scholarly journals BMP signalling differentially regulates distinct haematopoietic stem cell types

2015 ◽  
Vol 6 (1) ◽  
Author(s):  
Mihaela Crisan ◽  
Parham Solaimani Kartalaei ◽  
Chris S. Vink ◽  
Tomoko Yamada-Inagawa ◽  
Karine Bollerot ◽  
...  
Keyword(s):  
Stem Cell ◽  
Developmental Stages ◽  
Fetal Liver ◽  
Cell Lineage ◽  
Cell Types ◽  
Haematopoietic Stem Cell ◽  
Control Mechanisms ◽  
Molecular Control ◽  
Bmp Signalling ◽  
Insight Into

Abstract Adult haematopoiesis is the outcome of distinct haematopoietic stem cell (HSC) subtypes with self-renewable repopulating ability, but with different haematopoietic cell lineage outputs. The molecular basis for this heterogeneity is largely unknown. BMP signalling regulates HSCs as they are first generated in the aorta-gonad-mesonephros region, but at later developmental stages, its role in HSCs is controversial. Here we show that HSCs in murine fetal liver and the bone marrow are of two types that can be prospectively isolated—BMP activated and non-BMP activated. Clonal transplantation demonstrates that they have distinct haematopoietic lineage outputs. Moreover, the two HSC types differ in intrinsic genetic programs, thus supporting a role for the BMP signalling axis in the regulation of HSC heterogeneity and lineage output. Our findings provide insight into the molecular control mechanisms that define HSC types and have important implications for reprogramming cells to HSC fate and treatments targeting distinct HSC types.

scholarly journals Correction: Corrigendum: BMP signalling differentially regulates distinct haematopoietic stem cell types

2015 ◽  
Vol 6 (1) ◽  
Author(s):  
Mihaela Crisan ◽  
Parham Solaimani Kartalaei ◽  
Chris S. Vink ◽  
Tomoko Yamada-Inagawa ◽  
Karine Bollerot ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Types ◽  
Haematopoietic Stem Cell ◽  
Bmp Signalling

scholarly journals Universal principles of lineage architecture and stem cell identity in renewing tissues

2020 ◽  
Author(s):  
Philip Greulich ◽  
Ben D. MacArthur ◽  
Cristina Parigini ◽  
Rubén J. Sánchez-García
Keyword(s):  
Stem Cell ◽  
Cell Lineage ◽  
Adult Stem Cell ◽  
Feedback Regulation ◽  
Cell Types ◽  
Universal Principles ◽  
Formal Framework ◽  
Cell Niche ◽  
Multicellular Organisms ◽  
The Relationship

Adult tissues in multicellular organisms typically contain a variety of stem, progenitor and differentiated cell types arranged in a lineage hierarchy that regulates healthy tissue turnover and repair. Lineage hierarchies in disparate tissues often exhibit common features, yet the general principles regulating their architecture are not known. Here, we provide a formal framework for understanding the relationship between cell molecular ‘states’ (patterns of gene, protein expression etc. in the cell) and cell ‘types’ that uses notions from network science to decompose the structure of cell state trajectories into functional units. Using this framework we show that many widely experimentally observed features of cell lineage architectures – including the fact that a single adult stem cell type always resides at the apex of a lineage hierarchy – arise as a natural consequence of homeostasis, and indeed are the only possible way that lineage architectures can be constructed to support homeostasis in renewing tissues. Furthermore, under suitable feedback regulation, for example from the stem cell niche, we show that the property of ‘stemness’ is entirely determined by the cell environment. Thus, we argue that stem cell identities are contextual and not determined by hard-wired, cell-intrinsic, characteristics.

scholarly journals Oncogenes, Proto-Oncogenes, and Lineage Restriction of Cancer Stem Cells

2021 ◽  
Vol 22 (18) ◽  
pp. 9667
Author(s):  
Geoffrey Brown
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Cell Lineage ◽  
Cell Types ◽  
Mature Cell ◽  
Cellular Gene ◽  
Hematopoietic Stem ◽  
Homeostatic Process ◽  
Epigenetic Events

In principle, an oncogene is a cellular gene (proto-oncogene) that is dysfunctional, due to mutation and fusion with another gene or overexpression. Generally, oncogenes are viewed as deregulating cell proliferation or suppressing apoptosis in driving cancer. The cancer stem cell theory states that most, if not all, cancers are a hierarchy of cells that arises from a transformed tissue-specific stem cell. These normal counterparts generate various cell types of a tissue, which adds a new dimension to how oncogenes might lead to the anarchic behavior of cancer cells. It is that stem cells, such as hematopoietic stem cells, replenish mature cell types to meet the demands of an organism. Some oncogenes appear to deregulate this homeostatic process by restricting leukemia stem cells to a single cell lineage. This review examines whether cancer is a legacy of stem cells that lose their inherent versatility, the extent that proto-oncogenes play a role in cell lineage determination, and the role that epigenetic events play in regulating cell fate and tumorigenesis.

