George Gabriel Stokes as a biologist.

It is universally acknowledged that George Gabriel Stokes (1819-1903) was a polymath who made major contributions to the fields of mathematics, chemistry, physics, fluidics and optics. However, his contributions to biology have received far less attention and this brief communication examines two of Stokes' major biological contributions, namely his description of the phenomenon of fluorescence and his studies on the changes in the colour of blood following oxidation and reduction. The paper on fluorescence is discussed because in it, Stokes demonstrates his wide-ranging biological knowledge and because the use of fluorescence is an invaluable experimental tool in biology.

Modeling the Hematopoietic Landscape.

Some time ago, we proposed a continuum-like view of the lineages open to hematopoietic stem cells (HSCs); each HSC self-renews or chooses from the spectrum of all end-cell options and can then "merely" differentiate. Having selected a cell lineage, an individual HSC may still "step sideways" to an alternative, albeit closely related, fate: HSC and their progeny therefore remain versatile. The hematopoietic cytokines erythropoietin, granulocyte colony-stimulating factor, macrophage colony-stimulating factor, granulocyte/macrophage colony-stimulating factor and ligand for the fms-like tyrosine kinase 3 instruct cell lineage.

Accumulation of Multipotent Hematopoietic Progenitors in Peripheral Lymphoid Organs of Mice Over-expressing Interleukin-7 and Flt3-Ligand.

Interleukin-7 (IL-7) and Flt3-ligand (FL) are two cytokines important for the generation of B cells, as manifested by the impaired B cell development in mice deficient for either cytokine or their respective receptors and by the complete block in B cell differentiation in the absence of both cytokines. IL-7 is an important survival and proliferation factor for B cell progenitors, whereas FL acts on several early developmental stages, prior to B cell commitment. We have generated mice constitutively over-expressing both IL-7 and FL.

The Making of Hematopoiesis: Developmental Ancestry and Environmental Nurture.

Evidence from studies of the behaviour of stem and progenitor cells and of the influence of cytokines on their fate determination, has recently led to a revised view of the process by which hematopoietic stem cells and their progeny give rise to the many different types of blood and immune cells. The new scenario abandons the classical view of a rigidly demarcated lineage tree and replaces it with a much more continuum-like view of the spectrum of fate options open to hematopoietic stem cells and their progeny. This is in contrast to previous lineage diagrams, which envisaged stem cells progressing stepwise through a series of fairly-precisely described intermediate progenitors in order to close down alternative developmental options.

DN2 Thymocytes Activate a Specific Robust DNA Damage Response to Ionizing Radiation-Induced DNA Double-Strand Breaks.

For successful bone marrow transplantation (BMT), a preconditioning regime involving chemo and radiotherapy is used that results in DNA damage to both hematopoietic and stromal elements. Following radiation exposure, it is well recognized that a single wave of host-derived thymocytes reconstitutes the irradiated thymus, with donor-derived thymocytes appearing about 7 days post BMT. Our previous studies have demonstrated that, in the presence of donor hematopoietic cells lacking T lineage potential, these host-derived thymocytes are able to generate a polyclonal cohort of functionally mature peripheral T cells numerically comprising ~25% of the peripheral T cell pool of euthymic mice.

The Transcription Factor Hif-1 Enhances the Radio-Resistance of Mouse MSCs.

Mesenchymal stromal cells (MSCs) are multipotent progenitors supporting bone marrow hematopoiesis. MSCs have an efficient DNA damage response (DDR) and are consequently relatively radio-resistant cells. Therefore, MSCs are key to hematopoietic reconstitution following total body irradiation (TBI) and bone marrow transplantation (BMT).

The changing face of hematopoiesis: a spectrum of options is available to stem cells.

For more than 30 years, the scheme whereby bone marrow hematopoietic stem cells give rise to the many different types of blood and immune cells has been represented as a lineage tree diagram. In this model, hematopoietic stem cells follow a preferred route to each of the end-cell types and gradually restrict their other lineage options via a series of intermediate oligo-potent progenitors. Recent findings of lineage biases or affiliations within hematopoietic stem and progenitor cells that are either pluripotent or uni-potent show that a continuum of fate options is open to hematopoietic stem cells.

Phenotypic and functional heterogeneity of human intermediate monocytes based on HLA-DR expression.

Human blood monocytes are subclassified as classical, intermediate and nonclassical. In this study, it was shown that conventionally defined human intermediate monocytes can be divided into two distinct subpopulations with mid- and high-level surface expression of HLA-DR (referred to as DR and DR intermediate monocytes). These IM subpopulations were phenotypically and functionally characterized in healthy adult blood by flow cytometry, migration assays and lipoprotein uptake assays.

Anti-donor antibody induction following intramuscular injections of allogeneic mesenchymal stromal cells.

Allogeneic mesenchymal stromal cells (allo-MSC) are a promising "off-the-shelf" therapy with anti-inflammatory and pro-repair properties. This study investigated humoral immune responses to intramuscular (IM) injections of allo-MSC. Total and isotype-specific anti-donor IgG and donor-specific complement-mediated lysis were determined in sera from healthy mice 2 weeks after single or repeated IM injections of fully mismatched-MHC allo-MSC with comparison to mice receiving syngeneic MSC, allogeneic splenocytes or saline.

