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PubMed1998

Deletion of a recombined Ig heavy chain transgene in B-lineage cells of transgenic mice.

Fully recombined transgenes are stable in their transmission in the germline of transgenic mice, in common with the endogenous genetic complement of most mammalian somatic tissues, including the genes for lymphoid Ag receptors somatically generated from germline minigenes. There have, however, been isolated reports of unusual low frequency transgene losses in various transgenic mice. Here we show, using Southern blots and PCR-based assays, that plasmablast hybridomas and B cells from three independently derived founder lines of transgenic mice bearing a recombined heavy chain Ig transgene we have been studying show a significant net loss of transgene copies. This loss is more marked in the B cells expressing endogenous heavy chains than in those expressing transgenic heavy chains. We have also examined cells of the B lineage in the bone marrow, and a small degree of deletion is also evident in CD19+ CD23- IgM- immature B-lineage cells. As greater deletion is observed in mature B cells, it is possible that the deletion process either continues into B cell maturity and/or provides a selective advantage. We have investigated the relationship between transgene expression and deletion, and we find that while thymocytes in these mice express the transgene well, T cell hybridomas derived from transgenic thymus do not show any loss of the transgene. Thus, a recombined Ig heavy chain transgene prominently undergoes somatic deletion in B-lineage cells independent of its insertion site or expression. This transgenic instability is significant to the analysis of genomic stability as well as to the design of gene therapy strategies.

Animals↗

PubMed1999

Threshold of pre-T-cell-receptor surface expression is associated with alphabeta T-cell lineage commitment.

BACKGROUND: The development of immature thymocytes is regulated by the pre-T-cell receptor (pre-TCR). The pre-TCR is involved in several developmental processes including rescuing cells from programmed cell death, allelic exclusion and alphabeta versus gammadelta T-cell lineage commitment. A major issue is how the pre-TCR functions to integrate these processes in developing thymocytes. RESULTS: We have used a sensitive immunofluorescence technique to reveal the surface-expression profile of the pre-TCR on immature thymocyte subsets. We show that early pre-T cells (CD25(+)CD44(-)) can be subdivided on the basis of the level of surface pre-TCR expression. Detectable surface pre-TCR expression identified a rapidly cycling population of early pre-T cells which had successfully undergone beta-selection and been rescued from programmed cell death. Late pre-T cells (CD25(-)CD44(-)), which had traversed the beta-selection checkpoint, expressed surprisingly heterogeneous surface levels of the pre-TCR: high levels of surface pre-TCR expression were associated with commitment to the alphabeta T-cell lineage, whereas late pre-T cells with lower levels of surface pre-TCR could develop along both the alphabeta or gammadelta T-cell lineages. CONCLUSIONS: These data demonstrate that the surface expression of the pre-TCR can be used to reveal newly identified stages of T-cell development and to provide insights into alphabeta T-cell lineage commitment. They show that, although pre-TCR expression does not act as a developmental switch per se, its level of surface expression on late pre-T cells predicts their developmental potential.

Animals↗

PubMed2001

Characterization of Mpl mutants using primary megakaryocyte-lineage cells from mpl(-/-) mice: a new system for Mpl structure-function studies.

Mpl is the thrombopoietin (TPO) receptor. The current molecular understanding of how Mpl activation stimulates proliferation of megakaryocyte-lineage cells is based largely on the engineered expression of Mpl in nonmegakaryocyte-lineage cell lines. However, the relevance of these findings to Mpl signaling in primary megakaryocyte-lineage cells remains largely unknown. Therefore, a system was developed to study Mpl function in primary mpl(-/-) megakaryocyte-lineage cells. Expressing avian retroviral receptors on the surfaces of mammalian cells overcomes their natural block to avian retroviral infection; 815 bp of human GPIIb regulatory sequence was used to generate transgenic mice with megakaryocyte-lineage expression of the subgroup A avian leukosis virus receptor, TVA. Avian retroviral infection of unfractionated bone marrow from these mice is restricted to megakaryocyte-lineage cells. The transgenic mice were crossed to an mpl(-/-) background generating GPIIb-tva+mpl(-/-) mice. By using avian retroviruses to express wild-type or mutant Mpl on the surfaces of primary megakaryocyte-lineage cells, it was demonstrated that (1) the 10 membrane-proximal, cytoplasmic amino acids of Mpl are required for TPO-induced proliferation; (2) Y582F mutation confers a proliferative advantage over wild-type Mpl and imparts a constitutive anti-apoptotic signal; (3) truncating the 50 C-terminal Mpl amino acids reduces but does not eliminate TPO-induced mitogen-activated protein kinase activation, yet it does not alter the synergistic effect of stem cell factor on TPO-induced proliferation; and (4) TPO-induced proliferation of early, primary megakaryocyte-lineage cells does not require Stat-5 phosphorylation. The system reported provides an improved approach for Mpl structure-function studies, and the method can be applied to any hematopoietic lineage.