scholarly journals Lineage Decision-Making within Normal Haematopoietic and Leukemic Stem Cells

2020 ◽  
Vol 21 (6) ◽  
pp. 2247
Author(s):  
Geoffrey Brown ◽  
Lucía Sánchez ◽  
Isidro Sánchez-García
Keyword(s):  
Stem Cells ◽  
Cell Fate ◽  
Immune Cell ◽  
Alternative Pathway ◽  
Cell Lineage ◽  
Cell Types ◽  
Haematopoietic Stem Cell ◽  
Haematopoietic Stem Cells ◽  
Wide Range ◽  
Lineage Decision

To produce the wide range of blood and immune cell types, haematopoietic stem cells can “choose” directly from the entire spectrum of blood cell fate-options. Affiliation to a single cell lineage can occur at the level of the haematopoietic stem cell and these cells are therefore a mixture of some pluripotent cells and many cells with lineage signatures. Even so, haematopoietic stem cells and their progeny that have chosen a particular fate can still “change their mind” and adopt a different developmental pathway. Many of the leukaemias arise in haematopoietic stem cells with the bulk of the often partially differentiated leukaemia cells belonging to just one cell type. We argue that the reason for this is that an oncogenic insult to the genome “hard wires” leukaemia stem cells, either through development or at some stage, to one cell lineage. Unlike normal haematopoietic stem cells, oncogene-transformed leukaemia stem cells and their progeny are unable to adopt an alternative pathway.

scholarly journals Are Leukaemic Stem Cells Restricted to a Single Cell Lineage?

2019 ◽  
Vol 21 (1) ◽  
pp. 45 ◽  
Author(s):  
Geoffrey Brown ◽  
Lucía Sánchez ◽  
Isidro Sánchez-García
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Cancer Cells ◽  
Lymphoblastic Leukaemia ◽  
Cell Lineage ◽  
Cell Development ◽  
Haematopoietic Stem Cell ◽  
Essential Difference ◽  
Normal Cells

Cancer-stem-cell theory states that most, if not all, cancers arise from a stem/uncommitted cell. This theory revolutionised our view to reflect that cancer consists of a hierarchy of cells that mimic normal cell development. Elegant studies of twins who both developed acute lymphoblastic leukaemia in childhood revealed that at least two genomic insults are required for cancer to develop. These ‘hits’ do not appear to confer a growth advantage to cancer cells, nor do cancer cells appear to be better equipped to survive than normal cells. Cancer cells created by investigators by introducing specific genomic insults generally belong to one cell lineage. For example, transgenic mice in which the LIM-only 2 (LMO2, associated with human acute T-lymphoblastic leukaemia) and BCR-ABLp210 (associated with human chronic myeloid leukaemia) oncogenes were active solely within the haematopoietic stem-cell compartment developed T-lymphocyte and neutrophil lineage-restricted leukaemia, respectively. This recapitulated the human form of these diseases. This ‘hardwiring’ of lineage affiliation, either throughout leukaemic stem cell development or at a particular stage, is different to the behaviour of normal haematopoietic stem cells. While normal cells directly commit to a developmental pathway, they also remain versatile and can develop into a terminally differentiated cell that is not part of the initial lineage. Many cancer stem cells do not have this versatility, and this is an essential difference between normal and cancer stem cells. In this report, we review findings that support this notion.

scholarly journals EPCO-20. RELATING GLIOBLASTOMA HETEROGENEITY TO HUMAN FETAL GLIAL DEVELOPMENT THROUGH HIGH RESOLUTION SINGLE NUCLEI TRANSCRIPTOMICS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii73-ii73
Author(s):  
Zarmeen Mussa ◽  
Susana Ramos ◽  
Elisa Nabel ◽  
Kimaada Allette ◽  
Ammar Hamid ◽  
...  
Keyword(s):  
Stem Cell ◽  
Regulatory Networks ◽  
Developmental Stages ◽  
Cell Types ◽  
Prenatal Development ◽  
Adult Brain ◽  
Stem Cell Population ◽  
Cortical Plate ◽  
Spatiotemporal Resolution ◽  
Germinal Matrix

