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Irving L. Weissman

Kipp Weiskopf, Peter J Schnorr, Wendy W Pang, Mark P Chao, Akanksha Chhabra, Jun Seita, Mingye Feng, Irving L Weissman
The hematopoietic stem cell (HSC) is a multipotent stem cell that resides in the bone marrow and has the ability to form all of the cells of the blood and immune system. Since its first purification in 1988, additional studies have refined the phenotype and functionality of HSCs and characterized all of their downstream progeny. The hematopoietic lineage is divided into two main branches: the myeloid and lymphoid arms. The myeloid arm is characterized by the common myeloid progenitor and all of its resulting cell types...
October 2016: Microbiology Spectrum
Akanksha Chhabra, Aaron M Ring, Kipp Weiskopf, Peter John Schnorr, Sydney Gordon, Alan C Le, Hye-Sook Kwon, Nan Guo Ring, Jens Volkmer, Po Yi Ho, Serena Tseng, Irving L Weissman, Judith A Shizuru
Hematopoietic stem cell (HSC) transplantation can cure diverse diseases of the blood system, including hematologic malignancies, anemias, and autoimmune disorders. However, patients must undergo toxic conditioning regimens that use chemotherapy and/or radiation to eliminate host HSCs and enable donor HSC engraftment. Previous studies have shown that anti-c-Kit monoclonal antibodies deplete HSCs from bone marrow niches, allowing donor HSC engraftment in immunodeficient mice. We show that host HSC clearance is dependent on Fc-mediated antibody effector functions, and enhancing effector activity through blockade of CD47, a myeloid-specific immune checkpoint, extends anti-c-Kit conditioning to fully immunocompetent mice...
August 10, 2016: Science Translational Medicine
Christina von Roemeling, Wen Jiang, Charles K Chan, Irving L Weissman, Betty Y S Kim
Nanomedicine offers unique advantages in treating human cancers. However, physiological and pathological barriers within normal and disease tissues, which are highly variable among individuals, often hinder its effectiveness. The body possesses specific innate responses to nanoparticles (NPs), which when combined with unique pathophysiological signatures in the tumor microenvironment, can severely limit the utility of nanomedicine in the oncological setting. Furthermore, with the successes of cancer immunotherapies, understanding nanoimmune interactions and developing immune-smart cancer nanomedicine that can take advantage of the body's immune functions will increasingly become clinically relevant...
August 1, 2016: Trends in Biotechnology
Michael Ngo, Arum Han, Anita Lakatos, Debashis Sahoo, Stephanie J Hachey, Kipp Weiskopf, Andrew H Beck, Irving L Weissman, Alexander D Boiko
The high rate of metastasis and recurrence among melanoma patients indicates the existence of cells within melanoma that have the ability to both initiate metastatic programs and bypass immune recognition. Here, we identify CD47 as a regulator of melanoma tumor metastasis and immune evasion. Protein and gene expression analysis of clinical melanoma samples reveals that CD47, an anti-phagocytic signal, correlates with melanoma metastasis. Antibody-mediated blockade of CD47 coupled with targeting of CD271(+) melanoma cells strongly inhibits tumor metastasis in patient-derived xenografts...
August 9, 2016: Cell Reports
Yoko Kojima, Jens-Peter Volkmer, Kelly McKenna, Mete Civelek, Aldons Jake Lusis, Clint L Miller, Daniel Direnzo, Vivek Nanda, Jianqin Ye, Andrew J Connolly, Eric E Schadt, Thomas Quertermous, Paola Betancur, Lars Maegdefessel, Ljubica Perisic Matic, Ulf Hedin, Irving L Weissman, Nicholas J Leeper
Atherosclerosis is the disease process that underlies heart attack and stroke. Advanced lesions at risk of rupture are characterized by the pathological accumulation of diseased vascular cells and apoptotic cellular debris. Why these cells are not cleared remains unknown. Here we show that atherogenesis is associated with upregulation of CD47, a key anti-phagocytic molecule that is known to render malignant cells resistant to programmed cell removal, or 'efferocytosis'. We find that administration of CD47-blocking antibodies reverses this defect in efferocytosis, normalizes the clearance of diseased vascular tissue, and ameliorates atherosclerosis in multiple mouse models...
