The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform

Irving L Weissman - One of the best experts on this subject based on the ideXlab platform.

  • clonal level lineage commitment pathways of Hematopoietic Stem Cells in vivo
    bioRxiv, 2018
    Co-Authors: Agnieszka Czechowicz, Jun Seita, Du Jiang, Irving L Weissman
    Abstract:

    While Hematopoietic Stem Cells (HSCs) have been extensively studied at the population level, little is known about the lineage commitment of individual clones. Here, we provide comprehensive maps of in vivo HSC clonal development in mice under homeostasis and after depletion of the endogenous Hematopoietic syStem. Under homeostasis, all donor-derived HSC clones regenerate blood homogeneously throughout all measured stages and lineages of hematopoiesis. In contrast, after the Hematopoietic syStem has been depleted by irradiation or by an anti-ckit antibody, only a small fraction of donor-derived HSC clones differentiates while dominantly expanding and exhibiting lineage bias. We identified the cellular origins of clonal dominance and lineage bias, and uncovered the lineage commitment pathways that lead HSC clones to differential blood production. This study reveals surprising alterations in HSC regulation by irradiation, and identifies the key hematopoiesis stages that may be manipulated to control blood production and balance.

  • clonal evolution of preleukemic Hematopoietic Stem Cells precedes human acute myeloid leukemia
    Science Translational Medicine, 2012
    Co-Authors: Max Jan, Irving L Weissman, Thomas M Snyder, Ryan M Corceszimmerman, Paresh Vyas, Stephen R Quake, Ravindra Majeti
    Abstract:

    Given that most bone marrow Cells are short-lived, the accumulation of multiple leukemogenic mutations in a single clonal lineage has been difficult to explain. We propose that serial acquisition of mutations occurs in self-renewing Hematopoietic Stem Cells (HSCs). We investigated this model through genomic analysis of HSCs from six patients with de novo acute myeloid leukemia (AML). Using exome sequencing, we identified mutations present in individual AML patients harboring the FLT3-ITD (internal tandem duplication) mutation. We then screened the residual HSCs and detected some of these mutations including mutations in the NPM1, TET2, and SMC1A genes. Finally, through single-cell analysis, we determined that a clonal progression of multiple mutations occurred in the HSCs of some AML patients. These preleukemic HSCs suggest the clonal evolution of AML genomes from founder mutations, revealing a potential mechanism contributing to relapse. Such preleukemic HSCs may constitute a cellular reservoir that should be targeted therapeutically for more durable remissions.

  • niche recycling through division independent egress of Hematopoietic Stem Cells
    Journal of Experimental Medicine, 2009
    Co-Authors: Deepta Bhattacharya, Derrick J Rossi, David Bryder, Agnieszka Czechowicz, A Lisa G Ooi, Irving L Weissman
    Abstract:

    Hematopoietic Stem Cells (HSCs) are thought to reside in discrete niches through stable adhesion, yet previous studies have suggested that host HSCs can be replaced by transplanted donor HSCs, even in the absence of cytoreductive conditioning. To explain this apparent paradox, we calculated, through cell surface phenotyping and transplantation of unfractionated blood, that ∼1–5% of the total pool of HSCs enters into the circulation each day. Bromodeoxyuridine (BrdU) feeding experiments demonstrated that HSCs in the peripheral blood incorporate BrdU at the same rate as do HSCs in the bone marrow, suggesting that egress from the bone marrow to the blood can occur without cell division and can leave behind vacant HSC niches. Consistent with this, repetitive daily transplantations of small numbers of HSCs administered as new niches became available over the course of 7 d led to significantly higher levels of engraftment than did large, single-bolus transplantations of the same total number of HSCs. These data provide insight as to how HSC replacement can occur despite the residence of endogenous HSCs in niches, and suggest therapeutic interventions that capitalize upon physiological HSC egress.

  • Hematopoietic Stem Cells and the aging Hematopoietic syStem
    Seminars in Hematology, 2008
    Co-Authors: Roi Gazit, Irving L Weissman, Derrick J Rossi
    Abstract:

    The etiology of the age-associated pathophysiological changes of the Hematopoietic syStem including the onset of anemia, diminished adaptive immune competence, and myelogenous disease development are underwritten by the loss of normal homeostatic control. As tissue and organ homeostasis in adults is primarily mediated by the activity of Stem and progenitor Cells, it has been suggested that the imbalances accompanying aging of the Hematopoietic syStem may Stem from alterations in the prevalence and/or functional capacity of Hematopoietic Stem Cells (HSCs) and progenitors. In this review, we examine evidence implicating a role for Stem Cells in the aging of the Hematopoietic syStem, and focus on the mechanisms suggested to contribute to Stem cell aging.

