Research in the Weissman Lab

Stem cell biology in health and disease and the development of macrophage-based immunotherapy:

Tissue stem cells are rare and only make the maturing and mature cells of the tissue they serve [HSC for blood, CNS stem cells for brain, skeletal stem cells for bone and cartilage and bone marrow inductive microenvironments, etc.]. Within a tissue they are the only cells that can self-renew throughout life. While the usual outcome is tissue and organ homeostasis, stem cells can accumulate and propagate mutations over many years, and those mutant stem cells can contribute to disease. Mutations that arise in any non-stem cell in a tissue are lost via the limited lifespan of non self-renewing cells. In leukemic cells, the lab discovered up-regulation of CD47 that acts as a ‘don’t eat me signal for macrophages and allows cancer cells to evade an immune response. They developed anti-CD47 as a cancer immunotherapy and continue to investigate how macrophages recognize and eliminate unhealthy cells, with a prospect of advancing medicine. 

The biology of HSC and their niche: Weissman was first to identify, prospectively isolate, and transplant hematopoietic [blood-forming] stem cells, called HSC from mice and humans. HSCs generate and regenerate the entire blood and immune systems throughout life. The lab has then isolated and studied the progenitor steps between the HSC and each of the blood cell type produced. He has also traced the formation of HSC during mouse embryogenesis and fetal development, and for all of these candidate stem and progenitor cells has optimized single cell RNAseq and utilized ATACseq and CHIPseq to elucidate the steady state expression of suites of genes that characterize each stem and progenitor cell in both species. These technologies have allowed the lab to propose candidate genes whose expression either characterize the molecular fingerprints of those cells, but point toward the events required for stem cell self-renewal and for differentiation to the next cell in the developmental pathways. To study HSC and their niche, the lab generated unique reporter mouse models in which HSC expressing a fluorescent marker, HoxB5.mCherry exist as single cells attached to a subtype of bone marrow blood vessel cell, surrounded also by stromal cells from the skeletal stem cell. In parabiotic pairs, mice with a joined vasculature to each other, these marked HSC migrate from one mouse to the partner bone marrow to occupy one of these vascular niches. Working out how these interactions and migrations occur and the molecules that are responsible is a current interest of the lab.

Human Brain Stem Cells [CNS SC]: Weissman and colleagues identified and prospectively isolated human fetal brain stem cells, and upon their transplantation into the brains of immune deficient mice, found that these CNS SC home to mouse brain stem cell niches near the lateral ventricles and in the dentate gyrus of the hippocampus. The progeny of these human CNS SC self-renew in these niches, migrate their progeny in a site appropriate manner long distances through the brain, and differentiate to neurons, astrocytes, and oligodendrocytes in site appropriate manners as well. This allows one to begin to understand adult human CNS SC behaviors. These human CNS SC can engraft in patients and have regenerative and neuroprotective properties. Each CNS SC can be propagated in vitro into clonal spheres of CNS SC. Recently students in the Weissman lab have found how to identify, isolate grow, and transplant human CNS SC from surgical samples. 

Stem Cells, Clonal Precancer Cells, and Progeny Cancer Stem Cells: Over the past 20 years the Weissman lab developed a method to identify mutations in single cells, and using that showed that preclinical progression occurs due to stepwise accumulation of driver mutations in a clone of HSCs leading to clonal expansions of preleukemic HSCs, competing with normal HSC for the single HSC cell niches, with the last step forming leukemia stem cells [LSC]. While random passenger mutations also occur, sometime creating new antigens; passenger mutations do not contribute to clonal expansions. The preleukemic HSC clones can become disease cells in CML, MDS, and acute leukemias. This model of preclinical cancer progression through accumulation of mutations in stem cells should apply to any somatic tissue. Work in the lab is currently focused on studying neural stem cells, their generation of oligolineage progenitors to form the brain neuropoietic tree similar to the hematopoietic  tree, to use them for study single cell RNAseq to discover genes enforcing or preventing each step of differentiation, and to identify genes that allow their progeny to self-renew, migrate, and differentiate in a site-appropriate manner. A current project in the lab is to isolate CNS-SC from surgical samples of brain tumors resected from patients with incurable brain cancers, to look for the order in which driver and passenger mutations occur, and to use their clonal expansion to neurospheres to work out the in vivo biological consequences of each driver mutation. 

