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PubMed2000

Karyotypic abnormalities associated with haemopoietic lineage switching are not linked with mutations to p53.

Leukemic cells can undergo lineage switching to display the phenotypic features of another haemopoietic pathway, as exemplified by B lymphoma and erythroleukemic cell lines generating variants with a monocytic appearance. Unlike the diploid parental lines, the vast majority of myeloid derivative lines examined (12 of 13 lines) were aneuploid. As p53 is involved in the maintenance of chromosomal stability, we investigated the role of p53 in the emergence of abnormal karyotypes in cells which had undergone lineage switching. Single strand conformation polymorphism and sequence analysis of cDNA, together with protein immunoprecipitations, were used to assess the p53 status of parental and variant cell lines. Unexpectedly, four or five monocytic lines with chromosomal alterations contained wild type p53. Conversely, a p53 point mutation found in one aneuploid monocytic line was also present in the diploid parental pre-B cell. These results provide strong evidence that mechanisms other than p53 mutations are responsible for karyotypic abnormalities seen in cells that have undergone lineage switching.

Aneuploidy↗

PubMedDate not supplied

Cytology and lineage of NG2-positive glia.

We present evidence that NG2+ glia are an integral part of an oligodendrocyte/synantocyte (OS) lineage stream the progenitors of which begin to produce both glial phenotypes at about birth. The NG2 CSPG is differentially distributed within the OS lineage, being expressed in progenitors and synantocytes but not in oligodendrocytes. All cells in the OS lineage, except the primordial stem cells, express O4. The oligodendrocyte line reacts with CD9, but synantocytes are CD9-. Nonetheless, synantocytes are morphologically complex and specialised glia which contact axolemma in myelinated fibres at nodes of Ranvier and synaptic terminals, and form >99% of all NG2+ glia in the adult CNS. Thus, the other NG2+ phenotype, the adult oligodendrocyte progenitor cell (AOPC), constitutes a small population of <1% of all NG2+ glia in the mature CNS. AOPC are a heterogeneous set of cells probably originating from multiple sources which, by definition, produce oligodendrocytes in the adult to replace loss after trauma, demyelination and normal 'wear and tear'. The definitive functions of synantocytes remain undefined.

Animals↗

PubMed2006

Cell lineage transport: a mechanism for molecular gradient formation.

Gradient formation is a fundamental patterning mechanism during embryo development, commonly related to secreted proteins that move along an existing field of cells. Here, we mathematically address the feasibility of gradients of mRNAs and non-secreted proteins. We show that these gradients can arise in growing tissues whereby cells dilute and transport their molecular content as they divide and grow, a mechanism we termed 'cell lineage transport.' We provide an experimental test by unveiling a distal-to-proximal gradient of Hoxd13 in the vertebrate developing limb bud driven by cell lineage transport, corroborating our model. Our study indicates that gradients of non-secreted molecules exhibit a power-law profile and can arise for a wide range of biologically relevant parameter values. Dilution and nonlinear growth confer robustness to the spatial gradient under changes in the cell cycle period, but at the expense of sensitivity in the timing of gradient formation. We expect that gradient formation driven by cell lineage transport will provide future insights into understanding the coordination between growth and patterning during embryonic development.

Animals↗

PubMed2004

Cell fusion-independent differentiation of neural stem cells to the endothelial lineage.

Somatic stem cells have been claimed to possess an unexpectedly broad differentiation potential (referred to here as plasticity) that could be induced by exposing stem cells to the extracellular developmental signals of other lineages in mixed-cell cultures. Recently, this and other experimental evidence supporting the existence of stem-cell plasticity have been refuted because stem cells have been shown to adopt the functional features of other lineages by means of cell-fusion-mediated acquisition of lineage-specific determinants (chromosomal DNA) rather than by signal-mediated differentiation. In this study we co-cultured mouse neural stem cells (NSCs), which are committed to become neurons and glial cells, with human endothelial cells, which form the lining of blood vessels. We show that in the presence of endothelial cells six per cent of the NSC population converted to cells that did not express neuronal or glial markers, but instead showed the stable expression of multiple endothelial markers and the capacity to form capillary networks. This was surprising because NSCs and endothelial cells are believed to develop from the ectoderm and mesoderm, respectively. Experiments in which endothelial cells were killed by fixation before co-culture with live NSCs (to prevent cell fusion) and karyotyping analyses, revealed that NSCs had differentiated into endothelial-like cells independently of cell fusion. We conclude that stem-cell plasticity is a true characteristic of NSCs and that the conversion of NSCs to unanticipated cell types can be accomplished without cell fusion.