  • Hematopoietic Stem Cells: the paradigmatic tissue-specific Stem cell
    American Journal of Pathology, 2006
    Co-Authors: David Bryder, Derrick J Rossi, Irving L Weissman
    Abstract:

    The recent prospective isolation of a wide variety of somatically derived Stem Cells has affirmed the notion that homeostatic maintenance of most tissues and organs is mediated by tissue-specific Stem and progenitor Cells and fueled enthusiasm for the use of such Cells in strategies aimed at repairing or replacing damaged, diseased, or genetically deficient tissues and organs. Hematopoietic Stem Cells (HSCs) are arguably the most well-characterized tissue-specific Stem cell, with decades of basic research and clinical application providing not only a profound understanding of the principles of Stem cell biology, but also of its potential pitfalls. It is our belief that emerging Stem cell fields can benefit greatly from an understanding of the lessons learned from the study of HSCs. In this review we discuss some general concepts regarding Stem cell biology learned from the study of HSCs with a highlight on recent work pertaining to emerging topics of interest for Stem cell biology.

Derrick J Rossi - One of the best experts on this subject based on the ideXlab platform.

  • transcription factor mediated reprogramming toward Hematopoietic Stem Cells
    The EMBO Journal, 2015
    Co-Authors: Wataru Ebina, Derrick J Rossi
    Abstract:

    De novo generation of human Hematopoietic Stem Cells (HSCs) from renewable cell types has been a long sought-after but elusive goal in regenerative medicine. Paralleling efforts to guide pluripotent Stem cell differentiation by manipulating developmental cues, substantial progress has been made recently toward HSC generation via combinatorial transcription factor (TF)-mediated fate conversion, a paradigm established by Yamanaka's induction of pluripotency in somatic Cells by mere four TFs. This review will integrate the recently reported strategies to directly convert a variety of starting cell types toward HSCs in the context of Hematopoietic transcriptional regulation and discuss how these findings could be further developed toward the ultimate generation of therapeutic human HSCs.

  • niche recycling through division independent egress of Hematopoietic Stem Cells
    Journal of Experimental Medicine, 2009
    Co-Authors: Deepta Bhattacharya, Derrick J Rossi, David Bryder, Agnieszka Czechowicz, A Lisa G Ooi, Irving L Weissman
    Abstract:

    Hematopoietic Stem Cells (HSCs) are thought to reside in discrete niches through stable adhesion, yet previous studies have suggested that host HSCs can be replaced by transplanted donor HSCs, even in the absence of cytoreductive conditioning. To explain this apparent paradox, we calculated, through cell surface phenotyping and transplantation of unfractionated blood, that ∼1–5% of the total pool of HSCs enters into the circulation each day. Bromodeoxyuridine (BrdU) feeding experiments demonstrated that HSCs in the peripheral blood incorporate BrdU at the same rate as do HSCs in the bone marrow, suggesting that egress from the bone marrow to the blood can occur without cell division and can leave behind vacant HSC niches. Consistent with this, repetitive daily transplantations of small numbers of HSCs administered as new niches became available over the course of 7 d led to significantly higher levels of engraftment than did large, single-bolus transplantations of the same total number of HSCs. These data provide insight as to how HSC replacement can occur despite the residence of endogenous HSCs in niches, and suggest therapeutic interventions that capitalize upon physiological HSC egress.

  • Hematopoietic Stem Cells and the aging Hematopoietic syStem
    Seminars in Hematology, 2008
    Co-Authors: Roi Gazit, Irving L Weissman, Derrick J Rossi
    Abstract:

    The etiology of the age-associated pathophysiological changes of the Hematopoietic syStem including the onset of anemia, diminished adaptive immune competence, and myelogenous disease development are underwritten by the loss of normal homeostatic control. As tissue and organ homeostasis in adults is primarily mediated by the activity of Stem and progenitor Cells, it has been suggested that the imbalances accompanying aging of the Hematopoietic syStem may Stem from alterations in the prevalence and/or functional capacity of Hematopoietic Stem Cells (HSCs) and progenitors. In this review, we examine evidence implicating a role for Stem Cells in the aging of the Hematopoietic syStem, and focus on the mechanisms suggested to contribute to Stem cell aging.