Macrophage regulation and its therapeutic application: By comparing leukemic to healthy hematopietic stem cells, the Weissman lab has identified CD47 overexpression on LSC, and then on all cancers tested. They showed that CD47 is a cell surface molecule used by cancer cells to evade macrophage phagocytosis by binding to its receptor, SIRPa on macrophages. This led to the development of a new type of immunotherapy based on macrophage checkpoint inhibition through blockade of CD47 which is perhaps the first target  expressed on all human cancers tested. In pre-clinical research using patient-derived xenografts, we showed dramatic effects in the treatment of diverse types of human cancer with anti-CD47 antibodies or blocking agents that neutralize the inhibitory effect of CD47-SIRPa interaction and unleashes the ability of macrophages to engulf and eliminate cancer cells.  Importantly, antibody blockade of CD47 did not affect normal cells expressing CD47. This suggested that cancer cells but not normal cells display an ‘eat me’ signal, which they discovered to be calreticulin, a signal recognized by macrophage prophagocytic receptor CD91. Blockade of CD47 allows macrophage removal only of cells that express calreticulin on their surface. Weissman et al discovered that calreticulin is mainly produced and secreted by activated macrophages, and that it binds to nearby cancer cells through recognition of surface asialoglycans, presumably via sialic acid removing enzymes that create the calreticulin binding sites. The molecular and cellular mechanisms for this system are currently under study. The lab has also found 3 additional don’t eat me molecules and their macrophage receptors. 

Our findings in collaboration with the Leeper lab re Atherosclerosis: This collaboration has shown that atherosclerotic plaque formation involves the clonal expansion of arterial smooth muscle cells from local stem or progenitor cells. These cells display both CD47 and calreticulin on their surface. Treatment with anti-CD47 antibodies in a mouse model (high fat diet on a genetically susceptible background), resulted in the elimination of atherosclerotic lesions, and preliminary studies implicate this process in human atherosclerosis, a process that leads to heart attacks, stroke, aortic aneurysms, and loss of tissues in diabetic atherosclerosis. Current research in the lab continues to explore the role of macrophages in disease prevention and treatment, through understanding how macrophages recognize their target cells, and the signals that impact the ability of these cells to maintain tissue integrity and sustain a state of health. 


Stem cell research in a marine model organism: At the Hopkins Marine Station, the Weissman lab has space where it’s been conducting stem cell research in the marine model organism Botryllus schlosseri.  This model organism has very interesting stem cell biology and immunology as related above.. It is a colonial organism, in which each individual within the colony undergoes a complete regeneration cycle weekly through a process of budding. When two adjacent colonies develop vascular anastomoses, stem cells from one colony can compete with stem cells of the other; for the germline stem cells, there is always a winner and a loser strain. Practically what this means is that stem cells from one colony invade the other and can take over the germline so that the invaded colony will now produce gametes, reproductive cells, of the genotype of its neighbor.

The discovery of this process is what led Weissman to realize that stem cells can compete and to hypothesize and then prove that both spermatogenic stem cells compete in mice, and led to the concept and proof of competition in preleukemic clonal expansions, in the leukemias and in aging.  