August 4, 2016: Nature
Kyle M Loh, Angela Chen, Pang Wei Koh, Tianda Z Deng, Rahul Sinha, Jonathan M Tsai, Amira A Barkal, Kimberle Y Shen, Rajan Jain, Rachel M Morganti, Ng Shyh-Chang, Nathaniel B Fernhoff, Benson M George, Gerlinde Wernig, Rachel E A Salomon, Zhenghao Chen, Hannes Vogel, Jonathan A Epstein, Anshul Kundaje, William S Talbot, Philip A Beachy, Lay Teng Ang, Irving L Weissman
Stem-cell differentiation to desired lineages requires navigating alternating developmental paths that often lead to unwanted cell types. Hence, comprehensive developmental roadmaps are crucial to channel stem-cell differentiation toward desired fates. To this end, here, we map bifurcating lineage choices leading from pluripotency to 12 human mesodermal lineages, including bone, muscle, and heart. We defined the extrinsic signals controlling each binary lineage decision, enabling us to logically block differentiation toward unwanted fates and rapidly steer pluripotent stem cells toward 80%-99% pure human mesodermal lineages at most branchpoints...
July 14, 2016: Cell
Irving L Weissman, Fiona M Watt
The California Institute for Regenerative Medicine (CIRM) and the UK Regenerative Medicine Platform (UKRMP) have similar objectives, but their histories, funding mechanisms, and governance could hardly be more different. Here, we compare the two programs and explore their impact in translating stem cell research into clinical applications.
July 7, 2016: Cell Stem Cell
Kipp Weiskopf, Nadine S Jahchan, Peter J Schnorr, Sandra Cristea, Aaron M Ring, Roy L Maute, Anne K Volkmer, Jens-Peter Volkmer, Jie Liu, Jing Shan Lim, Dian Yang, Garrett Seitz, Thuyen Nguyen, Di Wu, Kevin Jude, Heather Guerston, Amira Barkal, Francesca Trapani, Julie George, John T Poirier, Eric E Gardner, Linde A Miles, Elisa de Stanchina, Shane M Lofgren, Hannes Vogel, Monte M Winslow, Caroline Dive, Roman K Thomas, Charles M Rudin, Matt van de Rijn, Ravindra Majeti, K Christopher Garcia, Irving L Weissman, Julien Sage
Small-cell lung cancer (SCLC) is a highly aggressive subtype of lung cancer with limited treatment options. CD47 is a cell-surface molecule that promotes immune evasion by engaging signal-regulatory protein alpha (SIRPα), which serves as an inhibitory receptor on macrophages. Here, we found that CD47 is highly expressed on the surface of human SCLC cells; therefore, we investigated CD47-blocking immunotherapies as a potential approach for SCLC treatment. Disruption of the interaction of CD47 with SIRPα using anti-CD47 antibodies induced macrophage-mediated phagocytosis of human SCLC patient cells in culture...
July 1, 2016: Journal of Clinical Investigation
Yasuo Mori, Koichi Akashi, Irving L Weissman
Elucidating the developmental pathway leading to erythrocytes and being able to isolate their progenitors is crucial to understanding and treating disorders of red cell imbalance such as anemia, myelodysplastic syndrome, and polycythemia vera. Endoglin (CD105) is a key marker for purifying mouse erythroid lineage-committed progenitors (EPs) from bone marrow. Herein, we show that human EPs can also be isolated from adult bone marrow. We identified three subfractions that possessed different expression patterns of CD105 and CD71 within the previously defined human megakaryocyte/erythrocyte progenitor (hMEP; Lineage-CD34(+)CD38(+)IL-3Rα(-)CD45RA(-)) population...