Amino Acid Sequence↗

PubMed2026

LAML-Pro: Joint Maximum Likelihood Inference of Cell Genotypes and Cell Lineage Trees.

MOTIVATION: Recent dynamic lineage tracing technologies use genome editing to induce heritable mutations, or edits, that accumulate across successive cell divisions. These edits are measured using single-cell sequencing or imaging, providing data to reconstruct cell lineages at single-cell resolution. Current computational approaches to infer cell lineage trees, or phylogenies, from these data perform two separate steps: (1) Identify each cell's edits (genotype) from the raw sequencing or imaging data; (2) Infer a cell lineage tree from the cell genotypes. However, genotyping cells is an inexact process and genotype errors can yield an inaccurate lineage tree. For example, using fluorescence based-imaging to measure edits results in a high fraction (≈ 25-50%) of uncertain or erroneous genotypes. RESULTS: We introduce Lineage Analysis via Maximum Likelihood with PRobabilistic Observations (LAML-Pro), an algorithm that jointly infers cell genotypes and a cell lineage tree. LAML-Pro is based on the Probabilistic Mixed-type Missing Observation (PMMO) model, which we derive to describe both the genome editing and genotype observation processes. LAML-Pro constructs lineage trees from thousands of cells in under an hour by leveraging the sparsity of transitions under the PMMO model. On simulated data, we demonstrate that LAML-Pro corrects genotype errors and infers substantially more accurate trees than existing methods which are vulnerable to genotype errors. Applied to data from two recent imaging-based lineage tracing systems, LAML-Pro reduces genotype errors by 5-fold and produces more spatially coherent lineage trees compared to existing methods. AVAILABILITY AND IMPLEMENTATION: LAML-Pro is freely available at: github.com/raphael-group/LAML-Pro.

Journal Article↗

PubMed1998

Role of cell adhesion in the specification of pigment cell lineage in embryos of the sea urchin, Hemicentrotus pulcherrimus.

To clarify the role of cell adhesion in the specification of pigment cell lineage in sea urchin embryos, cell contacts were inhibited by Ca2+-free artificial seawater (ASW) treatment, and the number of differentiated pigment cells was examined by the method devised for the present study. Obtained results showed that inhibition of cell contacts during mid-to-late blastula stage greatly affects the number of pigment cells. Treatment with Ca2+-free ASW during 7.5-10.5 h of development drastically decreased the number of pigment cells, indicating that cell adhesion during this period is indispensable for the specification of pigment cell lineage. On the other hand, the number of pigment cells were increased by the treatment during 9.5 12.5 h of development. It was suggested that this increase was caused by excess divisions of the precursor cells, that is, the division schedule of the precursor cells was altered by inhibition of cell contacts at this period. Interestingly, the number of pigment cells was a multiple of four in a majority of embryos in which pigment cells were drastically decreased in number. These findings suggest that the founder blastomeres of the pigment cell lineage are specified during 7-10 h of development, and that these blastomeres divide twice before they differentiate into pigment cells.

Animals↗

PubMed1985

Interspecific cell markers and cell lineage in birds.

A cell marking technique based on the structural differences existing between the interphase nucleus in two closely related species of birds, the chick and the Japanese quail, is described. In all embryonic and adult cell types of the quail, a large mass of heterochromatin is associated with the nucleolus making quail and chick cells easy to identify at the single cell level after application of any DNA-specific staining procedure and also at the electron microscope level. This method has been largely used to construct chimeras in ovo and to study dynamic processes such as cell migrations or cell lineage segregation during ontogeny. Recently monoclonal antibodies specific for either quail or chick antigenic determinants (for example, class II MHC antigens) have been prepared, increasing the interest of the quail-chick chimera system as an experimental model.

