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Irving L. Weissman

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https://www.readbyqxmd.com/read/28224997/clonal-reversal-of-ageing-associated-stem-cell-lineage-bias-via-a-pluripotent-intermediate
#1
Martin Wahlestedt, Eva Erlandsson, Trine Kristiansen, Rong Lu, Cord Brakebusch, Irving L Weissman, Joan Yuan, Javier Martin-Gonzalez, David Bryder
Ageing associates with significant alterations in somatic/adult stem cells and therapies to counteract these might have profound benefits for health. In the blood, haematopoietic stem cell (HSC) ageing is linked to several functional shortcomings. However, besides the recent realization that individual HSCs might be preset differentially already from young age, HSCs might also age asynchronously. Evaluating the prospects for HSC rejuvenation therefore ultimately requires approaching those HSCs that are functionally affected by age...
February 22, 2017: Nature Communications
https://www.readbyqxmd.com/read/28137963/the-role-of-efferocytosis-in-atherosclerosis
#2
Yoko Kojima, Irving L Weissman, Nicholas J Leeper
The necrotic core has long been a hallmark of the vulnerable atherosclerotic plaque. Although apoptotic cells are cleared quickly in almost all other tissue beds, their removal appears to be significantly impaired in the diseased blood vessel. Emerging evidence indicates that this phenomenon is caused by a defect in efferocytosis, the process by which apoptotic tissue is recognized for engulfment by phagocytic cells such as macrophages. Genetic and experimental data suggest that efferocytosis is impaired during atherogenesis caused by dysregulation of so-called eat me ligands, which govern the edibility of cells undergoing programmed cell death...
January 31, 2017: Circulation
https://www.readbyqxmd.com/read/28088986/age-associated-changes-in-human-hematopoietic-stem-cells
#3
REVIEW
Wendy W Pang, Stanley L Schrier, Irving L Weissman
Aging has a broad impact on the function of the human hematopoietic system. This review will focus primarily on the effect of aging on the human hematopoietic stem cell (HSC) population. With age, even though human HSCs increase in number, they have decreased self-renewal capacity and reconstitution potential upon transplantation. As a population, human HSCs become more myeloid-biased in their differentiation potential. This is likely due to the human HSC population becoming more clonal with age, selecting for myeloid-biased HSC clones...
January 2017: Seminars in Hematology
https://www.readbyqxmd.com/read/28077677/pharmacological-rescue-of-diabetic-skeletal-stem-cell-niches
#4
Ruth Tevlin, Eun Young Seo, Owen Marecic, Adrian McArdle, Xinming Tong, Bryan Zimdahl, Andrey Malkovskiy, Rahul Sinha, Gunsagar Gulati, Xiyan Li, Taylor Wearda, Rachel Morganti, Michael Lopez, Ryan C Ransom, Christopher R Duldulao, Melanie Rodrigues, Allison Nguyen, Michael Januszyk, Zeshaan Maan, Kevin Paik, Kshemendra-Senarath Yapa, Jayakumar Rajadas, Derrick C Wan, Geoffrey C Gurtner, Michael Snyder, Philip A Beachy, Fan Yang, Stuart B Goodman, Irving L Weissman, Charles K F Chan, Michael T Longaker
Diabetes mellitus (DM) is a metabolic disease frequently associated with impaired bone healing. Despite its increasing prevalence worldwide, the molecular etiology of DM-linked skeletal complications remains poorly defined. Using advanced stem cell characterization techniques, we analyzed intrinsic and extrinsic determinants of mouse skeletal stem cell (mSSC) function to identify specific mSSC niche-related abnormalities that could impair skeletal repair in diabetic (Db) mice. We discovered that high serum concentrations of tumor necrosis factor-α directly repressed the expression of Indian hedgehog (Ihh) in mSSCs and in their downstream skeletogenic progenitors in Db mice...
January 11, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28076333/surgical-debulking-promotes-recruitment-of-macrophages-and-triggers-glioblastoma-phagocytosis-in-combination-with-cd47-blocking-immunotherapy
#5
Huaiyang Zhu, Lina Leiss, Ning Yang, Cecilie B Rygh, Siddhartha S Mitra, Samuel H Cheshier, Irving L Weissman, Bin Huang, Hrvoje Miletic, Rolf Bjerkvig, Per Ø Enger, Xingang Li, Jian Wang
Surgical resection is a standard component of treatment in the clinical management of patients with glioblastoma multiforme (GBM). However, experimental therapies are rarely investigated in the context of tumor debulking in preclinical models. Here, a surgical debulking GBM xenograft model was developed in nude rats, and was used in combination with CD47 blocking immunotherapy, a novel treatment strategy that triggers phagocytosis of tumor cells by macrophages in diverse cancer types including GBM. Orthotopic patient-derived xenograft tumors expressing CD47 were resected at 4 weeks after implantation and immediately thereafter treated with anti-CD47 or control antibodies injected into the cavity...
January 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/27996962/an-atlas-of-transcriptional-chromatin-accessibility-and-surface-marker-changes-in-human-mesoderm-development
#6
Pang Wei Koh, Rahul Sinha, Amira A Barkal, Rachel M Morganti, Angela Chen, Irving L Weissman, Lay Teng Ang, Anshul Kundaje, Kyle M Loh
Mesoderm is the developmental precursor to myriad human tissues including bone, heart, and skeletal muscle. Unravelling the molecular events through which these lineages become diversified from one another is integral to developmental biology and understanding changes in cellular fate. To this end, we developed an in vitro system to differentiate human pluripotent stem cells through primitive streak intermediates into paraxial mesoderm and its derivatives (somites, sclerotome, dermomyotome) and separately, into lateral mesoderm and its derivatives (cardiac mesoderm)...