Animals↗

PubMed2005

Blimp1 is a critical determinant of the germ cell lineage in mice.

Germ cell fate in mice is induced in pluripotent epiblast cells in response to signals from extraembryonic tissues. The specification of approximately 40 founder primordial germ cells and their segregation from somatic neighbours are important events in early development. We have proposed that a critical event during this specification includes repression of a somatic programme that is adopted by neighbouring cells. Here we show that Blimp1 (also known as Prdm1), a known transcriptional repressor, has a critical role in the foundation of the mouse germ cell lineage, as its disruption causes a block early in the process of primordial germ cell formation. Blimp1-deficient mutant embryos form a tight cluster of about 20 primordial germ cell-like cells, which fail to show the characteristic migration, proliferation and consistent repression of homeobox genes that normally accompany specification of primordial germ cells. Furthermore, our genetic lineage-tracing experiments indicate that the Blimp1-positive cells originating from the proximal posterior epiblast cells are indeed the lineage-restricted primordial germ cell precursors.

Animals↗

PubMed1998

Chimaeric analysis reveals role of Pdgf receptors in all muscle lineages.

Blood vessels originate as simple endothelial cell tubes. It has been proposed that platelet-derived growth factor B polypeptide (Pdgfb) secreted by these endothelial cells drives the formation of the surrounding muscular wall by recruiting nearby mesenchymal cells. However, targetted inactivation of the Pdgfb gene or the Pdgf receptor beta (Pdgfrb) gene, by homologous recombination, does not prevent the development of apparently normal large arteries and connective tissue. We have used an in vivo competition assay in which we prepared chimaeric blastocysts, composed of a mixture of wild-type (Pdgfrb[+/+]) and Pdgfrb(+/-) or wild-type and Pdgfrb(-/-) cells, and quantified the relative success of cells of the two component genotypes in competing for representation in different cell lineages as the chimaeric embryos developed. This study revealed that the participation of Pdgfrb(-/-) cells in all muscle lineages (smooth, cardiac, skeletal and pericyte) was reduced by eightfold compared with Pdgfrb(+/+) cells, and that participation of Pdgfrb(+/-) cells was reduced by twofold (eightfold for pericytes). Pdgfrb inactivation did not affect cell contribution to non-muscle mesodermal lineages, including fibroblasts and endothelial cells. Chimaera competition is therefore a sensitive, quantitative method for determining developmental roles of specific genes, even when those roles are not apparent from analysis of purebred mutants; most likely because they are masked by homeostatic mechanisms.

Achilles Tendon↗

PubMed2004

Duration of TCR signaling controls CD4-CD8 lineage differentiation in vivo.

The duration of T cell receptor (TCR) signaling is thought to be important for thymocyte differentiation into the CD4 or CD8 lineage. However, the in vivo relevance of this hypothesis is unclear. Here we divided T cell positive selection into genetically separable developmental steps by confining TCR signal transduction to discrete thymocyte developmental windows. TCR signals confined to the double-positive thymocyte stage promoted CD8, but not CD4, lineage differentiation. Major histocompatibility complex (MHC) class II-restricted thymocytes were, instead, redirected into the CD8 lineage. These findings support the hypothesis that distinct kinetics of MHC class I- and MHC class II-induced TCR signals direct intrathymic developmental decisions.

Animals↗

PubMed2005

Initial T cell frequency dictates memory CD8+ T cell lineage commitment.

Memory T cells can be divided into central memory T cell (T(CM) cell) and effector memory T cell (T(EM) cell) subsets based on homing characteristics and effector functions. Whether T(EM) and T(CM) cells represent interconnected or distinct lineages is unclear, although the present paradigm suggests that T(EM) and T(CM) cells follow a linear differentiation pathway from naive T cells to effector T cells to T(EM) cells to T(CM) cells. We show here that naive T cell precursor frequency profoundly influenced the pathway along which CD8+ memory T cells developed. At low precursor frequency, those T(EM) cells generated represented a stable cell lineage that failed to further differentiate into T(CM) cells. These findings do not adhere to the present dogma regarding memory T cell generation and provide a means for identifying factors controlling memory T cell lineage commitment.

Animals↗

PubMed2002

T-cell development and the CD4-CD8 lineage decision.

