Irving L Weissman

Stanford University, Palo Alto, California, United States

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Publications (752)8372.3 Total impact

  • Kipp Weiskopf, Irving L Weissman
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    ABSTRACT: Macrophages are innate immune cells that derive from circulating monocytes, reside in all tissues, and participate in many states of pathology. Macrophages play a dichotomous role in cancer, where they promote tumor growth but also serve as critical immune effectors of therapeutic antibodies. Macrophages express all classes of Fcγ receptors, and they have immense potential to destroy tumors via the process of antibody-dependent phagocytosis. A number of studies have demonstrated that macrophage phagocytosis is a major mechanism of action of many antibodies approved to treat cancer. Consequently, a number of approaches to augment macrophage responses to therapeutic antibodies are under investigation, including the exploration of new targets and development of antibodies with enhanced functions. For example, the interaction of CD47 with signal-regulatory protein α (SIRPα) serves as a myeloid-specific immune checkpoint that limits the response of macrophages to antibody therapies, and CD47-blocking agents overcome this barrier to augment phagocytosis. The response of macrophages to antibody therapies can also be enhanced with engineered Fc variants, bispecific antibodies, or antibody-drug conjugates. Macrophages have demonstrated success as effectors of cancer immunotherapy, and further investigation will unlock their full potential for the benefit of patients.
    mAbs 02/2015; · 4.73 Impact Factor
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    ABSTRACT: Macrophage-mediated programmed cell removal (PrCR) is an important mechanism of eliminating diseased and damaged cells before programmed cell death. The induction of PrCR by eat-me signals on tumor cells is countered by don't-eat-me signals such as CD47, which binds macrophage signal-regulatory protein α to inhibit phagocytosis. Blockade of CD47 on tumor cells leads to phagocytosis by macrophages. Here we demonstrate that the activation of Toll-like receptor (TLR) signaling pathways in macrophages synergizes with blocking CD47 on tumor cells to enhance PrCR. Bruton's tyrosine kinase (Btk) mediates TLR signaling in macrophages. Calreticulin, previously shown to be an eat-me signal on cancer cells, is activated in macrophages for secretion and cell-surface exposure by TLR and Btk to target cancer cells for phagocytosis, even if the cancer cells themselves do not express calreticulin.
    Proceedings of the National Academy of Sciences 02/2015; · 9.81 Impact Factor
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    Ayelet Voskoboynik, Irving L. Weissman
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    ABSTRACT: The decline of tissue regenerative potential with the loss of stem cell function is a hallmark of mammalian aging. We study Botryllus schlosseri, a colonial chordate which exhibits robust stem cell-mediated regeneration capacities throughout life. Larvae, derived by sexual reproduction and chordate development, metamorphose to clonal founders that undergo weekly formation of new individuals by budding from stem cells. Individuals are transient structures which die through massive apoptosis, and successive buds mature to replicate an entire new body. As a result, their stem cells, which are the only self-renewing cells in a tissue, are the only cells which remain through the entire life of the genotype and retain the effects of time. During aging, a significant decrease in the colonies’ regenerative potential is observed and both sexual and asexual reproductions will eventually halt. When a parent colony is experimentally separated into a number of clonal replicates, they frequently undergo senescence simultaneously, suggesting a heritable factor that determines lifespan in these colonies. The availability of the recently published B. schlosseri genome coupled with its unique life cycle features promotes the use of this model organism for the study of the evolution of aging, stem cells, and mechanisms of regeneration.
    Invertebrate Reproduction and Development 01/2015; 59. · 0.67 Impact Factor
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    ABSTRACT: How are skeletal tissues derived from skeletal stem cells? Here, we map bone, cartilage, and stromal development from a population of highly pure, postnatal skeletal stem cells (mouse skeletal stem cells, mSSCs) to their downstream progenitors of bone, cartilage, and stromal tissue. We then investigated the transcriptome of the stem/progenitor cells for unique gene-expression patterns that would indicate potential regulators of mSSC lineage commitment. We demonstrate that mSSC niche factors can be potent inducers of osteogenesis, and several specific combinations of recombinant mSSC niche factors can activate mSSC genetic programs in situ, even in nonskeletal tissues, resulting in de novo formation of cartilage or bone and bone marrow stroma. Inducing mSSC formation with soluble factors and subsequently regulating the mSSC niche to specify its differentiation toward bone, cartilage, or stromal cells could represent a paradigm shift in the therapeutic regeneration of skeletal tissues. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell. 01/2015; 160(1-2):285-298.
