Weissman directs a research group consisting of graduate students, medical student-scientists, and postdoctoral fellows, all of whom study stem cell biology and regenerative medicine. He has trained and supervised hundreds of students and fellows, authored more than scientific articles and has numerous awards and honorary degrees for his research accomplishments. Weissman is an expert in the field of hematopoiesis, leukemia, and hematopoietic stem cells [HSC], and most recently, the clonal events leading from HSC to leukemia stem cells..
His research also encompasses the phylogeny and developmental biology of the cells that make up the blood-forming and immune systems. He has a laboratory at Hopkins Marine Station of Stanford University, where he studies the histocompatibility systems in colonial protochordate, a system which he proposed evolved to prevent predatory germline stem cell lineages from passing from one individual to another in multi-individual colonies that share a common extracorporeal blood vascular system; only histocompatible stem cells can colonize allogeneic natural parabionts.
His laboratory was first to identify and isolate the blood-forming stem cell [HSC] from mice, and has defined, by lineage analysis, the stages of development between the stem cells and mature progeny. His laboratories have also discovered the human HSC, a human brain-forming stem cell population, mouse skeletal muscle stem cells, and an osteochondral stem cell in mice. He has worked in the area of cancer since , and is a leader in the field of cancer stem cell biology. In recent years his work has included studying the potential of CD47 as a cancer therapeutic and identifying cancer stem cells from a variety of blood and solid cancers.
This research brings into focus the primary role of phagocytic cells such as macrophages of the innate immune system, in tumor surveillance. Stanford is currently not accepting patients for this trial. For more information, please contact Linda Quinn, View full details. This study will help us understand the gene expression profiles of lung cancer. We will identify genes related to lung cancer development, their growth and metastasis to the lung. In addition, we will examine the role nicotine in the development and progression of lung tumors of smokers, ex-smokers, non-smokers on supplemental nicotine and non smokers with no exposure to nicotine.
For more information, please contact Susan Jacobs, RN, Mutations in Wnt downstream signalling components have revealed diverse functions thought to be carried out by Wnt ligands themselves.
However, redundancy between the 19 mammalian Wnt proteins and 10 FZD receptors and Wnt hydrophobicity have made it difficult to attribute these functions directly to Wnt ligands. However, the interchangeability, functional cooperation and relative contributions of Wnt versus RSPO ligands to in vivo canonical Wnt signalling and ISC biology remain unknown. Here we identify the functional roles of Wnt and RSPO ligands in the intestinal crypt stem-cell niche.
However, gain-of-function studies using RSPO ligands and a new non-lipidated Wnt analogue reveal that these ligands have qualitatively distinct, non-interchangeable roles in ISCs. This functionally non-equivalent yet cooperative interaction between Wnt and RSPO ligands establishes a molecular precedent for regulation of mammalian stem cells by distinct priming and self-renewal factors, with broad implications for precise control of tissue regeneration. View details for DOI View details for PubMedID View details for Web of Science ID Morbidity and mortality associated with pediatric malignant primary brain tumors remain high in the absence of effective therapies.
We demonstrate the effect of a humanized anti-CD47 antibody, Hu5F9-G4, on five aggressive and etiologically distinct pediatric brain tumors: group 3 medulloblastoma primary and metastatic , atypical teratoid rhabdoid tumor, primitive neuroectodermal tumor, pediatric glioblastoma, and diffuse intrinsic pontine glioma. Hu5F9-G4 demonstrated therapeutic efficacy in vitro and in vivo in patient-derived orthotopic xenograft models. Intraventricular administration of Hu5F9-G4 further enhanced its activity against disseminated medulloblastoma leptomeningeal disease.
Notably, Hu5F9-G4 showed minimal activity against normal human neural cells in vitro and in vivo, a phenomenon reiterated in an immunocompetent allograft glioma model.
Thus, Hu5F9-G4 is a potentially safe and effective therapeutic agent for managing multiple pediatric central nervous system malignancies. 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.
Therefore, a better understanding of the important native and acquired biological processes that dictate the fate of nanomedicine is integral to developing more effective individualized platforms for treating cancer patients.
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.
When hedgehog signaling was inhibited during fracture repair, injury-induced mSSC expansion was suppressed, resulting in impaired healing. We reversed this deficiency by precise delivery of purified Ihh to the fracture site via a specially formulated, slow-release hydrogel. In the presence of exogenous Ihh, the injury-induced expansion and osteogenic potential of mSSCs were restored, culminating in the rescue of Db bone healing.
