Research in the Weissman Lab
Irving L. Weissman's research encompasses the phylogeny and developmental biology of the cells that make up the blood-forming and immune systems. His laboratory identified and isolated the blood-forming stem cell from mice, and has defined, by lineage analysis, the stages of development between the stem cells and mature progeny (granulocytes, macrophages, etc.). This required developing and cloning stromal cells of the hematolymphoid microenvironmentsfrom the bone marrow for myeloid and B cells, and from the thymus for T cells. While the adhesion molecules and factors from these stromal cells proved important as molecules (and the genes that encode them) for myeloid and B cells, the analysis of T cell development required in vivo studies of thymic development.
In addition, the Weissman laboratory has pioneered the study of the genes and proteins involved in cell adhesion events required for lymphocyte homing to lymphoid organs in vivo, either as a normal function or as events involved in malignant leukemic metastases.
The Weissman laboratory also has a small group at Hopkins Marine Station, where they have developed a model organism for laboratory and field study of allorecognitionthe invertebrate counterpart of transplantation immunity. Working with the protochordate Botryllus schlosseri (which has a chordate larval stage and an invertebrate adult form) they have identified a single major gene locus that governs rapid allorecognition, and 2-3 other loci involved in delayed allorecognition events. They are using this model to study the genes, proteins, and cells that govern protochordate allorecognition, and the effects of these genes on their population dynamics in the field.
- Non-equivalence of Wnt and R-spondin ligands during Lgr5(+) intestinal stem-cell self-renewal NATURE 2017; 545 (7653): 238-? Hide More
intestinal stem-cell self-renewal.
2017; 545 (7653): 238-242
The canonical Wnt/β-catenin signalling pathway governs diverse developmental, homeostatic and pathological processes. Palmitoylated Wnt ligands engage cell-surface frizzled (FZD) receptors and LRP5 and LRP6 co-receptors, enabling β-catenin nuclear translocation and TCF/LEF-dependent gene transactivation. 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. For example, individual mutations in Wnt ligands have not revealed homeostatic phenotypes in the intestinal epithelium-an archetypal canonical, Wnt pathway-dependent, rapidly self-renewing tissue, the regeneration of which is fueled by proliferative crypt Lgr5(+) intestinal stem cells (ISCs). R-spondin ligands (RSPO1-RSPO4) engage distinct LGR4-LGR6, RNF43 and ZNRF3 receptor classes, markedly potentiate canonical Wnt/β-catenin signalling, and induce intestinal organoid growth in vitro and Lgr5(+) ISCs in vivo. 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. We show that the default fate of Lgr5(+) ISCs is to differentiate, unless both RSPO and Wnt ligands are present. 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. Wnt proteins are unable to induce Lgr5(+) ISC self-renewal, but instead confer a basal competency by maintaining RSPO receptor expression that enables RSPO ligands to actively drive and specify the extent of stem-cell expansion. 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 10.1038/nature22313
View details for PubMedID 28467820
Disrupting the CD47-SIRP alpha anti-phagocytic axis by a humanized anti-CD47 antibody is an efficacious treatment for malignant pediatric brain tumors
SCIENCE TRANSLATIONAL MEDICINE
2017; 9 (381)
Morbidity and mortality associated with pediatric malignant primary brain tumors remain high in the absence of effective therapies. Macrophage-mediated phagocytosis of tumor cells via blockade of the anti-phagocytic CD47-SIRPα interaction using anti-CD47 antibodies has shown promise in preclinical xenografts of various human malignancies. 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.
View details for DOI 10.1126/scitranslmed.aaf2968
View details for Web of Science ID 000396307600001
View details for PubMedID 28298418
- Breaking Down the Barriers to Precision Cancer Nanomedicine TRENDS IN BIOTECHNOLOGY 2017; 35 (2): 159-171 Hide More
Pharmacological rescue of diabetic skeletal stem cell niches.
Science translational medicine
2017; 9 (372)
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. 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.
View details for DOI 10.1126/scitranslmed.aag2809
View details for PubMedID 28077677