Cell-fate decisions are controlled typically by conserved receptors that interact with co-evolved ligands. Therefore, the lineage-specific differentiation of immature CD4+ CD8+ T cells into CD4+ or CD8+ mature T cells is unusual in that it is regulated by clonally expressed, somatically generated T-cell receptors (TCRs) of unpredictable fine specificity. Yet, each mature T cell generally retains expression of the co-receptor molecule (CD4 or CD8) that has an MHC-binding property that matches that of its TCR. Two models were proposed initially to explain this remarkable outcome--'instruction' of lineage choice by initial signalling events or 'selection' after a stochastic fate decision that limits further development to cells with coordinated TCR and co-receptor specificities. Aspects of both models now appear to be correct; mistake-prone instruction of lineage choice precedes a subsequent selection step that filters out most incorrect decisions.

Animals↗

PubMed2025

Tracking HIV persistence across T cell lineages during early ART-treated HIV-1-infection using a reservoir-marking humanized mouse model.

Human immunodeficiency virus (HIV) infection depletes CD4 T-cells, and long-term persistence of latent virus prevents full clearance of HIV even in the presence of effective antiretroviral therapy (ART), Here we present the HIV-1-induced lineage tracing (HILT) system, a model that irreversibly marks infected cells within a humanized mouse model, which detects rare latently infected cells. Immunodeficient mice transplanted with genetically modified hematopoietic stem cells develop a human immune system, in which CD4 T-cells contain a genetic switch that permanently labels cells infected by HIV-1 expressing cre-recombinase. Through single-cell RNA sequencing of HILT-marked cells during acute infection and post-ART treatment, we identify distinct CD4+ T-cell transcriptional lineages enriched in either active or latent infections. Comparative gene expression analysis highlights common pathways modulated in both states, including EIF2, Sirtuin, and protein ubiquitination. Critical regulators of these pathways, including JUN, BCL2, and MDM2, change to opposite directions in the two states, highlighting gene expression programs that may support HIV persistence across T-cell lineages and states.

Animals↗

PubMed2026

IRAK4 constrains cellular plasticity during chemically-induced cell fate reprogramming into multiple lineages.

Chemical reprogramming holds transformative potential for regenerative medicine. However, the regulatory mechanisms governing cell fate transitions are not well understood. Here, we identify Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) as a barrier to multi-lineage reprogramming. Pharmacological inhibition of IRAK4 enhances the reprogramming of mouse embryonic fibroblasts (MEFs) through a chemically activated multi-lineage priming (CaMP) state and extraembryonic endoderm (XEN)-like intermediates, increasing colony formation, and the expression of core XEN regulators (Sox17, Gata4, Sall4, and Foxa2). Genetic knockdown of Irak4 similarly accelerates reprogramming, whereas its overexpression blocks cell fate transitions. IRAK4 inhibition enhances chromatin accessibility and reshapes cell cycle dynamics, characterized by G0/G1 shortening and G2/M lengthening, potentially contributing to multi-lineage state establishment. Furthermore, IRAK4 suppression enhances the direct conversion of MEFs to neuron-like and hepatocyte-like cells, which exhibit enhanced functional maturity, including increased glycogen storage and improved detoxification capacity. Our findings establish IRAK4 as a regulator that constrains cellular plasticity potentially by coordinating chromatin accessibility and cell cycle dynamics.

Animals↗

PubMed2005

Mll fusions generated by Cre-loxP-mediated de novo translocations can induce lineage reassignment in tumorigenesis.

Chromosomal translocations are primary events in tumorigenesis. Those involving the mixed lineage leukaemia (MLL) gene are found in various guises and it is unclear whether MLL fusions can affect haematopoietic differentiation. We have used a model in which chromosomal translocations are generated in mice de novo by Cre-loxP-mediated recombination (translocator mice) to compare the functionally relevant haematopoietic cell contexts for Mll fusions, namely pluripotent stem cells, semicommitted progenitors or committed cells. Translocations between Mll and Enl or Af9 cause myeloid neoplasias, initiating in pluripotent stem cells or multipotent myeloid progenitors. However, while Mll-Enl translocations can also cause leukaemia from T-cell progenitors, no tumours arose with Mll-Af9 translocations in the T-cell compartment. Furthermore, Mll-Enl translocations in T-cell progenitors can cause lineage reassignment into myeloid tumours. Therefore, a permissive cellular environment is required for oncogenicity of Mll-associated translocations and Mll fusions can influence haematopoietic lineage commitment.