A current list of publications

 

Virginia & D.K. Ludwig Professor of Clinical Investigation in Cancer Research, Professor of Pathology, and of Developmental Biology

Publications

  • Radiotherapy in combination with CD47 blockade elicits a macrophage-mediated abscopal effect. Nature cancer Nishiga, Y., Drainas, A. P., Baron, M., Bhattacharya, D., Barkal, A. A., Ahrari, Y., Mancusi, R., Ross, J. B., Takahashi, N., Thomas, A., Diehn, M., Weissman, I. L., Graves, E. E., Sage, J. 2022

    Abstract

    Radiation therapy is a mainstay of cancer treatment but does not always lead to complete tumor regression. Here we combine radiotherapy with blockade of the 'don't-eat-me' cell-surface molecule CD47 in small cell lung cancer (SCLC), a highly metastatic form of lung cancer. CD47 blockade potently enhances the local antitumor effects of radiotherapy in preclinical models of SCLC. Notably, CD47 blockade also stimulates off-target 'abscopal' effects inhibiting non-irradiated SCLC tumors in mice receiving radiation. These abscopal effects are independent of T cells but require macrophages that migrate into non-irradiated tumor sites in response to inflammatory signals produced by radiation and are locally activated by CD47 blockade to phagocytose cancer cells. Similar abscopal antitumor effects were observed in other cancer models treated with radiation and CD47 blockade. The systemic activation of antitumor macrophages following radiotherapy and CD47 blockade may be particularly important in patients with cancer who suffer from metastatic disease.

    View details for DOI 10.1038/s43018-022-00456-0

    View details for PubMedID 36411318

  • Increased macrophage phagocytic activity with TLR9 agonist conjugation of an anti- Borrelia burgdorferi monoclonal antibody. Clinical immunology (Orlando, Fla.) Jahanbani, S., Hansen, P. S., Blum, L. K., Bastounis, E. E., Ramadoss, N. S., Pandrala, M., Kirschmann, J. M., Blacker, G. S., Love, Z. Z., Weissman, I. L., Nemati, F., Tal, M. C., Robinson, W. H. 2022: 109180

    Abstract

    Borrelia burgdorferi (Bb) infection causes Lyme disease, for which there is need for more effective therapies. Here, we sequenced the antibody repertoire of plasmablasts in Bb-infected humans. We expressed recombinant monoclonal antibodies (mAbs) representing the identified plasmablast clonal families, and identified their binding specificities. Our recombinant anti-Bb mAbs exhibit a range of activity in mediating macrophage phagocytosis of Bb. To determine if we could increase the macrophage phagocytosis-promoting activity of our anti-Bb mAbs, we generated a TLR9-agonist CpG-oligo-conjugated anti-BmpA mAb. We demonstrated that our CpG-conjugated anti-BmpA mAb exhibited increased peak Bb phagocytosis at 12-24 h, and sustained macrophage phagocytosis over 60+ hrs. Further, our CpG-conjugated anti-BmpA mAb induced macrophages to exhibit a sustained activation morphology. Our findings demonstrate the potential for TLR9-agonist CpG-oligo conjugates to enhance mAb-mediated clearance of Bb, and this approach might also enhance the activity of other anti-microbial mAbs.

    View details for DOI 10.1016/j.clim.2022.109180

    View details for PubMedID 36396013

  • MDS-482 Impact Of Magrolimab in Combination With Azacitidine on Red Blood Cells (RBCs) in Patients With Higher-Risk Myelodysplastic Syndromes (HR MDS). Clinical lymphoma, myeloma & leukemia Chen, J., Johnson, L., McKenna, K., Choi, T., Duan, J., Feng, D., Tsai, J., Garcia-Martin, N., Sompalli, K., Maute, R., Vyas, P., Majeti, R., Takimoto, C., Liu, J., Ramsingh, G., Chao, M., Volkmer, J., Weissman, I. 2022; 22 Suppl 2: S317-S318