2016: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Daniel M Corey, Benyamin Rosental, Mark Kowarsky, Rahul Sinha, Katherine J Ishizuka, Karla J Palmeri, Stephen R Quake, Ayelet Voskoboynik, Irving L Weissman
In a primitive chordate model of natural chimerism, one chimeric partner is often eliminated in a process of allogeneic resorption. Here, we identify the cellular framework underlying loss of tolerance to one partner within a natural Botryllus schlosseri chimera. We show that the principal cell type mediating chimeric partner elimination is a cytotoxic morula cell (MC). Proinflammatory, developmental cell death programs render MCs cytotoxic and, in collaboration with activated phagocytes, eliminate chimeric partners during the "takeover" phase of blastogenic development...
June 7, 2016: Proceedings of the National Academy of Sciences of the United States of America
Geoffrey Wayne Krampitz, Benson M George, Stephen B Willingham, Jens-Peter Volkmer, Kipp Weiskopf, Nadine Jahchan, Aaron M Newman, Debashis Sahoo, Allison J Zemek, Rebecca L Yanovsky, Julia K Nguyen, Peter J Schnorr, Pawel K Mazur, Julien Sage, Teri A Longacre, Brendan C Visser, George A Poultsides, Jeffrey A Norton, Irving L Weissman
Pancreatic neuroendocrine tumors (PanNETs) are a type of pancreatic cancer with limited therapeutic options. Consequently, most patients with advanced disease die from tumor progression. Current evidence indicates that a subset of cancer cells is responsible for tumor development, metastasis, and recurrence, and targeting these tumor-initiating cells is necessary to eradicate tumors. However, tumor-initiating cells and the biological processes that promote pathogenesis remain largely uncharacterized in PanNETs...
April 19, 2016: Proceedings of the National Academy of Sciences of the United States of America
Mariko L Bennett, F Chris Bennett, Shane A Liddelow, Bahareh Ajami, Jennifer L Zamanian, Nathaniel B Fernhoff, Sara B Mulinyawe, Christopher J Bohlen, Aykezar Adil, Andrew Tucker, Irving L Weissman, Edward F Chang, Gordon Li, Gerald A Grant, Melanie G Hayden Gephart, Ben A Barres
The specific function of microglia, the tissue resident macrophages of the brain and spinal cord, has been difficult to ascertain because of a lack of tools to distinguish microglia from other immune cells, thereby limiting specific immunostaining, purification, and manipulation. Because of their unique developmental origins and predicted functions, the distinction of microglia from other myeloid cells is critically important for understanding brain development and disease; better tools would greatly facilitate studies of microglia function in the developing, adult, and injured CNS...
March 22, 2016: Proceedings of the National Academy of Sciences of the United States of America
Irving L Weissman, Fred H Gage
Double-strand break repair is required for neural development, and brain cells contain somatic genomic variations. Now, Wei et al. demonstrate that neural stem and progenitor cells undergo very frequent DNA breaks in a very restricted set of genes involved in neural cell adhesion and synapse function.
February 11, 2016: Cell
James Y Chen, Masanori Miyanishi, Sean K Wang, Satoshi Yamazaki, Rahul Sinha, Kevin S Kao, Jun Seita, Debashis Sahoo, Hiromitsu Nakauchi, Irving L Weissman
Haematopoietic stem cells (HSCs) are arguably the most extensively characterized tissue stem cells. Since the identification of HSCs by prospective isolation, complex multi-parameter flow cytometric isolation of phenotypic subsets has facilitated studies on many aspects of HSC biology, including self-renewal, differentiation, ageing, niche, and diversity. Here we demonstrate by unbiased multi-step screening, identification of a single gene, homeobox B5 (Hoxb5, also known as Hox-2.1), with expression in the bone marrow that is limited to long-term (LT)-HSCs in mice...
February 11, 2016: Nature
Daniel M Corey, Yuval Rinkevich, Irving L Weissman
Although tumor blood vessels have been a major therapeutic target for cancer chemotherapy, little is known regarding the stepwise development of the tumor microenvironment. Here, we use a multicolor Cre-dependent marker system to trace clonality within the tumor microenvironment to show that tumor blood vessels follow a pattern of dynamic clonal evolution. In an advanced melanoma tumor microenvironment, the vast majority of tumor vasculature clones are derived from a common precursor. Quantitative lineage analysis reveals founder clones diminish in frequency and are replaced by subclones as tumors evolve...