Single-cell RNA sequencing reveals developmental heterogeneity among early lymphoid progenitors.

Single-cell RNA sequencing is a powerful technology for assessing heterogeneity within defined cell populations. Here, we describe the heterogeneity of a B220CD117CD19NK1.1 uncommitted hematopoietic progenitor having combined lymphoid and myeloid potential.

Distinctive Surface Glycosylation Patterns Associated With Mouse and Human CD4 Regulatory T Cells and Their Suppressive Function.

Regulatory T-cells (Treg) are essential for maintaining immune homeostasis and tolerance. Surface glycosylation is ubiquitous on mammalian cells and regulates diverse biological processes. While it is currently well accepted that surface glycan expression influences multiple aspects of T-cell function, little is known about the relevance of glycosylation to Treg biology.

Differential Response of Mouse Thymic Epithelial Cell Types to Ionizing Radiation-Induced DNA Damage.

Thymic epithelial cells (TECs) are the main components of the thymic stroma that support and control T-cell development. Preparative regimens using DNA-damaging agents, such as total body irradiation and/or chemotherapeutic drugs, that are necessary prior to bone marrow transplantation (BMT) have profound deleterious effects on the hematopoietic system, including the thymic stroma, which may be one of the main causes for the prolonged periods of T-cell deficiency and the inefficient T cell reconstitution that are common following BMT. The DNA damage response (DDR) is a complex signaling network that allows cells to respond to all sorts of genotoxic insults.

A Database of Human Immune Receptor Alleles Recovered from Population Sequencing Data.

High-throughput sequencing data from TCRs and Igs can provide valuable insights into the adaptive immune response, but bioinformatics pipelines for analysis of these data are constrained by the availability of accurate and comprehensive repositories of TCR and Ig alleles. We have created an analytical pipeline to recover immune receptor alleles from genome sequencing data. Applying this pipeline to data from the 1000 Genomes Project we have created Lym1K, a collection of immune receptor alleles that combines known, well-supported alleles with novel alleles found in the 1000 Genomes Project data.

Pro-B cells propagated in stromal cell-free cultures reconstitute functional B-cell compartments in immunodeficient mice.

Up to now long-term in vitro growth of pro-B cells was thought to require stromal cells. However, here we show that fetal liver (FL) and bone marrow (BM) derived pro-B cells can be propagated long-term in stromal cell-free cultures supplemented with IL-7, stem cell factor and FLT3 ligand. Within a week, most cells expressed surface CD19, CD79A, λ5, and VpreB antigens and had rearranged immunoglobulin D-J heavy chain genes.

Permissive roles of cytokines interleukin-7 and Flt3 ligand in mouse B-cell lineage commitment.

Hematopoietic cells are continuously generated throughout life from hematopoietic stem cells, thus making hematopoiesis a favorable system to study developmental cell lineage commitment. The main factors incorporating environmental signals to developing hematopoietic cells are cytokines, which regulate commitment of hematopoietic progenitors to the different blood lineages by acting either in an instructive or a permissive manner. Fms-like tyrosine kinase-3 (Flt3) ligand (FL) and Interleukin-7 (IL-7) are cytokines pivotal for B-cell development, as manifested by the severely compromised B-cell development in their absence.

Infliximab Selectively Modulates the Circulating Blood Monocyte Repertoire in Crohn's Disease.

Background: Infliximab (IFX), an anti-tumour necrosis factor alpha (TNFα) monoclonal antibody, provides clinical benefits in treating Crohn's disease (CD) but its mechanisms of action are not fully elucidated. This study investigated blood monocyte repertoires and the acute effects of IFX infusion on monocyte subset phenotype and function in IFX-treated patients with CD.

Methods: Monocytes and monocyte subsets were enumerated and phenotypically characterized by multicolor flow cytometry in freshly isolated blood from healthy controls (n = 21) and patients with CD treated with (IFX, n = 24) and without (non-IFX, n = 20) IFX.

Development of a flow cytometry-based potency assay for measuring the in vitro immunomodulatory properties of mesenchymal stromal cells.

Human bone marrow-derived mesenchymal stromal/stem cells (MSC) have well-documented modulatory effects on multiple immune cell types. Although these effects are linked to their therapeutic benefit in diverse diseases, a reliable, quantitative assay of the immunomodulatory potency of individual human MSC preparations is lacking. The aims of this study were to develop an optimised rapid turnaround, flow cytometry-based whole-blood assay to monitor MSC potency and to validate its application to MSC immunomodulation.

Immunomodulatory effects of natural polysaccharides assessed in human whole blood culture and THP-1 cells show greater sensitivity of whole blood culture.

Immunomodulatory drugs are available to maintain immune homeostasis but some have undesirable side effects. Six oligo- and poly-saccharides were assessed for their pro- and anti-inflammatory responses in two in vitro model systems, the monocytic THP-1 cell line and human whole blood cultures (HWBC). The compounds were first characterised for their molecular mass and physical properties.