Irving L. Weissman

Targeting CD24 activates macrophages to reduce tumor burden in preclinical models of solid tumors

Shows enhanced anti-tumor activity in solid tumors, suggesting CD24 as a key target for immunotherapy.

Defective efferocytosis drives atherosclerotic plaque expansion and represents a reversible therapeutic target.

Impaired efferocytosis is a major driver of atherosclerotic plaque progression and a potential therapeutic target.

Scalable single-cell total RNA sequencing unifies coding and noncoding transcriptomics

Xenophagocytosis blockade enhances interspecies chimerism

This analysis reveals xenophagocytosis as a barrier in transplantation, suggesting macrophages hinder xenogeneic chimerism.

Regional Signaling Controls Stem Cell-Mediated Regeneration in an Invertebrate Chordate

Analysis reveals how local signaling affects regeneration in Ciona robusta fragments, suggesting signaling cues are crucial for stem cell activation.

Abstract B052: PHST001, a humanized anti-CD24 antibody, induces phagocytosis of ovarian tumor cells in vitro and inhibits their growth in vivo

In vitro analysis shows PHST001 enhances phagocytosis by macrophages, suggesting significant in vivo tumor growth inhibition in ovarian cancer models.

The Effects of Essential Amino Acid Supplementation on Hippocampal Neurotrophin, Dopaminergic and Serotonergic Changes in an Overtraining Mouse Model

This study shows EAA supplementation improved neurotrophins and serotonin levels in mice with overtraining syndrome.

The Effect of an American Football Practice on Physical and Cognitive Performance and Recovery.

Observational analysis revealed physical performance declines but cognitive performance improvements in athletes, indicating unique recovery pathways.

Scalable single-cell total RNA-seq reveals non-coding programs in immunity, infection, and brain development

This study uncovers diverse non-coding rna programs in immune cells and brain tissues, suggesting new regulatory layers.

Beyond polyA: scalable single-cell total RNA-seq unifies coding and non-coding transcriptomics

Adapted techniques capture non-coding RNAs in diverse cell types, indicating new insights into gene regulation.

Modeling glioma intratumoral heterogeneity with primary human neural stem and progenitor cells

Gliomas are notorious for their intratumoral heterogeneity, which drives therapy resistance. Glioma tumor cells mimic a neural stem cell (NSC) hierarchy reminiscent of normal brain development. How intratumoral heterogeneity is shaped by cell-of-origin and various driver mutations is not fully understood. We develop a model of glioma initiation using neural stem and progenitor cells (NSPCs) purified from midgestational human brain tissue, including tripotent NSCs, bipotent glial progenitor cells (GPCs), and unipotent oligodendrocyte progenitor cells (OPCs). We transduced these isogenic lines with defined combinations of oncogenic drivers (TP53, NF1, CDK4, EGFR, and PDGFRA) and transplanted them into mice. We find that OPC-derived tumors harbored a higher proportion of differentiated oligodendrocyte-like cells, reminiscent of low-grade oligodendrogliomas. CDK4 drove a neuron-like subtype, while EGFR drove a GPC-like subtype. Our platform is highly adaptable and allows for modular and systematic interrogation of how cell-of-origin and specific driver mutations shape the tumor landscape.

Mouse lemur cell atlas informs primate genes, physiology and disease

, we performed large-scale single-cell RNA sequencing of 27 organs from mouse lemurs. We identified more than 750 molecular cell types, characterized their transcriptomic profiles and provided insight into primate evolution of cell types. Here we use the generated atlas to characterize mouse lemur genes, physiology, disease and mutations. We uncover thousands of previously unidentified lemur genes and hundreds of thousands of new splice junctions including over 85,000 primate splice junctions missing in mice. We systematically explore the lemur immune system by comparing global expression profiles of key immune genes in health and disease, and by mapping immune cell development, trafficking and activation. We characterize primate-specific and lemur-specific physiology and disease, including molecular features of the immune program, lemur adipocytes and metastatic endometrial cancer that resembles the human malignancy. We present expression patterns of more than 400 primate genes missing in mice, many with similar expression patterns to humans and some implicated in human disease. Finally, we provide an experimental framework for reverse genetic analysis by identifying naturally occurring nonsense mutations in three primate immune genes missing in mice and by analysing their transcriptional phenotypes. This work establishes a foundation for molecular and genetic analyses of mouse lemurs and prioritizes primate genes, isoforms, physiology and disease for future study.