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    ABSTRACT: The generation of pluripotent stem cells by somatic cell nuclear transfer (SCNT) has recently been achieved in human cells and sparked new interest in this technology. The authors reporting this methodical breakthrough speculated that SCNT would allow the creation of patient-matched embryonic stem cells, even in patients with hereditary mitochondrial diseases. However, herein we show that mismatched mitochondria in nuclear-transfer-derived embryonic stem cells (NT-ESCs) possess alloantigenicity and are subject to immune rejection. In a murine transplantation setup, we demonstrate that allogeneic mitochondria in NT-ESCs, which are nucleus-identical to the recipient, may trigger an adaptive alloimmune response that impairs the survival of NT-ESC grafts. The immune response is adaptive, directed against mitochondrial content, and amenable for tolerance induction. Mitochondrial alloantigenicity should therefore be considered when developing therapeutic SCNT-based strategies. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell Stem Cell 11/2014; · 22.15 Impact Factor
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    ABSTRACT: In the last decade there has been a rapid expansion in clinical trials using mesenchymal stromal cells (MSCs) from a variety of tissues. However, despite similarities in morphology, immunophenotype and differentiation behavior in vitro, MSCs sourced from distinct tissues do not necessarily have equivalent biological properties. We performed a genome-wide methylation, transcription and in vivo evaluation of MSCs from human bone marrow (BM), white adipose tissue, umbilical cord and skin cultured in humanized media. Surprisingly, only BM-derived MSCs spontaneously formed a bone marrow cavity through a vascularized cartilage intermediate in vivo that was progressively replaced by hematopoietic tissue and bone. Only BM-derived MSCs exhibited a chondrogenic transcriptional program with hypomethylation and increased expression of RUNX3, RUNX2, BGLAP, MMP13 and ITGA10 consistent with a latent and primed skeletal developmental potential. The humanized MSC-derived microenvironment permitted homing and maintenance of long-term murine SLAM(+) hematopoietic stem cells (HSCs) as well as human CD34(+)/CD38(-)/CD90(+)/CD45RA(+) HSCs after cord blood transplantation. These studies underscore the profound differences in developmental potential between MSC sources independent of donor age with implications for their clinical use. We also demonstrate a tractable human niche model for studying homing and engraftment of human hematopoietic cells in normal and neoplastic states. Copyright © 2014 American Society of Hematology.
    Blood 11/2014; 125(2). · 9.78 Impact Factor
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    ABSTRACT: Small numbers of hematopoietic stem cells (HSCs) generate large numbers of mature effector cells through the successive amplification of transiently proliferating progenitor cells. HSCs and their downstream progenitors have been extensively characterized based on their cell-surface phenotype and functional activities during transplantation assays. These cells dynamically lose and acquire specific sets of surface markers during differentiation, leading to the identification of markers that allow for more refined separation of HSCs from early hematopoietic progenitors. Here, we describe a marker, CD11A, which allows for the enhanced purification of mouse HSCs. We show through in vivo transplantations that upregulation of CD11A on HSCs denotes the loss of their long-term reconstitution potential. Surprisingly, nearly half of phenotypic HSCs (defined as Lin(?)KIT(+)SCA-1(+)CD150(+)CD34(?)) are CD11A(+) and lack long-term self-renewal potential. We propose that CD11A(+)Lin(?)KIT(+)SCA-1(+)CD150(+)CD34(?) cells are multipotent progenitors and CD11A(?)Lin(?)KIT(+)SCA-1(+)CD150(+)CD34(?) cells are true HSCs.
    Stem cell reports. 11/2014; 3(5):707-15.
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    ABSTRACT: A combination of optical imaging technologies with cancer-specific molecular imaging agents is a potentially powerful strategy to improve cancer detection and enable image-guided surgery. Bladder cancer is primarily managed endoscopically by white light cystoscopy with suboptimal diagnostic accuracy. Emerging optical imaging technologies hold great potential for improved diagnostic accuracy but lack imaging agents for molecular specificity. Using fluorescently labeled CD47 antibody (anti-CD47) as molecular imaging agent, we demonstrated consistent identification of bladder cancer with clinical grade fluorescence imaging systems, confocal endomicroscopy, and blue light cystoscopy in fresh surgically removed human bladders. With blue light cystoscopy, the sensitivity and specificity for CD47-targeted imaging were 82.9 and 90.5%, respectively. We detected variants of bladder cancers, which are diagnostic challenges, including carcinoma in situ, residual carcinoma in tumor resection bed, recurrent carcinoma following prior intravesical immunotherapy with Bacillus Calmette-Guérin (BCG), and excluded cancer from benign but suspicious-appearing mucosa. CD47-targeted molecular imaging could improve diagnosis and resection thoroughness for bladder cancer.