Abstract Glioblastoma (GBM) is thought to be driven by a therapy-resistant cancer stem cell population that recapitulates developmental phenotypes. Direct comparisons of GBM to glial states during human fetal development are limited due to paucity of data from late prenatal gestation, when gliogenesis is thought to occur. Here, we generated a comprehensive single nuclei RNA sequencing (snRNAseq) dataset of approximately 200,000 nuclei taken from the germinal matrix and the cortical plate of 16 fetal postmortem samples, ranging from 17 to 41 gestational weeks, enabling high spatiotemporal resolution of late neurogenesis and early-to-peak gliogenesis. We performed unbiased clustering to identify broad cell types within each sample and integrated all fetal samples to analyze evolving glial states and relationships across two regions and four developmental stages. Subclustering analysis of developing glia from the germinal matrix and cortical plate resolved developmental cell type signatures that are absent in the adult brain. Trajectory inference and pseudo-time analyses reconstructed relationships within these glial lineages and states, identifying a robust common glial progenitor population (GPC) with distinct signature, preceding both oligodendrocyte progenitor cell (OPC) and astrocyte lineage commitment during late prenatal development. We then performed snRNAseq on approximately 30,000 nuclei taken from the core and infiltrating edge of two surgically resected GBM samples with IDH-mutant and IDH-wildtype status and EGFR amplification. Uniform manifold approximation and projection (UMAP) dimensionality reduction revealed distinct neoplastic and non-neoplastic population clusters within each GBM sample. Projecting our previously defined neural stem cell / progenitor signatures onto each GBM UMAP identified notable predominance of the GPC-like developmental signature throughout both GBM tumors with focal minor contributions from the OPC-, transit amplifying-, and astrocyte-like signatures. The high spatial and temporal resolution of the generated roadmap dissolves GBM intratumoral heterogeneity into distinct developmental molecular states driven by potentially targetable regulatory networks.

scholarly journals Bi-directional cell-pericellular matrix interactions direct stem cell fate

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Silvia A. Ferreira ◽  
Meghna S. Motwani ◽  
Peter A. Faull ◽  
Alexis J. Seymour ◽  
Tracy T. L. Yu ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Fate ◽  
Cell Lineage ◽  
Local Environment ◽  
Pericellular Matrix ◽  
Lineage Specification ◽  
Reciprocal Interactions ◽  
Stem Cell Lineage ◽  
Matrix Interactions ◽  
Insight Into

Abstract Modifiable hydrogels have revealed tremendous insight into how physical characteristics of cells’ 3D environment drive stem cell lineage specification. However, in native tissues, cells do not passively receive signals from their niche. Instead they actively probe and modify their pericellular space to suit their needs, yet the dynamics of cells’ reciprocal interactions with their pericellular environment when encapsulated within hydrogels remains relatively unexplored. Here, we show that human bone marrow stromal cells (hMSC) encapsulated within hyaluronic acid-based hydrogels modify their surroundings by synthesizing, secreting and arranging proteins pericellularly or by degrading the hydrogel. hMSC’s interactions with this local environment have a role in regulating hMSC fate, with a secreted proteinaceous pericellular matrix associated with adipogenesis, and degradation with osteogenesis. Our observations suggest that hMSC participate in a bi-directional interplay between the properties of their 3D milieu and their own secreted pericellular matrix, and that this combination of interactions drives fate.

scholarly journals Ceramide in Stem Cell Differentiation and Embryo Development: Novel Functions of a Topological Cell-Signaling Lipid and the Concept of Ceramide Compartments

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Erhard Bieberich
Keyword(s):  
Stem Cell ◽  
Cell Differentiation ◽  
Cell Signaling ◽  
Embryo Development ◽  
Knockout Mice ◽  
Lipid A ◽  
Developmental Stages ◽  
Stem Cell Differentiation ◽  
Cell Types

In the last two decades, the view on the function of ceramide as a sole metabolic precursor for other sphingolipids has completely changed. A plethora of studies has shown that ceramide is an important lipid cell-signaling factor regulating apoptosis in a variety of cell types. With the advent of new stem cell technologies and knockout mice for specific steps in ceramide biosynthesis, this view is about to change again. Recent studies suggest that ceramide is a critical cell-signaling factor for stem cell differentiation and cell polarity, two processes at the core of embryo development. This paper discusses studies on ceramide usingin vitrodifferentiated stem cells, embryo cultures, and knockout mice with the goal of linking specific developmental stages to exciting and novel functions of this lipid. Particular attention is devoted to the concept of ceramide as a topological cell-signaling lipid: a lipid that forms distinct structures (membrane domains and vesicles termed “sphingosome”), which confines ceramide-induced cell signaling pathways to localized and even polarized compartments.

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