo. Macrophages are present in both these embryonic hemogenic sites, and recent studies indicate a functional interaction of macrophages with hematopoietic cells as they are generated in the aorta. Whereas brain macrophages or "microglia" are known to affect neuronal patterning and vascular circuitry in the embryonic brain, it is unknown whether macrophages play a role in head hematopoiesis.

Pro-inflammatory Aorta-Associated Macrophages Are Involved in Embryonic Development of Hematopoietic Stem Cells.

Hematopoietic stem cells (HSCs) are generated from specialized endothelial cells of the embryonic aorta. Inflammatory factors are implicated in regulating mouse HSC development, but which cells in the aorta-gonad-mesonephros (AGM) microenvironment produce these factors is unknown. In the adult, macrophages play both pro- and anti-inflammatory roles.

Macrophages restrict the nephrogenic field and promote endothelial connections during kidney development.

The origins and functions of kidney macrophages in the adult have been explored, but their roles during development remain largely unknown. Here we characterise macrophage arrival, localisation, heterogeneity, and functions during kidney organogenesis. Using genetic approaches to ablate macrophages, we identify a role for macrophages in nephron progenitor cell clearance as mouse kidney development begins.

Publisher Correction: Disease-relevant transcriptional signatures identified in individual smooth muscle cells from healthy mouse vessels.

The original version of this Article contained errors in the author affiliations.Martin R. Bennett was incorrectly associated with Nuclear Dynamics Programme, Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK.

Disease-relevant transcriptional signatures identified in individual smooth muscle cells from healthy mouse vessels.

Vascular smooth muscle cells (VSMCs) show pronounced heterogeneity across and within vascular beds, with direct implications for their function in injury response and atherosclerosis. Here we combine single-cell transcriptomics with lineage tracing to examine VSMC heterogeneity in healthy mouse vessels. The transcriptional profiles of single VSMCs consistently reflect their region-specific developmental history and show heterogeneous expression of vascular disease-associated genes involved in inflammation, adhesion and migration.

Rapid Mast Cell Generation from Gata2 Reporter Pluripotent Stem Cells.

Mast cells are tissue-resident immune cells. Their overgrowth/overactivation results in a range of common distressing, sometimes life-threatening disorders, including asthma, psoriasis, anaphylaxis, and mastocytosis. Currently, drug discovery is hampered by use of cancer-derived mast cell lines or primary cells.

Blood Development: Hematopoietic Stem Cell Dependence and Independence.

Evidence of the diversity and multi-layered organization of the hematopoietic system is leading to new insights that may inform ex vivo production of blood cells. Interestingly, not all long-lived hematopoietic cells derive from hematopoietic stem cells (HSCs). Here we review the current knowledge on HSC-dependent cell lineages and HSC-independent tissue-resident hematopoietic cells and how they arise during embryonic development.

In Vitro Differentiation of Gata2 and Ly6a Reporter Embryonic Stem Cells Corresponds to In Vivo Waves of Hematopoietic Cell Generation.

In vivo hematopoietic generation occurs in waves of primitive and definitive cell emergence. Differentiation cultures of pluripotent embryonic stem cells (ESCs) offer an accessible source of hematopoietic cells for blood-related research and therapeutic strategies. However, despite many approaches, it remains a goal to robustly generate hematopoietic progenitor and stem cells (HP/SCs) in vitro from ESCs.

In vivo single cell analysis reveals Gata2 dynamics in cells transitioning to hematopoietic fate.

Cell fate is established through coordinated gene expression programs in individual cells. Regulatory networks that include the Gata2 transcription factor play central roles in hematopoietic fate establishment. Although Gata2 is essential to the embryonic development and function of hematopoietic stem cells that form the adult hierarchy, little is known about the in vivo expression dynamics of Gata2 in single cells.