Biology subjects

Schwartz, R. E.

Publications and source records attributed to Schwartz, R. E..

16 recordsLinked to original sources

bioRxiv2026

HLiCA: An integrated cell atlas of the healthy human liver

The human liver is composed of a heterogeneous mix of cell types. How these distinct populations contribute individually and collectively to liver function remains poorly understood. Although single-cell technologies have advanced our understanding of liver biology, individual studies have often been limited by small donor cohorts and inconsistent cell type annotations. Integrating multiple datasets can overcome these challenges and better capture biological variability. We present the Human Liver Cell Atlas (HLiCA), an integrated reference of non-disease liver cells assembled from eight datasets across six research centers, encompassing more than 525,000 cells from 110 donors. Developed in collaboration with the Human Cell Atlas Liver Bionetwork, the HLiCA incorporates expert-curated cell annotations refined through community feedback and dedicated cell type annotation meetings. The HLiCA classifies cells into six lineages and expands the cell type resolution to include 47 distinct cell types. Starting from raw sequencing reads, we realigned all data and performed rigorous benchmarking to ensure robust integration across technical and biological variables. Genetic ancestry was inferred for all samples to evaluate the range of ancestral backgrounds represented in the atlas. The expanded cell type annotation enabled identification of previously unrecognized liver cell types, including NRXN1+ stromal cells. Their presence was validated using spatial transcriptomics, which localized NRXN1+ stromal cells to periportal regions. With the number of donors included in the HLiCA we were able to examine cell type specific associations with demographic covariates. In hepatocytes, drug metabolism genes showed differential expression between sexes, and in cholangiocytes, mucus-production genes varied with age. As the largest and most genetically diverse human liver cell atlas to date, the HLiCA provides a comprehensive, well-annotated reference for the field, annotated by expert consensus. This resource will enable deeper interrogation of liver cellular diversity, architecture, and function in the healthy human liver and serve as a reference to understand changes that occur with disease.

genomics↗

bioRxiv2026

Multi-omic analysis identifies mitochondrial dysfunction as a conserved driver of acute severity and long-term complications in RSV infection

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection in infants, older adults, and immunocompromised individuals. The molecular mechanisms linking acute RSV infection to disease severity and long-term complications remain incompletely understood. Herein, we conducted a comprehensive multi-omic analysis of 12 independent datasets encompassing epigenomics, transcriptomics, proteomics, and metabolomics across diverse systems, including in vitro infection models, clinical cohorts, longitudinal pediatric studies, vaccination models, and multiple viral strains. Across these experimental platforms and omic analysis, RSV consistently triggered suppression of oxidative phosphorylation (OXPHOS), alongside HIF-1-driven glycolytic metabolism and mitochondrial stress response. This coordinated reprogramming was consistent across transcriptomic, proteomic, and chromatin datasets. In adult challenge studies, symptomatic individuals exhibited prolonged OXPHOS suppression and greater activation of HIF-1 immune signaling than asymptomatic individuals. Similarly, pediatric intensive care cohorts showed comparable signatures associated with severe disease. Vaccinated mice showed attenuation of infection-induced metabolic disruption, further supporting a link between mitochondrial dysfunction and disease severity. Longitudinal analyses in pediatric samples revealed that these metabolic alterations persist for up to 1-year post-infection, with sustained metabolic dysfunction, persistent epigenetic remodeling, and single-cell evidence of epithelial remodeling, including depletion of multiciliated cells, expansion of secretory populations, and prolonged OXPHOS suppression, in children who developed wheezing. Comparative analysis across RSV strains revealed variable OXPHOS suppression and variable HIF-1 activation, indicating strain-specific differences in metabolic reprogramming. Together, these findings establish mitochondrial dysfunction as a central and conserved feature of RSV pathogenesis, encompassing acute severity, viral strain variation, and long-term complications, and highlight mitochondrial pathways as promising therapeutic targets to mitigate both acute disease severity and post-viral sequelae. Ultimately, demonstrating that distinct viral lineages drive unique bioenergetic phenotypes establishes a foundation for predictive molecular epidemiology and gaining insight into host-pathogen dynamics in response to novel interventions. HighlightsO_LIMulti-omic integration of 13 independent RSV datasets reveals mitochondrial dysfunction as a conserved hallmark of infection. C_LIO_LIRSV consistently suppresses oxidative phosphorylation (OXPHOS) while activating HIF-1 signaling, glycolysis, mitochondrial stress responses, and immune pathways. C_LIO_LIGreater mitochondrial dysfunction correlates with increased disease severity, persists in children who develop wheezing, and is partially ameliorated by vaccination. C_LIO_LIDistinct RSV strains display variable patterns of metabolic reprogramming, linking viral genetic diversity to differential host mitochondrial responses. C_LI