Animals↗

PubMed2000

Stromal cell-independent differentiation of human cord blood CD34+CD38- lymphohematopoietic progenitors toward B cell lineage.

To study the cytokine regulation of early stages of human B-lymphopoiesis, we developed a stroma-free two-step culture system. Single human cord blood CD34+CD38- cells were individually cultured by micromanipulation with interleukin (IL)-3, stem cell factor (SCF), fIt3 ligand (FL), IL-6 and granulocyte colony-stimulating factor (G-CSF). About 10% of the cells formed primary colonies, which were individually tested for myeloid and B-lymphoid potentials by reculturing aliquots of the primary colony cells into secondary myeloid and B-lymphoid cultures. One third of the primary colonies proved capable of differentiation into CD19+IgM+ cells, as well as into myeloid lineage cells. RT-PCR analyses revealed that some cells in the primary culture had already matured to express B cell-specific transcripts. Thus, the combination of IL-3, SCF, FL, IL-6 and G-CSF supported the differentiation of CD34+CD38- lymphohematopoietic progenitors toward B cell lineage in addition to myeloid lineages. Screening of cytokines to identify the minimum requirement of cytokines in the primary culture revealed that IL-3 and SCF were essential and that the addition of FL, and to a lesser extent IL-6 or G-CSF, to the combination of IL3 and SCF remarkably enhanced the primary colony formation and the generation of CD19+ cells in the secondary B-lymphoid culture.

Antigens, CD34↗

PubMed2005

New insights into MLL gene rearranged acute leukemias using gene expression profiling: shared pathways, lineage commitment, and partner genes.

Rearrangements of the MLL gene occur in both acute lymphoblastic and acute myeloid leukemias (ALL, AML). This study addressed the global gene expression pattern of these two leukemia subtypes with respect to common deregulated pathways and lineage-associated differences. We analyzed 73 t(11q23)/MLL leukemias in comparison to 290 other acute leukemias and demonstrate that 11q23 leukemias combined are characterized by a common specific gene expression signature. Additionally, in unsupervised and supervised data analysis algorithms, ALL and AML cases with t(11q23) segregate according to the lineage they are derived from, that is, myeloid or lymphoid, respectively. This segregation can be explained by a highly differing transcriptional program. Through the use of novel biological network analyses, essential regulators of early B cell development, PAX5 and EBF, were shown to be associated with a clear B-lineage commitment in lymphoblastic t(11q23)/MLL leukemias. Also, the influence of the different MLL translocation partners on the transcriptional program was directly assessed. Interestingly, gene expression profiling did not reveal a clear distinct pattern associated with one of the analyzed partner genes. Taken together, the identified molecular expression pattern of MLL fusion gene samples and biological networks revealed new insights into the aberrant transcriptional program in 11q23/MLL leukemias.

Acute Disease↗

PubMed2002

Hematopoietic cytokines, transcription factors and lineage commitment.

The past two decades have witnessed significant advances in our understanding of the cellular physiology and molecular regulation of hematopoiesis. At the heart of stem cell self-renewal and lineage commitment decisions lies the relative expression levels of lineage-specific transcription factors. The expression of these transcription factors in early stem cells may be promiscuous and fluctuate, but ultimately comes under the influence of extracellular regulatory signals in the form of hematopoietic cytokines. In this review, we first summarize our current understanding of the phenotypic characterization of hematopoietic stem cells. Next, we describe key known transcription factors which govern stem cell self-renewal and lineage commitment decisions. Finally, we review data concerning the role of specific cytokines in influencing these decisions. From this review, a picture emerges in which stem cell fate decisions are governed by the integrated effects of intrinsic transcription factors and external signaling pathways initiated by regulatory cytokines.

Apoptosis↗

PubMed2005

Selectively frequent expression of CXCR5 enhances resistance to apoptosis in CD8(+)CD34(+) T cells from patients with T-cell-lineage acute lymphocytic leukemia.