Animals↗

PubMed1989

Thymic stroma is required for the development of human T cell lineages in vitro.

Development of the T cell lineage is characterized by the homing of hematopoietic precursors to thymus, followed by their acquisition of receptors for antigen. T cell receptors are alpha beta or gamma delta heterodimers associated with CD3 (TCR-CD3). Very early T cell precursors in humans have been characterized as CD7+ 45+ cells which lack the T cell differentiation antigens CD1, CD2, CD3, CD4, and CD8. A phenotypically equivalent early thymocyte population also occurs in postnatal life, and we have previously shown that interleukin 2 (IL2) promotes the development in vitro of both the alpha beta and the gamma delta T cells from these early thymocytes. Here we have analyzed the requirements of the induction of the IL2 pathway in early thymocytes, and their developmental potential. We show that: (i) thymic stromal cells, which are present in thymocyte suspensions, are necessary to induce the IL2 pathway and the development of alpha beta or gamma delta T cell lineages from early thymocytes in vitro; and (ii) when removed from the in vivo environment, early thymocytes can develop in vitro into TCR-CD3- cells of the natural killer (NK) lineage. We conclude that CD7+ 45+, CD1-2-3-4-8- early thymocytes are multipotential progenitors that, at least, have the capacity to develop into alpha beta or gamma delta T cell and NK lineages. The analysis of the mechanisms of generation and selection of human T and NK cell diversity, not feasible in bone marrow cultures, is now possible.

Antigens, Differentiation, T-Lymphocyte↗

PubMed1976

"Early T cells" and "late T cells"; suggestive evidence for two T cell lineages with separate developmental pathways.

Peripheral lymphocytes from mice have been analyzed by a combination of cell electrophoresis and size distribution analysis and the data have been processed with a computer into two-dimensional distribution patterns (fingerprints). The fingerprints of lymph node cells revealed the existence of at least three major classes of small lymphocytes. Cells with similar physical properties were found in the spleen and thoracic duct lymph. The data also allowed calculation of the quantitative ratios of the three cell types. In the normal mouse, the two electrophoretically faster cell classes represent essentially two subclasses of T cells. The quantitative ratios are here always in agreement with the known percentages of B and T cells. Lethally irradiated mice that have been reconstituted with syngeneic bone marrow or fetal liver cells often lack one of the T cell subclasses. This has two important implications. 1) It indicates that the widely used syngeneic or allogeneic bone marrow chimeras may be incomplete in respect to their T cell repertoire and that experiments with these models should be interpreted with caution. 2) The deficiency was found to correlate strictly with a deficiency in a physically defined subset of small cortical thymocytes that has been described previously. This correlation suggests strongly that the fast peripheral T cells and the "early small cortical thymocytes" represent two developmental stages of a distinct cell lineage ("early T cell lineage"), while the thymic pool of "late small cortical thymocytes" gives rise to electrophoretically slow peripheral T cells, which may be called "late T cells). The possibility that both T cell lineages are derived from different classes of prethymic stem cells in the reconstitlting stem cell preparation is discussed. The proportion of "early T cells" in the lymph nodes decreases with age. The ratio of "late" and "early T cells" is similar in the spleen and in the lymph nodes, and both cell classes contain a significant proportion of cells that are not affected by the early effects of adult thymectomy. Thus, they do not correspond to T1 and T2 cells.

Age Factors↗

PubMed1985

Cell lineage of zebrafish blastomeres. III. Clonal analyses of the blastula and gastrula stages.

Aspects of the early lineages of blastomeres in the embryo of the zebrafish, Brachydanio rerio have been described. Because of the optical clarity of the embryo, lineages of selected cells can be followed directly by microscopy through many cell divisions. Also, it is shown here that the fluorescent molecules fluorescein-dextran and rhodamine-horseradish peroxidase can be used as cell lineage tracers, marking the clonal progeny of founding blastomeres. The labeled cells can be easily visualized in the live embryo, and utilizing a sensitive video camera to amplify fluorescence, the same clone may be examined repeatedly while the cells divide and migrate. Cells that descend from a single blastomere remain closely associated together through the end of the blastula stage. At the time when epiboly begins (early gastrula) cells in the labeled clone scatter and become dispersed among unlabeled cells. It has been observed that there is no invariant mapping of the embryo's midline (determined by the position of the embryonic shield in the gastrula) with respect to the early planes of cleavage. This finding shows that in the zebrafish the region of the embryo that a cell will occupy is not specified by the cell's early ancestory.