systems biology↗

bioRxiv2025

Off-the-Shelf Engineered Liver Tissue Reverses Acute Liver Failure Without Immunosuppression

There is an urgent need for effective solutions to replace liver functions in patients with acute liver failure (ALF). We describe here a human engineered liver tissue composed of induced pluripotent stem cell (iPSC)-derived liver organoids encapsulated within a non-degradable biomaterial. Unlike most stem cell-derived products, this encapsulated liver tissue (ELT) achieves functional maturation during manufacturing. When transiently implanted into the peritoneal cavity of immunocompetent mice with ALF, the human ELT improves survival, treats hepatic encephalopathy and promotes liver regeneration, without requiring immunosuppression. Based on robust processes and designed to overcome challenges such as foreign body reaction, loss of function and cryopreservation, the ELT does not require vascularization and provides immediate and long-lasting functional replacement. Once the liver regenerated, the ELT is explanted, leaving the subjects cured. Macroencapsulation prevents rejection by shielding the organoids from the host immune system, and minimizes the risk of tumorigenicity. The data shown demonstrate the ELTs potential to be developed into a safe and effective off-the-shelf treatment that, if validated in upcoming clinical trials, could replace liver transplantation for many patients with ALF.

bioengineering↗

bioRxiv2025

The Spatial Atlas of Human Anatomy (SAHA): A Multimodal Subcellular-Resolution Reference Across Human Organs

The Spatial Atlas of Human Anatomy (SAHA) represents the first multimodal, subcellular- resolution reference of healthy adult human tissues across multiple organ systems. Integrating spatial transcriptomics, proteomics, and histological features across over 15 million cells from more than 100 donors, SAHA maps conserved and organ-specific cellular niches in gastrointestinal and immune tissues. High-resolution profiling using CosMx SMI, 10x Xenium, RNAscope, GeoMx DSP, and single-nucleus RNA-seq reveals spatially organized cell states, rare adaptive immune populations, and tissue-specific cell-cell interactions and ligand-receptor pairs. Comparative analyses with colorectal cancer and inflammatory bowel disease demonstrate the power of SAHA to detect disease-associated spatial disruptions, including crypt dedifferentiation, perineural invasion, and therapy-resistant immune remodeling. All data are openly accessible through a FAIR-compliant interactive portal to support exploration, benchmarking, and machine learning model training. Through SAHA, we provide a foundational framework for spatial diagnostics and next-generation precision medicine grounded in a comprehensive human tissue atlas, enabling the development of context-aware models that simulate tissue behavior, decode complex pathologies, and accelerate therapeutic innovation at unprecedented scale.

systems biology↗

bioRxiv2024

Human Vascularized Macrophage-Islet Organoids to Model Immune-Mediated Pancreatic β cell Pyroptosis upon Viral Infection