Our results present a feasible strategy for precise treatment of molecular aberrations in stem and progenitor cell populations to correct skeletal manifestations of systemic disease. Immune checkpoint blockade has emerged as a promising cancer treatment paradigm. Unfortunately, there are still a large number of patients and malignancies that do not respond to therapy.
A major barrier to validating biomarkers for the prediction and monitoring of responders to clinical checkpoint blockade has been the lack of imaging tools to accurately assess dynamic immune checkpoint expression. Six HAC-PD1 radiotracer variants were developed and used in preclinical imaging and biodistribution studies to assess their ability to detect human PD-L1 expression in vivo. Radiotracer design modifications included chelate, glycosylation, and radiometal. When the tumors had grown to an average size of 1 cm in diameter, mice were injected with 0.
At 1 h after injection, organs were harvested for biodistribution. Of the practical immuno-PET tracer modifications considered, glycosylation was the most prominent design factor affecting tracer uptake, specificity, and clearance.
We reasoned that because of the scaffold's small size 14 kDa , its pharmacokinetics may be suitable for labeling with the short-lived and widely clinically available radiometal 68 Ga. This work provides a template for assessing immuno-PET tracer design parameters and supports the translation of small engineered protein radiotracers for imaging human immune checkpoints. Most YS HSPCs and erythro-myeloid progenitors were Lyve1-Cre lineage traced, but primitive erythroid cells were not, suggesting that they represent distinct lineages.
FL proerythroblast marking was extensive at embryonic day E Lyve1-Cre thus marks the divergence between YS primitive and definitive hematopoiesis and provides a tool for targeting YS definitive hematopoiesis and FL colonization. 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. In addition, BCL2 expression enabled rat EpiSCs to contribute to mouse embryonic chimeras, thereby forming interspecies chimeras that could survive to adulthood.
Our system therefore provides a method to overcome cellular compatibility issues that typically restrict chimera formation. Application of this type of approach could broaden the use of embryonic chimeras, including region-specific chimeras, for basic developmental biology research and regenerative medicine.
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 , 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. The stages of hematopoiesis have been defined in both mice and humans.
During embryological development, the earliest hematopoiesis takes place in yolk sac blood islands and then migrates to the fetal liver and hematopoietic organs. Some adult myeloid populations develop directly from yolk sac progenitors without apparent bone marrow intermediates, such as tissue-resident macrophages.
Hematopoiesis also changes over time, with a bias of the dominating HSCs toward myeloid development as animals age. Defects in myelopoiesis contribute to many hematologic disorders, and some of these can be overcome with therapies that target the aberrant stage of development.
Furthermore, insights into myeloid development have informed us of mechanisms of programmed cell removal. Therapeutics targeting CD47 represent a new strategy for treating cancer. Overall, an understanding of hematopoiesis and myeloid cell development has implications for regenerative medicine, hematopoietic cell transplantation, malignancy, and many other diseases.
Hematopoietic stem cell HSC transplantation can cure diverse diseases of the blood system, including hematologic malignancies, anemias, and autoimmune disorders. 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.
This targeted conditioning regimen that uses only biologic agents has the potential to transform the practice of HSC transplantation and enable its use in a wider spectrum of patients. 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. 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 CDblocking antibodies reverses this defect in efferocytosis, normalizes the clearance of diseased vascular tissue, and ameliorates atherosclerosis in multiple mouse models.
Similar to recent observations in cancer, impaired efferocytosis appears to play a pathogenic role in cardiovascular disease, but is not a fixed defect and may represent a novel therapeutic target. 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. Mapping stepwise chromatin and single-cell gene expression changes in mesoderm development uncovered somite segmentation, a previously unobservable human embryonic event transiently marked by HOPX expression. Collectively, this roadmap enables navigation of mesodermal development to produce transplantable human tissue progenitors and uncover developmental processes.
Small-cell lung cancer SCLC is a highly aggressive subtype of lung cancer with limited treatment options. In a murine model, administration of CDblocking antibodies or targeted inactivation of the Cd47 gene markedly inhibited SCLC tumor growth. Furthermore, using comprehensive antibody arrays, we identified several possible therapeutic targets on the surface of SCLC cells. This approach could enable personalized immunotherapeutic regimens in patients with SCLC and other cancers. 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.