Macrophages release neuraminidase and cleaved calreticulin for programmed cell removal

Calreticulin (CALR) is primarily an endoplasmic reticulum chaperone protein that also plays a key role in facilitating programmed cell removal (PrCR) by acting as an "eat-me" signal for macrophages, directing their recognition and engulfment of dying, diseased, or unwanted cells. Recent findings have demonstrated that macrophages can transfer their own CALR onto exposed asialoglycans on target cells, marking them for PrCR. Despite the critical role CALR plays in this process, the molecular mechanisms behind its secretion by macrophages and the formation of binding sites on target cells remain unclear. Our findings show that CALR undergoes C-terminal cleavage upon secretion, producing a truncated form that functions as the active eat-me signal detectable on target cells. We identify cathepsins as potential proteases involved in this cleavage process. Furthermore, we demonstrate that macrophages release neuraminidases, which modify the surface of target cells and facilitate CALR binding. These insights reveal a coordinated mechanism through which lipopolysaccharide (LPS)-activated macrophages regulate CALR cleavage and neuraminidase activity to mark target cells for PrCR. How they recognize the cells to be targeted remains unknown.

CAR macrophages with built-In CD47 blocker combat tumor antigen heterogeneity and activate T cells via cross-presentation

Macrophage-based cancer cellular therapy has gained substantial interest. However, the capability of engineered macrophages to target cancer heterogeneity and modulate adaptive immunity remains unclear. Here, exploiting the myeloid antibody-dependent cellular phagocytosis biology and phagocytosis checkpoint blockade, we report the enhanced synthetic phagocytosis receptor (eSPR) that integrate FcRγ-driven phagocytic chimeric antigen receptors (CAR) with built-in secreted CD47 blockers. The eSPR engineering empowers macrophages to combat tumor antigen heterogeneity. Transduced by adenoviral vectors, eSPR macrophages are intrinsically pro-inflammatory imprinted and resist tumoral polarization. Transcriptomically and phenotypically, eSPR macrophages elicit a more favorable tumor immune landscape. Mechanistically, eSPR macrophages in situ stimulate CD8 T cells via phagocytosis-dependent antigen cross-presentation. We also validate the functionality of the eSPR system in human primary macrophages. Engineering macrophages to express chimeric antigen receptors (CARs) for targeted tumor cell phagocytosis has shown encouraging results. Here the authors engineer macrophages with enhanced synthetic phagocytosis receptors which incorporate a FcRɣ-driven phagocytosis CAR and an auto-secreted CD47 blocker, showing improved anti-tumor efficacy

Immunotherapy of endometrial cancer via CD47 blockade-mediated macrophage phagocytosis

The interaction between CD47 expressed on cancer cells and signal regulatory protein-α located on macrophages blocks the phagocytosis of tumor cells by macrophages. Our data reveal that human endometrial cancer cells (hECCs) upregulate the CD47 level on their surface and that there is a high density of tumor-associated macrophages within the microenvironment of human endometrial cancer. In vitro functional assay shows that an anti-CD47 monoclonal antibody (mAb) promotes the phagocytosis of hECCs by macrophages. Systemic and in situ treatments with an anti-CD47 mAb effectively reduce tumor burden in vivo in a genetically engineered mouse model of endometrial cancer. Thus, this study provides preclinical evidence that CD47 blockade using an anti-CD47 mAb to augment macrophage phagocytosis is a potential therapeutic strategy for endometrial cancer.

High-Throughput Screening on Primary Tumor-Associated Microglia and Macrophages Identifies HDAC Inhibitors as Enhancers of Phagocytosis and Potent Partners for Immunotherapy in Glioblastoma

Glioblastoma multiforme (GBM) is a lethal brain tumor with limited treatment options. Tumor-associated macrophages and microglia (TAMs) drive immune suppression and tumor progression, making them a key therapeutic target for GBM. Enhancing TAM phagocytosis in GBM has shown promise, particularly with innate checkpoint inhibitors, such as CD47-blocking antibodies. However, small molecule approaches, which offer tunable and potentially synergistic mechanisms, remain underexplored in this context. In this study, we conducted the first large-scale chemical screen on primary TAMs from patients with GBM, identifying histone deacetylase (HDAC) inhibitors as potent inducers of phagocytosis. These compounds demonstrated phagocytosis-inducing effects across multiple GBM patient samples, with further amplification when combined with CD47 blockade. In a xenograft GBM model, HDAC inhibitors enhanced phagocytosis and suppressed tumor growth, with even greater efficacy in combination with CD47 antibodies. Our findings highlight HDAC inhibitors as promising agents to reprogram TAMs and synergize with immune checkpoint therapies, offering a novel strategy to bolster anti-tumor immunity in GBM.