Animals↗

PubMed2000

Epithelial stem cell repertoire in the gut: clues to the origin of cell lineages, proliferative units and cancer.

Gastrointestinal stem cells are shown to be pluripotential and to give rise to all cell lineages in the epithelium. After damage, gut stem cells produce reparative cell lineages that produce a wide range of peptides with important actions on cell proliferation and migration, and promote regeneration and healing. Increase in stem cell number is considered to induce crypt fission, and lead to increases in the number of crypts, even in the adult; it is also the mode of spread of mutated clones in the colorectal mucosa. Stem cell repertoire is defined by both intrinsic programming of the stem cell itself, but signalling from the mesenchyme is also vitally important for defining both stem cell progeny and proliferation. Carcinogenesis in the colon occurs through sequential mutations, possibly occurring in a single cell. A case is made for this being the stem cell, but recent studies indicate that several stem cells may need to be so involved, since early lesions appear to be polyclonal in derivation.

Animals↗

PubMed2002

Multiple hematopoietic cell lineages develop in vivo from transplanted Pax5-deficient pre-B I-cell clones.

Pax5-deficient pre-B I-cell clones, transplanted into natural killer (NK)-cell-deficient RAG2(-/-) IL-2Rgamma(-/-) hosts, populate the NK-cell compartment with functional NK cells. NK-cell generation from Pax5(-/-) pre-B I cells is also observed in NK-cell-proficient Balb/c RAG2(-/-) hosts. In the same Balb/c RAG2(-/-) hosts, Pax5(-/-) pre-B I-cell clones not only populate the pre-B I-cell compartment and fill the deficient T-cell-lineage compartment in the thymus and the periphery of all hosts, as shown before, they also generate CD8alpha(-) and CD8alpha(+) dendritic cells (DCs), macrophages, and granulocytes in vivo in approximately half the hosts. In some recipients, practically all the mature myeloid cells are of Pax5(-/-) origin, indicating the effectiveness by which Pax5(-/-) pre-B I cells can compete with endogenous myeloid precursors. In a smaller percentage of hosts, the generation of Pax5(-/-) pre-B I-cell-derived erythrocytes is observed 4 to 6 months after transplantation. The results indicate that Pax5(-/-) pre-B I cells can develop in vivo in hosts that have undergone transplantation to erythroid, myeloid, and lymphoid cell lineages. Hence, the Pax5(-/-) mutation introduces an unusual instability of differentiation in pre-B I cells so that they appear to dedifferentiate as far back as the pluripotent hematopoietic stem cell.

Animals↗

PubMed1995

B-cell lineage confers a favorable outcome among children and adolescents with large-cell lymphoma: a Pediatric Oncology Group study.

PURPOSE: The goal of this study was to assess the immunophenotype of uniformly treated cases of pediatric large-cell non-Hodgkin's lymphoma (NHL) to determine the prognostic importance of B-cell and T-cell lineages and of CD30 positivity. PATIENTS AND METHODS: Sixty-nine patients were analyzed by immunochemistry. All patients were classified histologically, staged in a uniform manner, and treated according to one of two protocols for localized (stage I and II) NHL or advanced (stage III and IV) large-cell NHL. Antibodies included anti-CD45, CD20, CD45Ra, MB-2 (not clustered), CD3, CD45Ro, CD43, CD15, CD30, and CD68. Statistical analysis used the exact conditional chi 2 and Kruskall-Wallace tests for clinical features and the log-rank test to evaluate event-free survival (EFS). RESULTS: Immunophenotypic results demonstrated 25 B-cell, 23 T-cell, and 21 indeterminate lineage. Twenty-seven patients expressed CD30 (17 T-cell and 10 indeterminate lineage), and of these, 22 showed histology of anaplastic large-cell lymphoma (ALCL). B-cell patients were older (P = .018) and showed more favorable survival than patients with T-cell or indeterminate lineage (96% EFS at 3 years, 96% v 67% and 74%, B v T and indeterminate lineage [P = .027]). B-cell lineage was seen more frequently in limited-stage patients, but was also associated with favorable survival when stratified for stage (P = .036). CD30 expression (P = .96) and ALCL histology (P = .90) did not show significant associations with survival. CONCLUSION: We conclude that among pediatric large-cell lymphomas, B-cell lineage is proportionately less frequent than in adults and CD30 antigen-expressing lymphomas are frequent among patients with T-cell and indeterminate lineage. B-cell phenotype tends to occur in older children and is associated with superior survival.