  • Hematopoietic Stem Cells: the paradigmatic tissue-specific Stem cell
    American Journal of Pathology, 2006
    Co-Authors: David Bryder, Derrick J Rossi, Irving L Weissman
    Abstract:

    The recent prospective isolation of a wide variety of somatically derived Stem Cells has affirmed the notion that homeostatic maintenance of most tissues and organs is mediated by tissue-specific Stem and progenitor Cells and fueled enthusiasm for the use of such Cells in strategies aimed at repairing or replacing damaged, diseased, or genetically deficient tissues and organs. Hematopoietic Stem Cells (HSCs) are arguably the most well-characterized tissue-specific Stem cell, with decades of basic research and clinical application providing not only a profound understanding of the principles of Stem cell biology, but also of its potential pitfalls. It is our belief that emerging Stem cell fields can benefit greatly from an understanding of the lessons learned from the study of HSCs. In this review we discuss some general concepts regarding Stem cell biology learned from the study of HSCs with a highlight on recent work pertaining to emerging topics of interest for Stem cell biology.

  • biological perspectives Hematopoietic Stem Cells the paradigmatic tissue specific Stem cell
    2006
    Co-Authors: David Bryder, Derrick J Rossi, Irving L Weissman
    Abstract:

    The recent prospective isolation of a wide variety of somatically derived Stem Cells has affirmed the notion that homeostatic maintenance of most tissues and organs is mediated by tissue-specific Stem and progenitor Cells and fueled enthusiasm for the use of such Cells in strategies aimed at repairing or replacing damaged, diseased, or genetically deficient tissues and organs. Hematopoietic Stem Cells (HSCs) are arguably the most well-characterized tissue-specific Stem cell , with decades of basic research and clinical application providing not only a profound understanding of the principles of Stem cell biology, but also of its potential pitfalls. It is our belief that emerging Stem cell fields can benefit greatly from an understanding of the lessons learned from the study of HSCs. In this review we discuss some general concepts regarding Stem cell biology learned from the study of HSCs with a highlight on recent work pertaining to emerging topics of interest for Stem cell biology. (Am J Pathol 2006, 169:338–346; DOI: 10.2353/ajpath.2006.060312)

Camille Sindhu - One of the best experts on this subject based on the ideXlab platform.

  • gene correction for scid x1 in long term Hematopoietic Stem Cells
    Nature Communications, 2019
    Co-Authors: Mara Paveldinu, Volker Wiebking, Beruh T Dejene, Waracharee Srifa, Sruthi Mantri, Carmencita E Nicolas, Eric J Kildebeck, Niraj Punjya, Camille Sindhu
    Abstract:

    Gene correction in human long-term Hematopoietic Stem Cells (LT-HSCs) could be an effective therapy for monogenic diseases of the blood and immune syStem. Here we describe an approach for X-linked sSevere cCombined iImmunodeficiency (SCID-X1) using targeted integration of a cDNA into the endogenous start codon to functionally correct disease-causing mutations throughout the gene. Using a CRISPR-Cas9/AAV6 based strategy, we achieve up to 20% targeted integration frequencies in LT-HSCs. As measures of the lack of toxicity we observe no evidence of abnormal hematopoiesis following transplantation and no evidence of off-target mutations using a high-fidelity Cas9 as a ribonucleoprotein complex. We achieve high levels of targeting frequencies (median 45%) in CD34+ HSPCs from six SCID-X1 patients and demonstrate rescue of lymphopoietic defect in a patient derived HSPC population in vitro and in vivo. In sum, our study provides specificity, toxicity and efficacy data supportive of clinical development of genome editing to treat SCID-Xl.

  • gene correction for scid x1 in long term Hematopoietic Stem Cells
    bioRxiv, 2018
    Co-Authors: Mara Paveldinu, Volker Wiebking, Beruh T Dejene, Waracharee Srifa, Sruthi Mantri, Carmencita E Nicolas, Eric J Kildebeck, Niraj Punjya, Camille Sindhu, Matthew A Inlay
    Abstract:

    Gene correction in human long-term Hematopoietic Stem Cells (LT-HSCs) could be an effective therapy for monogenic diseases of the blood and immune syStem. High frequencies of reproducible targeted integration of a wild-type cDNA into the endogenous start codon of a gene in LT-HSCs could provide a robust genome editing approach to cure genetic diseases in which patients have different mutations throughout the gene. We describe a clinically relevant method for correcting X-linked severe combined immunodeficiency (SCID-X1). By using a highly specific and active CRISPR/Cas9-AAV6 based strategy and selection-free approach, we achieve up to 20% genome integration frequencies in LT-HSCs of a full-length IL2RG cDNA at the endogenous start site as demonstrated by serial transplantation and analysis of genome edited human Cells eight months following initial transplantation. In addition to high frequencies of functional gene correction in LT-HSCs we observed no evidence of abnormal hematopoiesis following transplantation, a functional measure of the lack of genotoxicity. Deep analysis of potential off-target activity detected two sites with low frequency (

Wataru Ebina - One of the best experts on this subject based on the ideXlab platform.

  • transcription factor mediated reprogramming toward Hematopoietic Stem Cells
    The EMBO Journal, 2015
    Co-Authors: Wataru Ebina, Derrick J Rossi
    Abstract:

    De novo generation of human Hematopoietic Stem Cells (HSCs) from renewable cell types has been a long sought-after but elusive goal in regenerative medicine. Paralleling efforts to guide pluripotent Stem cell differentiation by manipulating developmental cues, substantial progress has been made recently toward HSC generation via combinatorial transcription factor (TF)-mediated fate conversion, a paradigm established by Yamanaka's induction of pluripotency in somatic Cells by mere four TFs. This review will integrate the recently reported strategies to directly convert a variety of starting cell types toward HSCs in the context of Hematopoietic transcriptional regulation and discuss how these findings could be further developed toward the ultimate generation of therapeutic human HSCs.

Niraj Punjya - One of the best experts on this subject based on the ideXlab platform.

  • gene correction for scid x1 in long term Hematopoietic Stem Cells
    Nature Communications, 2019
    Co-Authors: Mara Paveldinu, Volker Wiebking, Beruh T Dejene, Waracharee Srifa, Sruthi Mantri, Carmencita E Nicolas, Eric J Kildebeck, Niraj Punjya, Camille Sindhu
    Abstract:

    Gene correction in human long-term Hematopoietic Stem Cells (LT-HSCs) could be an effective therapy for monogenic diseases of the blood and immune syStem. Here we describe an approach for X-linked sSevere cCombined iImmunodeficiency (SCID-X1) using targeted integration of a cDNA into the endogenous start codon to functionally correct disease-causing mutations throughout the gene. Using a CRISPR-Cas9/AAV6 based strategy, we achieve up to 20% targeted integration frequencies in LT-HSCs. As measures of the lack of toxicity we observe no evidence of abnormal hematopoiesis following transplantation and no evidence of off-target mutations using a high-fidelity Cas9 as a ribonucleoprotein complex. We achieve high levels of targeting frequencies (median 45%) in CD34+ HSPCs from six SCID-X1 patients and demonstrate rescue of lymphopoietic defect in a patient derived HSPC population in vitro and in vivo. In sum, our study provides specificity, toxicity and efficacy data supportive of clinical development of genome editing to treat SCID-Xl.

  • gene correction for scid x1 in long term Hematopoietic Stem Cells
    bioRxiv, 2018
    Co-Authors: Mara Paveldinu, Volker Wiebking, Beruh T Dejene, Waracharee Srifa, Sruthi Mantri, Carmencita E Nicolas, Eric J Kildebeck, Niraj Punjya, Camille Sindhu, Matthew A Inlay
    Abstract:

    Gene correction in human long-term Hematopoietic Stem Cells (LT-HSCs) could be an effective therapy for monogenic diseases of the blood and immune syStem. High frequencies of reproducible targeted integration of a wild-type cDNA into the endogenous start codon of a gene in LT-HSCs could provide a robust genome editing approach to cure genetic diseases in which patients have different mutations throughout the gene. We describe a clinically relevant method for correcting X-linked severe combined immunodeficiency (SCID-X1). By using a highly specific and active CRISPR/Cas9-AAV6 based strategy and selection-free approach, we achieve up to 20% genome integration frequencies in LT-HSCs of a full-length IL2RG cDNA at the endogenous start site as demonstrated by serial transplantation and analysis of genome edited human Cells eight months following initial transplantation. In addition to high frequencies of functional gene correction in LT-HSCs we observed no evidence of abnormal hematopoiesis following transplantation, a functional measure of the lack of genotoxicity. Deep analysis of potential off-target activity detected two sites with low frequency (