There is a paucity of human models to study immune-mediated host damage. Here, we utilized the GeoMx spatial multi-omics platform to analyze immune cell changes in COVID-19 pancreatic autopsy samples, revealing an accumulation of proinflammatory macrophages. Single cell RNA-seq analysis of human islets exposed to SARS-CoV-2 or Coxsackievirus B4 (CVB4) viruses identified activation of proinflammatory macrophages and {beta} cell pyroptosis. To distinguish viral versus proinflammatory macrophage-mediated {beta} cell pyroptosis, we developed human pluripotent stem cell (hPSC)-derived vascularized macrophage-islet (VMI) organoids. VMI organoids exhibited enhanced marker expression and function in both {beta} cells and endothelial cells compared to separately cultured cells. Notably, proinflammatory macrophages within VMI organoids induced {beta} cell pyroptosis. Mechanistic investigations highlighted TNFSF12-TNFRSF12A involvement in proinflammatory macrophage-mediated {beta} cell pyroptosis. This study established hPSC- derived VMI organoids as a valuable tool for studying immune cell-mediated host damage and uncovered mechanism of {beta} cell damage during viral exposure.

developmental biology↗

bioRxiv2024

Liver-specific Mettl14 deletion induces nuclear heterotypia and dysregulates RNA export machinery

Modification of RNA with N6-methyladenosine (m6A) has gained attention in recent years as a general mechanism of gene regulation. In the liver, m6A, along with its associated machinery, has been studied as a potential biomarker of disease and cancer, with impacts on metabolism, cell cycle regulation, and pro-cancer state signaling. However these observational data have yet to be causally examined in vivo. For example, neither perturbation of the key m6A writers Mettl3 and Mettl14, nor the m6A readers Ythdf1 and Ythdf2 have been thoroughly mechanistically characterized in vivo as they have been in vitro. To understand the functions of these machineries, we developed mouse models and found that deleting Mettl14 led to progressive liver injury characterized by nuclear heterotypia, with changes in mRNA splicing, processing and export leading to increases in mRNA surveillance and recycling.

molecular biology↗

bioRxiv2023

A nucleosome switch primes Hepatitis B Virus infection

Chronic hepatitis B virus (HBV) infection is an incurable global health threat responsible for causing liver disease and hepatocellular carcinoma. During the genesis of infection, HBV establishes an independent minichromosome consisting of the viral covalently closed circular DNA (cccDNA) genome and host histones. The viral X gene must be expressed immediately upon infection to induce degradation of the host silencing factor, Smc5/6. However, the relationship between cccDNA chromatinization and X gene transcription remains poorly understood. Establishing a reconstituted viral minichromosome platform, we found that nucleosome occupancy in cccDNA drives X transcription. We corroborated these findings in cells and further showed that the chromatin destabilizing molecule CBL137 inhibits X transcription and HBV infection in hepatocytes. Our results shed light on a long-standing paradox and represent a potential new therapeutic avenue for the treatment of chronic HBV infection.

molecular biology↗

bioRxiv2022

Astrocytic TDP-43 dysregulation impairs memory by modulating antiviral pathways and interferon-inducible chemokines

TDP-43 pathology is prevalent in dementia but the cell type-specific effects of TDP-43 are not clear and therapeutic strategies to alleviate TDP-43-linked cognitive decline are lacking. We found that patients with Alzheimers disease (AD) or frontotemporal dementia (FTD) have aberrant TDP-43 accumulation in hippocampal astrocytes. In mouse models, induction of widespread or hippocampus-targeted accumulation in astrocytic TDP-43 caused progressive memory loss and localized changes in antiviral gene expression. These changes were cell-autonomous and correlated with impaired astrocytic defense against infectious viruses. Among the changes, astrocytes had elevated levels of interferon-inducible chemokines and neurons had elevated levels of the corresponding chemokine receptor CXCR3 in presynaptic terminals. CXCR3 stimulation altered presynaptic function and promoted neuronal hyperexcitability, akin to the effects of astrocytic TDP-43, and blockade of CXCR3 reduced this activity. Ablation of CXCR3 also prevented TDP-43-linked memory loss. Thus, astrocytic TDP-43 dysfunction contributes to cognitive impairment through aberrant chemokine-mediated astrocytic-neuronal interactions. SummaryIn dementia, protein buildup in glia enhances chemokine signaling to synapses and impairs specific aspects of neurocognitive function.

neuroscience↗

bioRxiv2022

Epinephrine inhibits PI3K alpha via the Hippo kinases.