Adolescent↗

PubMed2003

Growth factor independence-1B expression leads to defects in T cell activation, IL-7 receptor alpha expression, and T cell lineage commitment.

T cell differentiation in the thymus is dependent upon signaling through the TCR and is characterized by the resulting changes in expression patterns of CD4 and CD8 surface coreceptor molecules. Although recent studies have characterized the effects of proximal TCR signaling on T cell differentiation, the downstream integration of these signals remains largely unknown. The growth factor independence-1 (GFI1) and GFI1B transcriptional repressors may regulate cytokine signaling pathways to affect lymphocyte growth and survival. In this study, we show that Gfi1 expression is induced upon induction of the T cell program. Gfi1B expression is low and dynamic during T cell development, but is terminated in mature thymocytes. Transgenic expression of GFI1 and GFI1B in T cells allowed us to determine the functional consequences of constitutive expression. GFI1 potentiates response to TCR stimulation and IL-2, whereas GFI1B-transgenic T cells are defective in T cell activation. Moreover, GFI1B-transgenic thymocytes display reduced expression of the late-activation marker IL-7R alpha, and a decrease in CD4(-)8(+) single-positive T cells that can be mitigated by transgenic expression of BCL2 or GFI1. These data show that GFI1 and GFI1B are functionally unique, and implicate a role for GFI1 in the integration of activation and survival signals.

Animals↗

PubMed1998

Genetic control of extraembryonic cell lineages studied with tetraploid<-->diploid chimeric concepti.

The first differentiation event during mammalian embryogenesis is the commitment of blastomeres to the trophectoderm cell lineage. Much remains to be learned about the genetic control of this first cell lineage commitment and the subsequent events underlying the differentiation of all extraembryonic cell lineages. Because of the unique features of intrauterine embryonic development, the study of embryogenesis in lower organisms has shed little light on mammalian extraembryonic lineage differentiation. Rather, two major methods in developmental genetics have contributed to our understanding of genetic control of extraembryonic cell lineages. First, abnormalities in extraembryonic tissues have been described in many genetically engineered mutant mouse lines. However, the histological description of these abnormalities does not demonstrate whether the observed defect is the primary cause of embryonic lethality. Second, tetraploid<-->diploid aggregation experiments have been used to generate chimeric concepti with distinct genotypes in the extraembryonic tissues and the embryo proper. This experimental approach has provided the definitive demonstration of the crucial role of several transcription factors, growth factors and cytoskeleton proteins in extraembryonic tissue formation. The present review summarizes the origin of tetraploid<-->diploid aggregation experiments and it usefulness for the study the genetic control of extraembryonic cell lineages.

Animals↗

PubMed2003

Notch-associated gene expression in embryonic and adult taste papillae and taste buds suggests a role in taste cell lineage decisions.