    Science translational medicine 10/2014; 6(260):260ra148. · 14.41 Impact Factor
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    ABSTRACT: Current methods for the isolation of fibroblasts require extended ex vivo manipulation in cell culture. As a consequence, prior studies investigating fibroblast biology may fail to adequately represent cellular phenotypes in vivo. To overcome this problem, we describe a detailed protocol for the isolation of fibroblasts from the dorsal dermis of mice that bypasses the need for cell culture thereby preserving the physiologic transcriptional and proteomic profiles of each cell. Using the described protocol we characterized the transcriptional programs and the surface expression of 176 CD markers in cultured vs. uncultured fibroblasts. The differential expression patterns we observed highlight the importance of a live harvest for investigations of fibroblast biology.
    Tissue Engineering Part C Methods 10/2014; · 4.64 Impact Factor
  • Journal of the American College of Surgeons 09/2014; 219(3):S82-S83. · 4.45 Impact Factor
  • Experimental Hematology 08/2014; 42(8S):S24. · 2.81 Impact Factor
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    ABSTRACT: The requirement and influence of the peripheral nervous system on tissue replacement in mammalian appendages remain largely undefined. To explore this question, we have performed genetic lineage tracing and clonal analysis of individual cells of mouse hind limb tissues devoid of nerve supply during regeneration of the digit tip, normal maintenance, and cutaneous wound healing. We show that cellular turnover, replacement, and cellular differentiation from presumed tissue stem/progenitor cells within hind limb tissues remain largely intact independent of nerve and nerve-derived factors. However, regenerated digit tips in the absence of nerves displayed patterning defects in bone and nail matrix. These nerve-dependent phenotypes mimic clinical observations of patients with nerve damage resulting from spinal cord injury and are of significant interest for translational medicine aimed at understanding the effects of nerves on etiologies of human injury.
    Proceedings of the National Academy of Sciences 06/2014; · 9.81 Impact Factor
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    ABSTRACT: The mammalian heart has long been considered a postmitotic organ, implying that the total number of cardiomyocytes is set at birth. Analysis of cell division in the mammalian heart is complicated by cardiomyocyte binucleation shortly after birth, which makes it challenging to interpret traditional assays of cell turnover [Laflamme MA, Murray CE (2011) Nature 473(7347):326-335; Bergmann O, et al. (2009) Science 324(5923):98-102]. An elegant multi-isotope imaging-mass spectrometry technique recently calculated the low, discrete rate of cardiomyocyte generation in mice [Senyo SE, et al. (2013) Nature 493(7432):433-436], yet our cellular-level understanding of postnatal cardiomyogenesis remains limited. Herein, we provide a new line of evidence for the differentiated α-myosin heavy chain-expressing cardiomyocyte as the cell of origin of postnatal cardiomyogenesis using the "mosaic analysis with double markers" mouse model. We show limited, life-long, symmetric division of cardiomyocytes as a rare event that is evident in utero but significantly diminishes after the first month of life in mice; daughter cardiomyocytes divide very seldom, which this study is the first to demonstrate, to our knowledge. Furthermore, ligation of the left anterior descending coronary artery, which causes a myocardial infarction in the mosaic analysis with double-marker mice, did not increase the rate of cardiomyocyte division above the basal level for up to 4 wk after the injury. The clonal analysis described here provides direct evidence of postnatal mammalian cardiomyogenesis.