    Abstract

    CONTEXT: Magrolimab is an antibody blocking CD47, a "don't eat me" signal expressed on cancer cells, to escape immune surveillance and macrophage-mediated clearance. Preclinical studies found that CD47 is critical to RBC homeostasis, with CD47 deficiency decreasing RBC half-life. Fc-mediated opsonization also depletes RBCs, raising concerns that potential on-target anemia could result from the use of anti-CD47 agents. Several clinical trials demonstrated that magrolimab can be safely administered as monotherapy, with an initial lower "priming" dose yielding transient anemia with compensatory reticulocytosis and no anemia observed at higher maintenance doses. However, the underlying mechanism has not been fully defined.OBJECTIVE: To describe manageable anemia in magrolimab-treated patients and further investigate the underlying mechanisms in preclinical models.DESIGN: Prospective analysis from a ph1 trial of magrolimab+azacitidine (NCT03248479). Complete blood counts (CBCs), peripheral blood, and bone marrow (BM) were collected from patients at prespecified time points. CBCs were measured, and blood and BM samples were analyzed by flow cytometry for CD47 expression on RBCs and white blood cells (WBCs). Preclinical modeling studies were conducted with intact and Fc-deficient anti-mouse CD47 (MIAP410) and anti-human CD47 (magrolimab) antibodies in murine models, including C57BL/6J B-hSIRPA/hCD47 mice.PATIENTS: 57 patients with HR MDS.INTERVENTIONS: Magrolimab IV 1 mg/kg (priming) then 30 mg/kg QW, then Q2W (maintenance). Azacitidine 75 mg/m2 days 1-7 (each 28-day cycle).RESULTS: Treatment with magrolimab+azacitidine resulted in tolerable anemia that correlated with rapid, near-complete loss of CD47 in RBCs but not WBCs. The initial 1-mg/kg priming dose was sufficient for CD47 loss, which persisted with subsequent 30-mg/kg maintenance doses. Both findings are consistent with prior clinical observations of magrolimab monotherapy in patients with solid tumors and magrolimab+rituximab in patients with lymphoma. Our preclinical studies with mouse models revealed that CD47 removal is mechanistically independent of previously described RBC antigen modulation mechanisms and cellular compartments. Instead, this CD47 loss requires anti-CD47 cross-linking between RBCs and non-RBCs.CONCLUSIONS: These results support the idea that on-target magrolimab-mediated anemia is mitigated by a near-complete loss of RBC CD47. Patients with HR MDS treated with magrolimab+azacitidine had tolerable anemia with priming and maintenance doses.

    View details for DOI 10.1016/S2152-2650(22)01421-5

    View details for PubMedID 36163968

  • Chimpanzee and pig-tailed macaque iPSCs: Improved culture and generation of primate cross-species embryos. Cell reports Roodgar, M., Suchy, F. P., Nguyen, L. H., Bajpai, V. K., Sinha, R., Vilches-Moure, J. G., Van Bortle, K., Bhadury, J., Metwally, A., Jiang, L., Jian, R., Chiang, R., Oikonomopoulos, A., Wu, J. C., Weissman, I. L., Mankowski, J. L., Holmes, S., Loh, K. M., Nakauchi, H., VandeVoort, C. A., Snyder, M. P. 2022; 40 (9): 111264

    Abstract

    As our closest living relatives, non-human primates uniquely enable explorations of human health, disease, development, and evolution. Considerable effort has thus been devoted to generating induced pluripotent stem cells (iPSCs) from multiple non-human primate species. Here, we establish improved culture methods for chimpanzee (Pan troglodytes) and pig-tailed macaque (Macaca nemestrina) iPSCs. Such iPSCs spontaneously differentiate in conventional culture conditions, but can be readily propagated by inhibiting endogenous WNT signaling. As a unique functional test of these iPSCs, we injected them into the pre-implantation embryos of another non-human species, rhesus macaques (Macaca mulatta). Ectopic expression of gene BCL2 enhances the survival and proliferation of chimpanzee and pig-tailed macaque iPSCs within the pre-implantation embryo, although the identity and long-term contribution of the transplanted cells warrants further investigation. In summary, we disclose transcriptomic and proteomic data, cell lines, and cell culture resources that may be broadly enabling for non-human primate iPSCs research.