The phosphoinositide 3-kinase, p110, is an essential mediator of insulin signaling and glucose homeostasis. We systematically interrogated the human serine, threonine, and tyrosine kinome to search for novel regulators of p110 and found that the Hippo kinases phosphorylate and completely inhibit its activity. This inhibitory state corresponds to a conformational change of a membrane binding domain on p110, which impairs its ability to engage membranes. In human primary hepatocytes, cancer cell lines, and rodent tissues, activation of the Hippo kinases, MST1/2, using forskolin or epinephrine is associated with phosphorylation and inhibition of p110, impairment of downstream insulin signaling, and suppression of glycolysis and glycogen synthesis. These changes are abrogated when MST1/2 are genetically deleted or inhibited with small molecules. Our study reveals a novel inhibitory pathway of PI3K signaling and a previously unappreciated link between epinephrine and insulin signaling.

physiology↗

bioRxiv2022

Targeted Down Regulation Of Core Mitochondrial Genes During SARS-CoV-2 Infection

Defects in mitochondrial oxidative phosphorylation (OXPHOS) have been reported in COVID-19 patients, but the timing and organs affected vary among reports. Here, we reveal the dynamics of COVID-19 through transcription profiles in nasopharyngeal and autopsy samples from patients and infected rodent models. While mitochondrial bioenergetics is repressed in the viral nasopharyngeal portal of entry, it is up regulated in autopsy lung tissues from deceased patients. In most disease stages and organs, discrete OXPHOS functions are blocked by the virus, and this is countered by the host broadly up regulating unblocked OXPHOS functions. No such rebound is seen in autopsy heart, results in severe repression of genes across all OXPHOS modules. Hence, targeted enhancement of mitochondrial gene expression may mitigate the pathogenesis of COVID-19. One-Sentence SummaryCovid-19 is associated with targeted inhibition of mitochondrial gene transcription.

molecular biology↗

bioRxiv2021

SARS-CoV-2 Infects Syncytiotrophoblast and Activates Inflammatory Responses in the Placenta

SARS-CoV-2 infection during pregnancy leads to an increased risk of adverse pregnancy outcomes. Although the placenta itself can be a target of virus infection, most neonates are virus free and are born healthy or recover quickly. Here, we investigated the impact of SARS-CoV-2 infection on the placenta from a cohort of women who were infected late during pregnancy and had tested nasal swab positive for SARS-CoV-2 by qRT-PCR at delivery. SARS-CoV-2 genomic and subgenomic RNA was detected in 23 out of 54 placentas. Two placentas with high virus content were obtained from mothers who presented with severe COVID-19 and whose pregnancies resulted in adverse outcomes for the fetuses, including intrauterine fetal demise and a preterm delivered baby still in newborn intensive care. Examination of the placental samples with high virus content showed efficient SARS-CoV-2 infection, using RNA in situ hybridization to detect genomic and replicating viral RNA, and immunohistochemistry to detect SARS-CoV-2 nucleocapsid protein. Infection was restricted to syncytiotrophoblast cells that envelope the fetal chorionic villi and are in direct contact with maternal blood. The infected placentas displayed massive infiltration of maternal immune cells including macrophages into intervillous spaces, potentially contributing to inflammation of the tissue. Ex vivo infection of placental cultures with SARS-CoV-2 or with SARS-CoV-2 spike (S) protein pseudotyped lentivirus targeted mostly syncytiotrophoblast and in rare events endothelial cells. Infection was reduced by using blocking antibodies against ACE2 and against Neuropilin 1, suggesting that SARS-CoV-2 may utilize alternative receptors for entry into placental cells.