The Notch signaling pathway is involved in cell fate decisions during development. To explore the role of this signaling cascade in the taste system, we investigated the expression patterns of Notch signaling genes in fetal and adult mouse tongues using in situ hybridization. Three of the four murine Notch receptors, their ligands, Delta-like 1 (Dll-1), Jagged1, and Jagged2, as well as three transcription factors, Hes1, Hes6, and Mash1, are expressed in the embryonic taste epithelium. Expression is first detected in the circumvallate papilla at embryonic day E14.5, when Notch1, Jagged1, and Jagged2 are expressed broadly in the papilla and general lingual epithelium. In contrast, Mash1 and Hes6 are restricted to only a few epithelial cells in the apical region of the developing papilla. By E18.5, many of the genes now exhibit a bimodal expression pattern in the papillary epithelium: apically and dorsally they are expressed in sparse clusters of cells, while more ventrally expression typically occurs throughout the lower regions of the trenches. The extent of papilla innervation was compared with Mash1 and Hes6 expression. At E14.5, when Hes6 and Mash1 are already expressed in small numbers of epithelial cells, PGP9.5 immunoreactive fibers have not yet invaded the epithelium, consistent with the specification of taste bud primordia prior to nerve contact. All of the genes examined (except Notch2) are also expressed in subsets of cells within circumvallate taste buds in adult mice, although Notch1 is restricted to basal cells adjacent to taste buds. The onset of embryonic Notch associated gene expression after the morphological differentiation of the circumvallate papilla argues that this signaling cascade may specify taste receptor cell lineages within an already specified taste papilla. Similarly, Notch gene expression in adult taste buds suggests continued roles in cell lineage determination and cell turnover.

Animals↗

PubMed1989

CD2 expression in murine B cell lineage.

CD2 expression in murine B cell lineage was examined by flow cytometric and immunoprecipitation studies with anti-murine CD2 mAb and by Northern blot analysis. Cell surface expression of CD2 was demonstrated on all peripheral B cells and cell lines of B lineage. The murine CD2 transcript of 1.3 kb was detected in these B cells. An identical glycoprotein of 55-67 KD was precipitated from the lysates of surface radioiodinated thymocytes, splenic T and B cells, T and B lymphomas, RL male 1 and BCL-1, with anti-murine CD2 mAb. The majority of bone marrow B cells and a half of pre-B cells were found to be positive for CD2 expression. These results indicate that murine CD2 is expressed on B cell lineage at certain differentiation stages.

Animals↗

PubMed2004

Plasticity of human adipose lineage cells toward endothelial cells: physiological and therapeutic perspectives.

BACKGROUND: Adipose tissue development and remodeling are closely associated with the growth of vascular network. We hypothesized that adipose tissue may contain progenitor cells with angiogenic potential and that therapy based on adipose tissue-derived progenitor cells administration may constitute a promising cell therapy in patients with ischemic disease. METHODS AND RESULTS: In mice, cultured stromal-vascular fraction (SVF) cells from adipose tissue have a great proangiogenic potential, comparable to that of bone marrow mononuclear cells in the mouse ischemic hindlimb model. Similarly, cultured human SVF cells differentiate into endothelial cells, incorporate into vessels, and promote both postischemic neovascularization in nude mice and vessel-like structure formation in Matrigel plug. In vitro, these cells represent a homogeneous population of CD34- and CD13-positive cells, which can spontaneously express the endothelial cell markers CD31 and von Willebrand factor when cultured in semisolid medium. Interestingly, dedifferentiated mature human adipocytes have the potential to rapidly acquire the endothelial phenotype in vitro and to promote neovascularization in ischemic tissue and vessel-like structure formation in Matrigel plug, suggesting that cells of endothelial and adipocyte phenotypes may have a common precursor. CONCLUSIONS: This study demonstrates, for the first time, that adipocytes and endothelial cells have a common progenitor. Such adipose lineage cells participate in vascular-like structure formation in Matrigel plug and enhance the neovascularization reaction in ischemic tissue. These results also highlight the concept that adipose lineage cells represent a suitable new cell source for therapeutic angiogenesis in ischemic disease.

Adipocytes↗

PubMed2006

Diversification of T-helper-cell lineages: finding the family root of IL-17-producing cells.

CD4+ T helper 1 (T(H)1) and T(H)2 cells have long been regarded as two sides of a coin in terms of adaptive immune responses. However, as I discuss here, this concept needs to be reconsidered. In particular, recent data indicate that interleukin-17 (IL-17) is produced by T(H) cells that are distinct from the traditional T(H)1- and T(H)2-cell subsets. Furthermore, the generation of these IL-17-producing CD4+ T cells from naive precursors during immune responses is not dependent on the cytokines and transcription factors that mediate T(H)1- and T(H)2-cell development. Given that IL-17 has crucial roles in regulating tissue inflammation and the development of disease in several animal models of autoimmunity, I propose that IL-17-producing CD4+ T cells represent a distinct inflammatory T(H)-cell lineage.

Animals↗