    View details for DOI 10.1016/j.celrep.2022.111264

    View details for PubMedID 36044843

  • ISSCR Presidents look back on their presidency, the evolution of the field, and the Society STEM CELL REPORTS Zon, L., Keller, G., Daley, G. Q., Watt, F. M., Weissman, I. L., Fuchs, E., Gage, F. H., Yamanaka, S., Rossant, J., Morrison, S., Temple, S., Clevers, H. C., Srivastava, D., Mummery, C. L., Little, M. 2022; 17 (6): 1237-1244

    Abstract

    In celebration of the ISSCR's 20th anniversary we asked past ISSCR presidents the question, "During your presidential year, what key achievements or issue(s) in the field stood out to you?" The collection of responses provides a glimpse of the evolution of the field and the ISSCR over the past 20 years.

    View details for Web of Science ID 000825548800003

    View details for PubMedID 35705012

    View details for PubMedCentralID PMC9214063

  • Systemic and mucosal IgA responses are variably induced in response to SARS-CoV-2 mRNA vaccination and are associated with protection against subsequent infection. Mucosal immunology Sheikh-Mohamed, S., Isho, B., Chao, G. Y., Zuo, M., Cohen, C., Lustig, Y., Nahass, G. R., Salomon-Shulman, R. E., Blacker, G., Fazel-Zarandi, M., Rathod, B., Colwill, K., Jamal, A., Li, Z., de Launay, K. Q., Takaoka, A., Garnham-Takaoka, J., Patel, A., Fahim, C., Paterson, A., Li, A. X., Haq, N., Barati, S., Gilbert, L., Green, K., Mozafarihashjin, M., Samaan, P., Budylowski, P., Siqueira, W. L., Mubareka, S., Ostrowski, M., Rini, J. M., Rojas, O. L., Weissman, I. L., Tal, M. C., McGeer, A., Regev-Yochay, G., Straus, S., Gingras, A., Gommerman, J. L. 2022

    Abstract

    Although SARS-CoV-2 infects the upper respiratory tract, we know little about the amount, type, and kinetics of antibodies (Ab) generated in the oral cavity in response to COVID-19 vaccination. We collected serum and saliva samples from participants receiving two doses of mRNA COVID-19 vaccines and measured the level of anti-SARS-CoV-2 Ab. We detected anti-Spike and anti-Receptor Binding Domain (RBD) IgG and IgA, as well as anti-Spike/RBD associated secretory component in the saliva of most participants after dose 1. Administration of a second dose of mRNA boosted the IgG but not the IgA response, with only 30% of participants remaining positive for IgA at this timepoint. At 6 months post-dose 2, these participants exhibited diminished anti-Spike/RBD IgG levels, although secretory component-associated anti-Spike Ab were more stable. Examining two prospective cohorts we found that participants who experienced breakthrough infections with SARS-CoV-2 variants had lower levels of vaccine-induced serum anti-Spike/RBD IgA at 2-4 weeks post-dose 2 compared to participants who did not experience an infection, whereas IgG levels were comparable between groups. These data suggest that COVID-19 vaccines that elicit a durable IgA response may have utility in preventing infection.

    View details for DOI 10.1038/s41385-022-00511-0

    View details for PubMedID 35468942

  • 2021 Jeffrey M. Hoeg Award Lecture: Defining the Role of Efferocytosis in Cardiovascular Disease: A Focus on the CD47 (Cluster of Differentiation 47) Axis. Arteriosclerosis, thrombosis, and vascular biology Jarr, K., Kojima, Y., Weissman, I. L., Leeper, N. J. 2022: 101161ATVBAHA122317049