December 20, 2016: Scientific Data
https://www.readbyqxmd.com/read/27880904/lyve1-marks-the-divergence-of-yolk-sac-definitive-hemogenic-endothelium-from-the-primitive-erythroid-lineage
#7
Lydia K Lee, Yasamine Ghorbanian, Wenyuan Wang, Yanling Wang, Yeon Joo Kim, Irving L Weissman, Matthew A Inlay, Hanna K A Mikkola
The contribution of the different waves and sites of developmental hematopoiesis to fetal and adult blood production remains unclear. Here, we identify lymphatic vessel endothelial hyaluronan receptor-1 (LYVE1) as a marker of yolk sac (YS) endothelium and definitive hematopoietic stem and progenitor cells (HSPCs). Endothelium in mid-gestation YS and vitelline vessels, but not the dorsal aorta and placenta, were labeled by Lyve1-Cre. Most YS HSPCs and erythro-myeloid progenitors were Lyve1-Cre lineage traced, but primitive erythroid cells were not, suggesting that they represent distinct lineages...
November 22, 2016: Cell Reports
https://www.readbyqxmd.com/read/27856424/eradication-of-canine-diffuse-large-b-cell-lymphoma-in-a-murine-xenograft-model-with-cd47-blockade-and-anti-cd20
#8
Kipp Weiskopf, Katie L Anderson, Daisuke Ito, Peter J Schnorr, Hirotaka Tomiyasu, Aaron M Ring, Kristin Bloink, Jem Efe, Sarah Rue, David Lowery, Amira Barkal, Susan Prohaska, Kelly M McKenna, Ingrid Cornax, Timothy D O'Brien, M Gerard O'Sullivan, Irving L Weissman, Jaime F Modiano
Cancer immunotherapies hold much promise, but their potential in veterinary settings has not yet been fully appreciated. Canine lymphomas are among the most common tumors of dogs and bear remarkable similarity to human disease. In this study, we examined the combination of CD47 blockade with anti-CD20 passive immunotherapy for canine lymphoma. The CD47/SIRPα axis is an immune checkpoint that regulates macrophage activation. In humans, CD47 is expressed on cancer cells and enables evasion from phagocytosis...
December 2016: Cancer Immunology Research
https://www.readbyqxmd.com/read/27814480/inhibition-of-apoptosis-overcomes-stage-related-compatibility-barriers-to-chimera-formation-in-mouse-embryos
#9
Hideki Masaki, Megumi Kato-Itoh, Yusuke Takahashi, Ayumi Umino, Hideyuki Sato, Keiichi Ito, Ayaka Yanagida, Toshinobu Nishimura, Tomoyuki Yamaguchi, Masumi Hirabayashi, Takumi Era, Kyle M Loh, Sean M Wu, Irving L Weissman, Hiromitsu Nakauchi
Cell types more advanced in development than embryonic stem cells, such as EpiSCs, fail to contribute to chimeras when injected into pre-implantation-stage blastocysts, apparently because the injected cells undergo apoptosis. Here we show that transient promotion of cell survival through expression of the anti-apoptotic gene BCL2 enables EpiSCs and Sox17(+) endoderm progenitors to integrate into blastocysts and contribute to chimeric embryos. Upon injection into blastocyst, BCL2-expressing EpiSCs contributed to all bodily tissues in chimeric animals while Sox17(+) endoderm progenitors specifically contributed in a region-specific fashion to endodermal tissues...
November 3, 2016: Cell Stem Cell
https://www.readbyqxmd.com/read/27763252/myeloid-cell-origins-differentiation-and-clinical-implications
#10
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
https://www.readbyqxmd.com/read/27510901/hematopoietic-stem-cell-transplantation-in-immunocompetent-hosts-without-radiation-or-chemotherapy
#11
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
https://www.readbyqxmd.com/read/27492049/breaking-down-the-barriers-to-precision-cancer-nanomedicine
#12
REVIEW
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...
February 2017: Trends in Biotechnology
https://www.readbyqxmd.com/read/27477289/antibody-therapy-targeting-cd47-and-cd271-effectively-suppresses-melanoma-metastasis-in-patient-derived-xenografts
#13
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
https://www.readbyqxmd.com/read/27437576/cd47-blocking-antibodies-restore-phagocytosis-and-prevent-atherosclerosis
#14
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
https://www.readbyqxmd.com/read/27419872/mapping-the-pairwise-choices-leading-from-pluripotency-to-human-bone-heart-and-other-mesoderm-cell-types
#15
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
https://www.readbyqxmd.com/read/27392224/cirm-and-ukrmp-different-ways-to-invest-in-regenerative-medicine
#16
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
https://www.readbyqxmd.com/read/27294525/cd47-blocking-immunotherapies-stimulate-macrophage-mediated-destruction-of-small-cell-lung-cancer
#17
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
https://www.readbyqxmd.com/read/27263782/identification-of-human-erythroid-lineage-committed-progenitors
#18
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...
May 2016: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/27217570/developmental-cell-death-programs-license-cytotoxic-cells-to-eliminate-histocompatible-partners
#19
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
https://www.readbyqxmd.com/read/27035983/identification-of-tumorigenic-cells-and-therapeutic-targets-in-pancreatic-neuroendocrine-tumors
#20
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
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