Human skeletal development and regeneration are shaped by functional diversity of stem cells across skeletal sites

) from ten skeletal sites with functional assays and single-cell RNA sequencing (scRNA-seq) analysis to identify chondrogenic, osteogenic, stromal, and fibrogenic subtypes of hSSCs during development and their linkage to skeletal phenotypes. We map the distinct composition of hSSC subtypes across multiple skeletal sites and demonstrate their unique in vivo clonal dynamics. We find that age-related changes in bone formation and regeneration disorders stem from a pathological fibroblastic shift in the hSSC pool. Utilizing a Boolean algorithm, we uncover gene regulatory networks that dictate differences in the ability of hSSCs to generate specific skeletal tissues. Importantly, hSSC lineage dynamics are pharmacologically malleable, providing a new strategy to treat aberrant hSSC diversity central to aging and skeletal maladies.

Lyme disease increases risk for multiple gynecological conditions

Lyme disease (LD) is an illness caused by the spirochete Borrelia burgdorferi ( B. burgdorferi ). Borrelia is known to disseminate through organs, including the skin, joints, spinal cord, bladder, and heart, leading to Lyme arthritis, neuroborreliosis, and Lyme carditis. While previous studies have investigated the impact of LD on pregnancy in both mice and humans and have found the presence of B. burgdorferi in the uterus of mice, we studied the impact of LD on the non-pregnant female reproductive tract. We use a mouse model for LD and find an ongoing and severe infection of the reproductive tract of female mice, which persists up to 15-months post-inoculation. This infection results in uterine glandular cysts and endometrial hyperplasia as well as vaginal epithelial thickening, polymorphonuclear and mononuclear cell epithelial infiltration, and epithelial desquamation into the vaginal lumen. Strikingly, we find that age has an impact on the extent of gynecologic pathology such that aged female mice (1-year old) that are reproductively senescent have more gynecologic pathology with infection compared to young mice (15-weeks old) when infected for the same length of time. Using large-scale electronic healthcare record data, we report that LD additionally results in increased infection-associated risk of menorrhagia (1.5-fold), miscarriage (1.62-fold), uterine fibroids (1.42-fold), and endometriosis (1.93-fold). Underreporting of gynecological outcomes is pervasive throughout many different infectious diseases, and LD-associated gynecological pathologies may have been similarly underappreciated in the field. This work suggests that further study of the female reproductive tract and the effects of B. burgdorferi infection therein will help clarify and expand the knowledge of myriad LD outcomes.

Elevated hematopoietic stem cell frequency in mouse alveolar bone marrow

Hematopoietic stem cells (HSCs) are crucial for maintaining hematopoietic homeostasis and are localized within distinct bone marrow (BM) niches. While BM niches are often considered similar across different skeletal sites, we discovered that the alveolar BM (al-BM) in the mandible harbors the highest frequency of immunophenotypic HSCs in nine different skeletal sites. Transplantation assays revealed significantly increased engraftment from al-BM compared to femur, tibia, or pelvis BM, likely due to a higher proportion of alveolar HSCs. Moreover, hematopoietic progenitor cells (c-Kit + Sca-1 + Lin − ) in al-BM exhibited increased quiescence and reduced apoptosis, indicating superior maintenance and survival characteristics. We also observed an enrichment of mesenchymal stromal cells and skeletal stem cells in al-BM, suggesting a more supportive microenvironment. These findings indicate that al-BM provides a unique microenvironment conducive to higher frequency of HSCs, offering new insights into site-specific hematopoiesis.

Polyclonal regeneration of mouse bone marrow endothelial cells after irradiative conditioning

Bone marrow endothelial cells (BM-ECs) are the essential components of the BM niche and support the function of hematopoietic stem cells (HSCs). However, conditioning for HSC transplantation causes damage to the recipients' BM-ECs and may lead to transplantation-related morbidity. Here, we investigated the cellular and clonal mechanisms of BM-EC regeneration after irradiative conditioning. Using single-cell RNA sequencing, imaging, and flow cytometry, we revealed how the heterogeneous pool of BM-ECs changes during regeneration from irradiation stress. Next, we developed a single-cell in vitro clonogenic assay and demonstrated that all EC fractions hold a high potential to reenter the cell cycle and form vessel-like structures. Finally, we used Rainbow mice and a machine-learning-based model to show that the regeneration of BM-ECs after irradiation is mostly polyclonal and driven by the broad fraction of BM-ECs; however, the cell output among clones varies at later stages of regeneration.