We investigated CD4(+)CD34(+), CD8(+)CD34(+), CD4(+)CD34(-), and CD8(+)CD34(-) T cells from cord blood and from typical patients with T-cell-lineage acute lymphocytic leukemia and T-cell-lineage chronic lymphocytic leukemia in terms of expression and functions of CXCR5/CXCL13. We found that CXCR5 was selectively frequently expressed on T-cell-lineage acute (chronic) lymphocytic leukemia (T-ALL) CD8(+)CD34(+) T cells, but not on T-ALL CD4(+)CD34(+), CD4(+)CD34(-), and CD8(+)CD34(-) T cells. CXCR5 was rarely expressed on all types of CD34(+) and CD34(-) CB or T-CLL T cells. CXCL13/B cells attracting chemokine 1 induced significant resistance to TNF-alpha-mediated apoptosis in T-ALL CD8(+)CD34(+) T cells, instead of induction of chemotactic and adhesive responsiveness. A proliferation-inducing ligand expression in T-ALL CD8(+)CD34(+) T cells was upregulated by CXCL13/BCA-1 (B-cell attracting chemokine 1). The CXCR5/CXCL13 pair by means of activation of APRIL (A proliferation-inducing ligand) induced resistance to apoptosis in T-ALL CD8(+)CD34(+) T cells in livin-dependent manner. In this process, cell-cell contact in culture was necessary. Based on our findings, we suggested that there were differential functions of CXCR5/CXCL13 in distinct types of cells. Normal lymphocytes, especially naive B and T cells, utilized CXCR5/CXCL13 for migration, homing, maturation, and cell homeostasis, as well as secondary lymphoid tissue organogenesis. Meanwhile, certain malignant cells took advantages of CXCR5/CXCL13 for infiltration, resistance to apoptosis, and inappropriate proliferation.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Lineage-dependent NF-kappaB activation contributes to the resistance of human macrophages to apoptosis.

Granulocytes and mononuclear phagocytes develop from the same myeloid progenitor cells in the bone marrow via distinct differentiation pathways. Yet, it is known that mature macrophages are more resistant than granulocytes to spontaneous apoptosis in cultures without hematopoietic growth factors. This fact suggests that the development of resistance to apoptosis during myeloid differentiation is differentially regulated by a lineage-dependent mechanism. Using primary cultures of human bone marrow cells, we now report that induction of monocytic differentiation into mature macrophages with M-CSF was correlated with a steady and gradual increase in the levels of X-chromosome-linked inhibitor of apotosis (XIAP) and Bcl-2, while induction of granulocytic differentiation with G-CSF had no significant effects on the expression of these proteins. Consistent with this, NF-kappaB activation is linked to monocytic, but not granulocytic differentiation, while ERK or STAT3 activation is not lineage-dependent. Blockade of NF-kappaB activation in mature macrophages resulted in a marked decrease in the levels of XIAP and Bcl-2, which was accompanied with cell death through an apoptotic mechanism. Thus lineage-dependent activation of NF-kappaB is responsible at least in part for the resistance of mature macrophages to 'spontaneous' apoptosis in vitro.

Apoptosis↗

PubMed2001

RGS18 is a myeloerythroid lineage-specific regulator of G-protein-signalling molecule highly expressed in megakaryocytes.

Myelopoiesis and lymphopoiesis are controlled by haematopoietic growth factors, including cytokines, and chemokines that bind to G-protein-coupled receptors (GPCRs). Regulators of G-protein signalling (RGSs) are a protein family that can act as GTPase-activating proteins for G(alphai)- and G(alphaq)-class proteins. We have identified a new member of the R4 subfamily of RGS proteins, RGS18. RGS18 contains clusters of hydrophobic and basic residues, which are characteristic of an amphipathic helix within its first 33 amino acids. RGS18 mRNA was most highly abundant in megakaryocytes, and was also detected specifically in haematopoietic progenitor and myeloerythroid lineage cells. RGS18 mRNA was not detected in cells of the lymphoid lineage. RGS18 was also highly expressed in mouse embryonic 15-day livers, livers being the principal organ for haematopoiesis at this stage of fetal development. RGS1, RGS2 and RGS16, other members of the R4 subfamily, were expressed in distinct progenitor and mature myeloerythroid and lymphoid lineage blood cells. RGS18 was shown to interact specifically with the G(alphai-3) subunit in membranes from K562 cells. Furthermore, overexpression of RGS18 inhibited mitogen-activated-protein kinase activation in HEK-293/chemokine receptor 2 cells treated with monocyte chemotactic protein-1. In yeast cells, RGS18 overexpression complemented a pheromone-sensitive phenotype caused by mutations in the endogeneous yeast RGS gene, SST2. These data demonstrated that RGS18 was expressed most highly in megakaryocytes, and can modulate GPCR pathways in both mammalian and yeast cells in vitro. Hence RGS18 might have an important role in the regulation of megakaryocyte differentiation and chemotaxis.

Amino Acid Sequence↗