    Proceedings of the National Academy of Sciences 06/2014; 111(24):8850. · 9.81 Impact Factor
  • Irving L Weissman
    The Journal of Immunology 06/2014; 192(11):4943-4. · 5.36 Impact Factor
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    ABSTRACT: Although in utero hematopoietic cell transplantation is a promising strategy to treat congenital hematopoietic disorders, levels of engraftment have not been therapeutic for diseases in which donor cells have no survival advantage. We used an antibody against the murine c-Kit receptor (ACK2) to deplete fetal host hematopoietic stem cells (HSCs) and increase space within the hematopoietic niche for donor cell engraftment. Fetal mice were injected with ACK2 on E13.5-14.5 and surviving pups were transplanted with congenic hematopoietic cells on day of life 1. Low-dose ACK2 treatment effectively depleted HSCs within the bone marrow with minimal toxicity and the antibody was cleared from the serum before the neonatal transplantation. Chimerism levels were significantly higher in treated pups than in controls; both myeloid and lymphoid cell chimerism increased due to higher engraftment of HSCs in the bone marrow. To test the strategy of repeated HSC depletion and transplantation, some mice were treated with ACK2 postnatally, but the increase in engraftment was lower than that seen with prenatal treatment. We demonstrate a successful fetal conditioning strategy associated with minimal toxicity. Such strategies could be used to achieve clinically relevant levels of engraftment to treat congenital stem cell disorders.
    Blood 05/2014; · 9.78 Impact Factor
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    ABSTRACT: The mechanism and magnitude by which the mammalian kidney generates and maintains its proximal tubules, distal tubules, and collecting ducts remain controversial. Here, we use long-term in vivo genetic lineage tracing and clonal analysis of individual cells from kidneys undergoing development, maintenance, and regeneration. We show that the adult mammalian kidney undergoes continuous tubulogenesis via expansions of fate-restricted clones. Kidneys recovering from damage undergo tubulogenesis through expansions of clones with segment-specific borders, and renal spheres developing in vitro from individual cells maintain distinct, segment-specific fates. Analysis of mice derived by transfer of color-marked embryonic stem cells (ESCs) into uncolored blastocysts demonstrates that nephrons are polyclonal, developing from expansions of singly fated clones. Finally, we show that adult renal clones are derived from Wnt-responsive precursors, and their tracing in vivo generates tubules that are segment specific. Collectively, these analyses demonstrate that fate-restricted precursors functioning as unipotent progenitors continuously maintain and self-preserve the mouse kidney throughout life.
    Cell reports. 05/2014;
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    ABSTRACT: Hematopoietic stem cells (HSCs) maintain homeostasis and regenerate the blood system throughout life. It has been postulated that HSCs may be uniquely capable of preserving their genomic integrity in order to ensure lifelong function. To directly test this, we quantified DNA damage in HSCs and downstream progenitors from young and old mice, revealing that strand breaks significantly accrue in HSCs during aging. DNA damage accumulation in HSCs was associated with broad attenuation of DNA repair and response pathways that was dependent upon HSC quiescence. Accordingly, cycling fetal HSCs and adult HSCs driven into cycle upregulated these pathways leading to repair of strand breaks. Our results demonstrate that HSCs are not comprehensively geno-protected during aging. Rather, HSC quiescence and concomitant attenuation of DNA repair and response pathways underlies DNA damage accumulation in HSCs during aging. These results provide a potential mechanism through which premalignant mutations accrue in HSCs.
    Cell stem cell 05/2014; · 23.56 Impact Factor
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    ABSTRACT: Hematopoiesis in the embryo proceeds in a series of waves, with primitive erythroid-biased waves succeeded by definitive waves, within which the properties of hematopoietic stem cells (multilineage potential, self-renewal, and engraftability) gradually arise. Whereas self-renewal and engraftability have previously been examined in the embryo, multipotency has not been thoroughly addressed, especially at the single-cell level or within well-defined populations. To identify when and where clonal multilineage potential arises during embryogenesis, we developed a single-cell multipotency assay. We find that, during the initiation of definitive hematopoiesis in the embryo, a defined population of multipotent, engraftable progenitors emerges that is much more abundant within the yolk sac (YS) than the aorta-gonad-mesonephros (AGM) or fetal liver. These experiments indicate that multipotent cells appear in concert within both the YS and AGM and strongly implicate YS-derived progenitors as contributors to definitive hematopoiesis.
    Stem cell reports. 04/2014; 2(4):457-72.