cell biology↗

bioRxiv2021

Coagulation factors directly cleave SARS-CoV-2 spike and enhance viral entry

Coagulopathy is a significant aspect of morbidity in COVID-19 patients. The clotting cascade is propagated by a series of proteases, including factor Xa and thrombin. While certain host proteases, including TMPRSS2 and furin, are known to be important for cleavage activation of SARS-CoV-2 spike to promote viral entry in the respiratory tract, other proteases may also contribute. Using biochemical and cell-based assays, we demonstrate that factor Xa and thrombin can also directly cleave SARS-CoV-2 spike, enhancing viral entry. A drug-repurposing screen identified a subset of protease inhibitors that promiscuously inhibited spike cleavage by both transmembrane serine proteases as well as coagulation factors. The mechanism of the protease inhibitors nafamostat and camostat may extend beyond inhibition of TMPRSS2 to coagulation-induced spike cleavage. Anticoagulation is critical in the management of COVID-19, and early intervention could provide collateral benefit by suppressing SARS-CoV-2 viral entry. We propose a model of positive feedback whereby infection-induced hypercoagulation exacerbates SARS-CoV-2 infectivity.

microbiology↗

bioRxiv2020

Identification of Candidate COVID-19 Therapeutics using hPSC-derived Lung Organoids

Summary ParagraphThe SARS-CoV-2 virus has caused already over 3.5 million COVID-19 cases and 250,000 deaths globally. There is an urgent need to create novel models to study SARS-CoV-2 using human disease-relevant cells to understand key features of virus biology and facilitate drug screening. As primary SARS-CoV-2 infection is respiratory-based, we developed a lung organoid model using human pluripotent stem cells (hPSCs) that could be adapted for drug screens. The lung organoids, particularly aveolar type II cells, express ACE2 and are permissive to SARS-CoV-2 infection. Transcriptomic analysis following SARS-CoV-2 infection revealed a robust induction of chemokines and cytokines with little type I/III interferon signaling, similar to that observed amongst human COVID-19 pulmonary infections. We performed a high throughput screen using hPSC-derived lung organoids and identified FDA-approved drug candidates, including imatinib and mycophenolic acid, as inhibitors of SARS-CoV-2 entry. Pre- or post-treatment with these drugs at physiologically relevant levels decreased SARS-CoV-2 infection of hPSC-derived lung organoids. Together, these data demonstrate that hPSC-derived lung cells infected by SARS-CoV-2 can model human COVID-19 disease and provide a valuable resource to screen for FDA-approved drugs that might be repurposed and should be considered for COVID-19 clinical trials.

microbiology↗

bioRxiv2020

Identification of Drugs Blocking SARS-CoV-2 Infection using Human Pluripotent Stem Cell-derived Colonic Organoids

Summary ParagraphThe current COVID-19 pandemic is caused by SARS-coronavirus 2 (SARS-CoV-2). There are currently no therapeutic options for mitigating this disease due to lack of a vaccine and limited knowledge of SARS-CoV-2 biology. As a result, there is an urgent need to create new disease models to study SARS-CoV-2 biology and to screen for therapeutics using human disease-relevant tissues. COVID-19 patients typically present with respiratory symptoms including cough, dyspnea, and respiratory distress, but nearly 25% of patients have gastrointestinal indications including anorexia, diarrhea, vomiting, and abdominal pain. Moreover, these symptoms are associated with worse COVID-19 outcomes1. Here, we report using human pluripotent stem cell-derived colonic organoids (hPSC-COs) to explore the permissiveness of colonic cell types to SARS-CoV-2 infection. Single cell RNA-seq and immunostaining showed that the putative viral entry receptor ACE2 is expressed in multiple hESC-derived colonic cell types, but highly enriched in enterocytes. Multiple cell types in the COs can be infected by a SARS-CoV-2 pseudo-entry virus, which was further validated in vivo using a humanized mouse model. We used hPSC-derived COs in a high throughput platform to screen 1280 FDA-approved drugs against viral infection. Mycophenolic acid and quinacrine dihydrochloride were found to block the infection of SARS-CoV-2 pseudo-entry virus in COs both in vitro and in vivo, and confirmed to block infection of SARS-CoV-2 virus. This study established both in vitro and in vivo organoid models to investigate infection of SARS-CoV-2 disease-relevant human colonic cell types and identified drugs that blocks SARS-CoV-2 infection, suitable for rapid clinical testing.

