Biology subjects

Ang, L. T.

Publications and source records attributed to Ang, L. T..

5 recordsLinked to original sources

bioRxiv2025

VEGF/ERK activation and PI3K inhibition together drive a vein-to-artery transition in an in vitro model of human angiogenesis

Artery endothelial cells (ECs) arise through different pathways, including differentiation from mesodermal cells (vasculogenesis) or from already established vein or capillary plexus ECs (angiogenesis), the latter being most common during embryonic development and regeneration. Understanding the vein-to-artery (v2a) transition could improve revascularization therapies, but progress is limited by a lack of human models. Here, we develop a human pluripotent stem cell (hPSC) differentiation protocol that models the v2a EC conversion. Comparing v2a and mesoderm-to-artery (m2a) transcriptomes with publicly available single cell RNA sequencing (scRNA-seq) data from human embryos showed they reflected angiogenesis- and vasculogenesis-derived artery ECs, respectively. This reductionist system revealed that VEGF activation alongside PI3K inhibition was sufficient for vein ECs to acquire arterial identity within 48 hours. We model a critical step in vascular development and define the minimal signals required for artery differentiation from veins, providing a framework to promote this conversion in revascularization or therapeutic contexts.

developmental biology↗

bioRxiv2025

A human arteriovenous differentiation roadmap reveals vein developmental mechanisms and vascular effects of viruses

Extracellular signals and cell-fate trajectories during vein development remain elusive, despite trailblazing insights into artery development. Here we exploit human pluripotent stem cell differentiation and mouse embryology to present a model that answers longstanding questions: vein endothelial cell (EC) differentiation unfolds in two steps driven by opposing extracellular signals. First, VEGF differentiates mesoderm into "primed" ECs, newly-defined progenitors that co-express certain arterial (SOX17) and venous (APLNR) markers. Second, primed ECs execute vein differentiation upon VEGF/ERK inhibition; however, upon VEGF activation they can instead form artery ECs. The arteriovenous plasticity of primed ECs was supported by intersectional lineage tracing. Future venous genes including NR2F2 harbor poised chromatin in primed ECs, but are only transcribed upon VEGF/ERK inhibition. SOXF transcription factors, including SOX17, confer primed ECs with vein differentiation competence. Collectively, this two-step vein differentiation model--entailing primed EC intermediates and VEGF/ERK inhibition to trigger vein differentiation--has implications for VEGF-modulating therapies.

developmental biology↗

bioRxiv2025

Egyptian rousette bat macrophages elicit divergent interferon responses and cytokine storm signalling against Marburg and Sudan viruses

Egyptian rousette bats (ERBs) are the only known natural reservoir of Marburg virus (MARV), etiologic agent of a highly-pathogenic zoonotic viral hemorrhagic fever. In ERBs, evolutionary adaptations allow for fine-tuned discrete pro-inflammatory immune responses that control MARV infection, yet permit population-level viral maintenance. To look for exclusive co-adapted responses between ERBs and MARV, we compared macrophage (M{Phi}) responses to MARV and Sudan virus (SUDV), a related filovirus not hosted by ERBs. We queried whether MARV counters normal ERB M{Phi} responses, illuminating co-adapted host responses not observed upon infection with SUDV, which fails to establish a productive infection and is efficiently immunologically cleared by ERBs. We observed stark differences in M{Phi} transcriptional responses to MARV and SUDV, including differences in Type I and III interferon (IFN)-related genes, cytokines, chemokines, cell growth and proliferation genes. We show for the first time that while MARV-infected bat M{Phi}s undergo muted IFN responses and cytokine storm signalling, SUDV induces unperturbed Type I and III IFN gene expression, stronger cytokine and chemokine responses resembling typical host responses to a foreign viral pathogen. Our findings therefore corroborate growing evidence of unique coevolutionary relationships between bats and the specific viruses they harbor.

immunology↗

bioRxiv2025

Metabolically purified human stem cell-derived hepatocytes reveal distinct effects of Ebola and Lassa viruses

Ebola and Lassa viruses require biosafety-level-4 (BSL4) containment, infect the liver, and cause deadly hemorrhagic fevers. The cellular effects of these viruses, and whether different families of hemorrhagic-fever viruses elicit similar effects, remain fundamental questions in BSL4 virology. Here, we introduce a new metabolic selection approach to create nearly-pure hepatocytes from human pluripotent stem cells, killing non-liver cells by withholding essential nutrients. Unexpectedly, Ebola and Lassa exerted starkly different effects on human hepatocytes. Ebola infection activated the integrated stress response (ISR) and WNT pathways in hepatocytes in vitro and killed them, whereas Lassa did not. Within non-human primates, Ebola likewise infected hepatocytes and activated ISR signaling in vivo. In summary, we present a single-cell transcriptional and chromatin accessibility roadmap of human hepatocyte differentiation, purification, and viral infection.

cell biology↗

bioRxiv2017

Accelerated human liver progenitor generation from pluripotent stem cells by inhibiting formation of unwanted lineages

Despite decisive progress in differentiating pluripotent stem cells (PSCs) into diverse cell-types, the often-lengthy differentiation and functional immaturity of such cell-types remain pertinent issues. Here we address the first challenge of prolonged differentiation in the generation of hepatocyte-like cells from PSCs. We delineate a roadmap describing the extracellular signals controlling six sequential branching lineage choices leading from pluripotency to endoderm, foregut, and finally, liver progenitors. By blocking formation of unwanted cell-types at each lineage juncture and manipulating temporally-dynamic signals, we accelerated generation of 89.0{+/-}3.1% AFP+ human liver bud progenitors and 87.3{+/-}9.4% ALBUMIN+ hepatocyte-like cells by days 6 and 18 of PSC differentiation, respectively. 81.5{+/-}3.2% of hepatocyte-like cells expressed metabolic enzyme FAH (as assayed by a new knock-in reporter line) and improved short-term survival in the Fah-/-Rag2-/-Il2rg-/- mouse model of liver failure. Collectively the timed signaling interventions indicated by this developmental roadmap enable accelerated production of human liver progenitors from PSCs.

cell biology↗