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    ABSTRACT: Analysis of hematopoietic stem cell function in nonhuman primates provides insights that are relevant for human biology and therapeutic strategies. In this study, we applied quantitative genetic barcoding to track the clonal output of transplanted autologous rhesus macaque hematopoietic stem and progenitor cells over a time period of up to 9.5 months. We found that unilineage short-term progenitors reconstituted myeloid and lymphoid lineages at 1 month but were supplanted over time by multilineage clones, initially myeloid restricted, then myeloid-B clones, and then stable myeloid-B-T multilineage, long-term repopulating clones. Surprisingly, reconstitution of the natural killer (NK) cell lineage, and particularly the major CD16(+)/CD56(-) peripheral blood NK compartment, showed limited clonal overlap with T, B, or myeloid lineages, and therefore appears to be ontologically distinct. Thus, in addition to providing insights into clonal behavior over time, our analysis suggests an unexpected paradigm for the relationship between NK cells and other hematopoietic lineages in primates.
    Cell stem cell 04/2014; 14(4):486-99. · 23.56 Impact Factor
  • European Urology Supplements 04/2014; 13(1):e622. · 3.37 Impact Factor

Publication Stats

73k Citations
8,372.30 Total Impact Points

Institutions

  • 1971–2015
    • Stanford University
      • • Institute for Stem Cell Biology and Regenerative Medicine
      • • Department of Pathology
      • • Division of Pediatric Cardiology
      • • Department of Medicine
      • • Hopkins Marine Station
      • • Department of Developmental Biology
      Palo Alto, California, United States
  • 1974–2014
    • Stanford Medicine
      • • Department of Developmental Biology
      • • Department of Pathology
      • • Institute for Stem Cell Biology and Regenerative Medicine
      • • Department of Radiation Oncology
      • • Division of Immunology and Rheumatology
      • • Department of Medicine
      Stanford, California, United States
  • 2004–2013
    • University of California, Los Angeles
      • Division of Cardiology
      Los Angeles, CA, United States
  • 2012
    • Indiana Blood and Marrow Transplantation
      Indianapolis, Indiana, United States
  • 2009–2012
    • Institute for Stem Cell Biology and Regenerative Medicine
      Bengalūru, Karnātaka, India
  • 2010
    • Baylor College of Medicine
      • Department of Molecular & Cellular Biology
      Houston, TX, United States
    • Boston Children's Hospital
      • Department of Pathology
      Boston, MA, United States
    • Joslin Diabetes Center
      Boston, Massachusetts, United States
  • 2008–2010
    • Harvard Medical School
      • Department of Pathology
      Boston, Massachusetts, United States
  • 1997–2008
    • California Institute of Technology
      • Division of Biology
      Pasadena, CA, United States
  • 2006
    • Harvard University
      • Department of Stem Cell and Regenerative Biology
      Cambridge, Massachusetts, United States
  • 1990–2006
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 2003
    • Bar Ilan University
      Gan, Tel Aviv, Israel
  • 1990–2003
    • Duke University Medical Center
      • Department of Medicine
      Durham, North Carolina, United States
  • 1974–2003
    • University of Michigan
      • Department of Internal Medicine
      Ann Arbor, MI, United States
  • 2002
    • StemCells, Inc.
      Newark, California, United States
  • 2001
    • Salk Institute
      • Laboratory of Genetics
      La Jolla, California, United States
  • 1997–2001
    • VU University Amsterdam
      • Department of Molecular Cell Biology and Immunology
      Amsterdamo, North Holland, Netherlands
  • 1974–2001
    • University of California, San Francisco
      • • Department of Laboratory Medicine
      • • School of Dentistry
      San Francisco, CA, United States
  • 2000
    • Union College
      New York City, New York, United States
  • 1998
    • University of Tsukuba
      Tsukuba, Ibaraki, Japan
    • University of Alabama at Birmingham
      • Department of Pathology
      Birmingham, AL, United States
  • 1997–1998
    • CSU Mentor
      Long Beach, California, United States
  • 1994
    • University of North Carolina at Wilmington
      Wilmington, North Carolina, United States
  • 1993
    • McGill University
      Montréal, Quebec, Canada
    • Albany Medical College
      • Department of Pediatrics
      Albany, NY, United States
  • 1992
    • Israel Oceanographic and Limnological Research Institute (IOLR)
      H̱efa, Haifa District, Israel
  • 1991
    • Oklahoma Medical Research Foundation
      • Immunobiology and Cancer Program
      Oklahoma City, Oklahoma, United States
    • National Institute of Allergy and Infectious Diseases
      Maryland, United States
  • 1989
    • University of Southern California
      • Department of Medicine
      Los Angeles, CA, United States
  • 1988
    • University of Amsterdam
      • Department of Histology
      Amsterdam, North Holland, Netherlands