March 15, 2016: Cancer Research
Roy L Maute, Sydney R Gordon, Aaron T Mayer, Melissa N McCracken, Arutselvan Natarajan, Nan Guo Ring, Richard Kimura, Jonathan M Tsai, Aashish Manglik, Andrew C Kruse, Sanjiv S Gambhir, Irving L Weissman, Aaron M Ring
Signaling through the immune checkpoint programmed cell death protein-1 (PD-1) enables tumor progression by dampening antitumor immune responses. Therapeutic blockade of the signaling axis between PD-1 and its ligand programmed cell death ligand-1 (PD-L1) with monoclonal antibodies has shown remarkable clinical success in the treatment of cancer. However, antibodies have inherent limitations that can curtail their efficacy in this setting, including poor tissue/tumor penetrance and detrimental Fc-effector functions that deplete immune cells...
November 24, 2015: Proceedings of the National Academy of Sciences of the United States of America
Graham G Walmsley, Kshemendra Senarath-Yapa, Taylor L Wearda, Siddharth Menon, Michael S Hu, Dominik Duscher, Zeshaan N Maan, Jonathan M Tsai, Elizabeth R Zielins, Irving L Weissman, Geoffrey C Gurtner, H Peter Lorenz, Michael T Longaker
Cell-based therapy is an emerging paradigm in skeletal regenerative medicine. However, the primary means by which transplanted cells contribute to bone repair and regeneration remain controversial. To gain an insight into the mechanisms of how both transplanted and endogenous cells mediate skeletal healing, we used a transgenic mouse strain expressing both the topaz variant of green fluorescent protein under the control of the collagen, type I, alpha 1 promoter/enhancer sequence (Col1a1(GFP)) and membrane-bound tomato red fluorescent protein constitutively in all cell types (R26(mTmG))...
January 2016: Tissue Engineering. Part A
Asya Rolls, Wendy W Pang, Ingrid Ibarra, Damien Colas, Patricia Bonnavion, Ben Korin, H Craig Heller, Irving L Weissman, Luis de Lecea
Many of the factors affecting the success of haematopoietic cell transplantation are still unknown. Here we show in mice that donor sleep deprivation reduces the ability of its haematopoietic stem cells (HSCs) to engraft and reconstitute the blood and bone marrow of an irradiated recipient by more than 50%. We demonstrate that sleep deprivation downregulates the expression of microRNA (miR)-19b, a negative regulator of the suppressor of cytokine signalling (SOCS) genes, which inhibit HSC migration and homing...
October 14, 2015: Nature Communications
Jodi L Murakami, Baohui Xu, Christopher B Franco, Xingbin Hu, Stephen J Galli, Irving L Weissman, Ching-Cheng Chen
α4β7 integrin is a cell adhesion receptor that is crucial for the migration of hematopoietic progenitors and mature effector cells in the periphery, but its role in adult hematopoiesis is controversial. We identified a subset of hematopoietic stem cells (HSCs) in the bone marrow (BM) that expressed β7 integrin. These β7(+) HSCs were capable of multilineage, long-term reconstitution and had an inherent competitive advantage over β7(-) HSCs. On the other hand, HSCs that lacked β7 integrin (β7KO) had reduced engraftment potential...
January 1, 2016: Stem Cells and Development
Ruth Tevlin, Eun Young Seo, Owen Marecic, Taylor Wearda, Adrian Mc Ardle, Michael Januszyk, Gunsagar Gulati, Zeshaan Maan, Michael S Hu, Graham G Walmsley, Geoffrey C Gurtner, Charles K F Chan, Irving L Weissman, Michael T Longaker
No abstract text is available yet for this article.
October 2015: Plastic and Reconstructive Surgery
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