    Abstract

    A key feature of atherogenesis is the accumulation of diseased and dying cells within the lesional necrotic core. While the burden of intraplaque apoptotic cells may be driven in part by an increase in programmed cell death, mounting evidence suggests that their presence may primarily be dictated by a defect in programmed cell removal, or efferocytosis. In this brief review, we will summarize the evidence suggesting that inflammation-dependent changes within the plaque render target cells inedible and reduce the appetite of lesional phagocytes. We will present the genetic causation studies, which indicate these phenomena promote lesion expansion and plaque vulnerability, and the interventional data which suggest that these processes can be reversed. Particular emphasis is provided related to the antiphagocytic CD47 (cluster of differentiation 47) do not eat me axis, which has emerged as a novel antiatherosclerotic translational target that is predicted to provide benefit independent of traditional cardiovascular risk factors.

    View details for DOI 10.1161/ATVBAHA.122.317049

    View details for PubMedID 35387480

  • Molecular hallmarks of heterochronic parabiosis at single-cell resolution. Nature Palovics, R., Keller, A., Schaum, N., Tan, W., Fehlmann, T., Borja, M., Kern, F., Bonanno, L., Calcuttawala, K., Webber, J., McGeever, A., Tabula Muris Consortium, Luo, J., Pisco, A. O., Karkanias, J., Neff, N. F., Darmanis, S., Quake, S. R., Wyss-Coray, T., Almanzar, N., Antony, J., Baghel, A. S., Bakerman, I., Bansal, I., Barres, B. A., Beachy, P. A., Berdnik, D., Bilen, B., Brownfield, D., Cain, C., Chan, C. K., Chen, M. B., Clarke, M. F., Conley, S. D., Demers, A., Demir, K., de Morree, A., Divita, T., du Bois, H., Ebadi, H., Espinoza, F. H., Fish, M., Gan, Q., George, B. M., Gillich, A., Gomez-Sjoberg, R., Green, F., Genetiano, G., Gu, X., Gulati, G. S., Hahn, O., Haney, M. S., Hang, Y., Harris, L., He, M., Hosseinzadeh, S., Huang, A., Huang, K. C., Iram, T., Isobe, T., Ives, F., Jones, R. C., Kao, K. S., Karnam, G., Kershner, A. M., Khoury, N., Kim, S. K., Kiss, B. M., Kong, W., Krasnow, M. A., Kumar, M. E., Kuo, C. S., Lam, J., Lee, D. P., Lee, S. E., Lehallier, B., Leventhal, O., Li, G., Li, Q., Liu, L., Lo, A., Lu, W., Lugo-Fagundo, M. F., Manjunath, A., May, A. P., Maynard, A., McKay, M., McNerney, M. W., Merrill, B., Metzger, R. J., Mignardi, M., Min, D., Nabhan, A. N., Ng, K. M., Nguyen, P. K., Noh, J., Nusse, R., Patkar, R., Peng, W. C., Penland, L., Pollard, K., Puccinelli, R., Qi, Z., Rando, T. A., Rulifson, E. J., Segal, J. M., Sikandar, S. S., Sinha, R., Sit, R. V., Sonnenburg, J., Staehli, D., Szade, K., Tan, M., Tato, C., Tellez, K., Torrez Dulgeroff, L. B., Travaglini, K. J., Tropini, C., Tsui, M., Waldburger, L., Wang, B. M., van Weele, L. J., Weinberg, K., Weissman, I. L., Wosczyna, M. N., Wu, S. M., Xiang, J., Xue, S., Yamauchi, K. A., Yang, A. C., Yerra, L. P., Youngyunpipatkul, J., Yu, B., Zanini, F., Zardeneta, M. E., Zee, A., Zhao, C., Zhang, F., Zhang, H., Zhang, M. J., Zhou, L., Zou, J. 2022