microbiology↗

bioRxiv2020

Comparative in vitro transcriptomic analyses of COVID-19 candidate therapy hydroxychloroquine suggest limited immunomodulatory evidence of SARS-CoV-2 host response genes.

Hydroxychloroquine (HCQ) has emerged as a potential and controversial antiviral candidate therapy for COVID-19. While many clinical trials are underway to test the efficacy of HCQ as a treatment for COVID-19, underlying mechanisms of HCQ in the setting of COVID-19 remain unclear. Hence, we examined differential gene expression signatures of HCQ exposure, in vitro SARS-CoV-2 infection, and host signatures of COVID-19 in blood, bronchoalveolar lavage, and postmortem lung to evaluate whether HCQ transcriptome signatures associate with restoration of SARS-CoV-2-related host transcriptional responses. Here, we show that 24 hours of in vitro treatment of peripheral blood mononuclear cells(PBMC) with HCQ significantly impacted transcription of 16 genes involved in immune regulation and lipid metabolism. Using transcriptome data from in vitro SARS-CoV-2 infected NHBE and A549 cells and PBMC derived from confirmed COVID-19 infected patients, we determined that only 0.24% of the COVID-19 PBMC differentially expressed gene set and 0.39% of the in vitro SARS-CoV-2 cells differentially expressed gene set overlapped with HCQ-related differentially expressed genes. Moreover, we observed that HCQ treatment significantly impacted transcription of 159 genes in human primary monocyte-derived macrophages involved in cholesterol biosynthetic process and chemokine activity. Notably, when we compared the macrophage HCQ-related gene lists with genes transcriptionally altered during SARS-CoV-2 infection and in bronchoalveolar lavage of COVID-19+ patients, the CXCL6 gene was impacted in all three transcriptional signatures revealing evidence in favor of chemokine modulation. HCQ-related transcriptional changes minimally overlapped with host genes altered in postmortem lung biopsies from COVID-19 participants. These results may provide insight into the immunomodulation mechanisms of HCQ treatment in the setting of COVID-19 and suggest HCQ is not a panacea to SARS-CoV-2 infection.

immunology↗

bioRxiv2019

Long-Term In Vivo Biocompatibility of Single-Walled Carbon Nanotubes

Over the past two decades, measurements of carbon nanotube toxicity and biodistribution have yielded a wide range of results. Properties such as nanotube type (single-walled vs. multi-walled), purity, length, aggregation state, and functionalization, as well as route of administration, greatly affect both the biocompatibility and biodistribution of carbon nanotubes. These differences suggest that generalizable conclusions may be elusive and that studies must be material- and application-specific. Here, we assess the short- and long-term biodistribution and biocompatibility of a single-chirality DNA-encapsulated single-walled carbon nanotube complex upon intravenous administration that was previously shown to function as an in-vivo reporter of endolysosomal lipid accumulation. Regarding biodistribution and fate, we found bulk specificity to the liver and >90% signal attenuation by 14 days in mice. Using near-infrared hyperspectral microscopy to measure single nanotubes, we found low-level, long-term persistence in organs such as the heart, liver, lung, kidney, and spleen. Measurements of histology, animal weight, complete blood count, and biomarkers of organ function all suggest short- and long-term biocompatibility. This work suggests that carbon nanotubes can be used as preclinical research tools in-vivo without affecting acute or long-term health.

bioengineering↗