The EHA Research Roadmap: Normal Hematopoiesis.

International audienceIn 2016, the European Hematology Association (EHA) published the EHA Roadmap for European Hematology Research1 aiming to highlight achievements in the diagnostics and treatment of blood disorders, and to better inform European policy makers and other stakeholders about the urgent clinical and scientific needs and priorities in the field of hematology. Each section was coordinated by 1–2 section editors who were leading international experts in the field. In the 5 years that have followed, advances in the field of hematology have been plentiful. As such, EHA is pleased to present an updated Research Roadmap, now including 11 sections, each of which will be published separately. The updated EHA Research Roadmap identifies the most urgent priorities in hematology research and clinical science, therefore supporting a more informed, focused, and ideally a more funded future for European hematology research. The 11 EHA Research Roadmap sections include Normal Hematopoiesis; Malignant Lymphoid Diseases; Malignant Myeloid Diseases; Anemias and Related Diseases; Platelet Disorders; Blood Coagulation and Hemostatic Disorders; Transfusion Medicine; Infections in Hematology; Hematopoietic Stem Cell Transplantation; CAR-T and Other Cell-based Immune Therapies; and Gene Therapy

A roadmap for the Human Developmental Cell Atlas

The Human Developmental Cell Atlas (HDCA) initiative, which is part of the Human Cell Atlas, aims to create a comprehensive reference map of cells during development. This will be critical to understanding normal organogenesis, the effect of mutations, environmental factors and infectious agents on human development, congenital and childhood disorders, and the cellular basis of ageing, cancer and regenerative medicine. Here we outline the HDCA initiative and the challenges of mapping and modelling human development using state-of-the-art technologies to create a reference atlas across gestation. Similar to the Human Genome Project, the HDCA will integrate the output from a growing community of scientists who are mapping human development into a unified atlas. We describe the early milestones that have been achieved and the use of human stem-cell-derived cultures, organoids and animal models to inform the HDCA, especially for prenatal tissues that are hard to acquire. Finally, we provide a roadmap towards a complete atlas of human development

Emerging properties of animal gene regulatory networks

Gene regulatory networks (GRNs) provide system level explanations of developmental and physiological functions in the terms of the genomic regulatory code. Depending on their developmental functions, GRNs differ in their degree of hierarchy, and also in the types of modular sub-circuit of which they are composed, although there is a commonly employed sub-circuit repertoire. Mathematical modelling of some types of GRN sub-circuit has deepened biological understanding of the functions they mediate. The structural organization of various kinds of GRN reflects their roles in the life process, and causally illuminates both developmental and evolutionary process

Cancer Stem Cells as a Result of a Reprogramming-Like Mechanism

Open Access: under CC BY-NCSA 3.0 license.Research in our groups is partially supported by FEDER and by MICINN (SAF2009-08803 to ISG), by Junta de Castilla y León (Proyecto Biomedicina 2009-2010 to ISG, and Proyecto Biomedicina 2010-2011 to CVD), by MEC OncoBIO Consolider-Ingenio 2010 (Ref. CSD2007- 0017) to ISG, by NIH grant (R01 CA109335-04A1) to ISG, by Sandra Ibarra Foundation to ISG, and by Group of Excellence Grant (GR15) from Junta de Castilla y Leon to ISG and JJC.Peer reviewe

An experimentally validated network of nine haematopoietic transcription factors reveals mechanisms of cell state stability.

Transcription factor (TF) networks determine cell-type identity by establishing and maintaining lineage-specific expression profiles, yet reconstruction of mammalian regulatory network models has been hampered by a lack of comprehensive functional validation of regulatory interactions. Here, we report comprehensive ChIP-Seq, transgenic and reporter gene experimental data that have allowed us to construct an experimentally validated regulatory network model for haematopoietic stem/progenitor cells (HSPCs). Model simulation coupled with subsequent experimental validation using single cell expression profiling revealed potential mechanisms for cell state stabilisation, and also how a leukaemogenic TF fusion protein perturbs key HSPC regulators. The approach presented here should help to improve our understanding of both normal physiological and disease processes.Research in the authors’ laboratories was supported by Bloodwise, The Wellcome Trust, Cancer Research UK, the Biotechnology and Biological Sciences Research Council, the National Institute of Health Research, the Medical Research Council, the MRC Molecular Haematology Unit (Oxford) core award, a Weizmann-UK “Making Connections” grant (Oxford) and core support grants by the Wellcome Trust to the Cambridge Institute for Medical Research (100140) and Wellcome Trust–MRC Cambridge Stem Cell Institute (097922).This is the final version of the article. It first appeared from eLife via http://dx.doi.org/10.7554/eLife.1146

Fitting structure to function in gene regulatory networks

Cascades of transcriptional regulation are the common source of the forward drive in all developmental systems. Increases in complexity and specificity of gene expression at successive stages are based on the collaboration of varied combinations of transcription factors already expressed in the cells to turn on new genes, and the logical relationships between the transcription factors acting and becoming newly expressed from stage to stage are best visualized as gene regulatory networks. However, gene regulatory networks used in different developmental contexts underlie processes that actually operate through different sets of rules, which affect the kinetics, synchronicity, and logical properties of individual network nodes. Contrasting early embryonic development in flies and sea urchins with adult mammalian hematopoietic development from stem cells, major differences are seen in transcription factor dosage dependence, the silencing or damping impacts of repression, and the impact of cellular regulatory history on the parts of the genome that are accessible to transcription factor action in a given cell type. These different features not only affect the kinds of models that can illuminate developmental mechanisms in the respective biological systems, but also reflect the evolutionary needs of these biological systems to optimize different aspects of development

Computational Stem Cell Biology: Open Questions and Guiding Principles

Computational biology is enabling an explosive growth in our understanding of stem cells and our ability to use them for disease modeling, regenerative medicine, and drug discovery. We discuss four topics that exemplify applications of computation to stem cell biology: cell typing, lineage tracing, trajectory inference, and regulatory networks. We use these examples to articulate principles that have guided computational biology broadly and call for renewed attention to these principles as computation becomes increasingly important in stem cell biology. We also discuss important challenges for this field with the hope that it will inspire more to join this exciting area

The Stem Cell Niche in Regenerative Medicine

Stem cells are fundamental units for achieving regenerative therapies, which leads naturally to a theoretical and experimental focus on these cells for therapeutic screening and intervention. A growing body of data in many tissue systems indicates that stem cell function is critically influenced by extrinsic signals derived from the microenvironment, or “niche.” In this vein, the stem cell niche represents a significant, and largely untapped, entry point for therapeutic modulation of stem cell behavior. This Perspective will discuss how the niche influences stem cells in homeostasis, in the progression of degenerative and malignant diseases, and in therapeutic strategies for tissue repair