    Abstract

    The ability to slow or reverse biological ageing would have major implications for mitigating disease risk and maintaining vitality1. Although an increasing number of interventions show promise for rejuvenation2, their effectiveness on disparate cell types across the body and the molecular pathways susceptible to rejuvenation remain largely unexplored. Here we performed single-cell RNA sequencing on 20 organs to reveal cell-type-specific responses to young and aged blood in heterochronic parabiosis. Adipose mesenchymal stromal cells, haematopoietic stem cells and hepatocytes are among those cell types that are especially responsive. On the pathway level, young blood invokes new gene sets in addition to reversing established ageing patterns, with the global rescue of genes encoding electron transport chain subunits pinpointing a prominent role of mitochondrial function in parabiosis-mediated rejuvenation. We observed an almost universal loss of gene expression with age that is largely mimicked by parabiosis: aged blood reduces global gene expression, and young blood restores it in select cell types. Together, these data lay the groundwork for a systemic understanding of the interplay between blood-borne factors and cellular integrity.

    View details for DOI 10.1038/s41586-022-04461-2

    View details for PubMedID 35236985

  • CD47 Blockade Leads to Chemokine-Dependent Monocyte Infiltration and Loss of B Cells from the Splenic Marginal Zone. Journal of immunology (Baltimore, Md. : 1950) Yiu, Y. Y., Hansen, P. S., Torrez Dulgeroff, L. B., Blacker, G., Myers, L., Galloway, S., Gars, E., Colace, O., Mansfield, P., Hasenkrug, K. J., Weissman, I. L., Tal, M. C. 2022

    Abstract

    CD47 is an important innate immune checkpoint through its interaction with its inhibitory receptor on macrophages, signal-regulatory protein alpha (SIRPalpha). Therapeutic blockade of CD47-SIRPalpha interactions is a promising immuno-oncology treatment that promotes clearance of cancer cells. However, CD47-SIRPalpha interactions also maintain homeostatic lymphocyte levels. In this study, we report that the mouse splenic marginal zone B cell population is dependent on intact CD47-SIRPalpha interactions and blockade of CD47 leads to the loss of these cells. This depletion is accompanied by elevated levels of monocyte-recruiting chemokines CCL2 and CCL7 and infiltration of CCR2+Ly6Chi monocytes into the mouse spleen. In the absence of CCR2 signaling, there is no infiltration and reduced marginal zone B cell depletion. These data suggest that CD47 blockade leads to clearance of splenic marginal zone B cells.

    View details for DOI 10.4049/jimmunol.2100352

    View details for PubMedID 35236754

  • The pleiotropic benefits of statins include the ability to reduce CD47 and amplify the effect of pro-efferocytic therapies in atherosclerosis. Nature cardiovascular research Jarr, K., Ye, J., Kojima, Y., Ye, Z., Gao, H., Schmid, S., Luo, L., Baylis, R. A., Lotfi, M., Lopez, N., Eberhard, A. V., Smith, B. R., Weissman, I. L., Maegdefessel, L., Leeper, N. J. 2022; 1 (3): 253-262

    Abstract

    The pleiotropic benefits of statins may result from their impact on vascular inflammation. The molecular process underlying this phenomenon is not fully elucidated. Here, RNA sequencing designed to investigate gene expression patterns following CD47-SIRPalpha inhibition identifies a link between statins, efferocytosis, and vascular inflammation. In vivo and in vitro studies provide evidence that statins augment programmed cell removal by inhibiting the nuclear translocation of NFkappaB1 p50 and suppressing the expression of the critical 'don't eat me' molecule, CD47. Statins amplify the phagocytic capacity of macrophages, and thus the anti-atherosclerotic effects of CD47-SIRPalpha blockade, in an additive manner. Analyses of clinical biobank specimens suggest a similar link between statins and CD47 expression in humans, highlighting the potential translational implications. Taken together, our findings identify efferocytosis and CD47 as pivotal mediators of statin pleiotropy. In turn, statins amplify the anti-atherosclerotic effects of pro-phagocytic therapies independently of any lipid-lowering effect.

    View details for DOI 10.1038/s44161-022-00023-x

    View details for PubMedID 35990913