Biology subjects

Scavuzzo, M. A.

Publications and source records attributed to Scavuzzo, M. A..

6 recordsLinked to original sources

bioRxiv2025

Epithelial and stromal remodeling in murine Crohn's disease-like ileitis

Background and AimsInflammatory bowel disease is characterized by progressive epithelial, immune, and stromal dysfunction. Human datasets yield important insights yet are inherently descriptive, requiring animal models for in vivo mechanistic interrogation. The SAMP1/YitFc (SAMP) mouse model develops spontaneous Crohns disease (CD)-like ileitis while allowing controlled manipulation of pathophysiologic pathways. To understand cell-specific disease-associated transcriptional changes, we defined the single-nucleus transcriptomes of inflamed SAMP ilea using single-nucleus RNA-sequencing (snRNA-seq). MethodsWe performed whole-ileum snRNA-seq on SAMP (n=4) and control AKR/J (n=3) mice using the gut-optimized CitraPrep protocol, generating 58,349 high-quality nuclei across epithelial, immune, and stromal lineages. We corroborated SAMP-associated changes with immunofluorescent staining, Western blotting, spatial transcriptomic, and human single-cell RNA-sequencing data. ResultsWe observed a primary type 2 immune phenotype in SAMP compared to AKR mice, but most transcriptional changes occurred in stromal and epithelial, not immune, cells. Stromal remodeling included increased fibroblast-derived Igf1. In SAMP epithelium, expansion of tuft cells and emergence of SAMP-specific Pcsk6+ crypt enterocytes were observed and confirmed in human CD patients. Finally, we identified cross-compartmental changes in cell-cell signaling, including enterocyte-to-type 3 innate lymphoid cell (ILC3) communication and enhanced global Igf1 signaling. These features recapitulate known, as well as novel, characteristics of CD and extend our understanding of disease-associated multicellular networks. ConclusionThis atlas of ileitis-prone SAMP mice provides a high-resolution resource for dissecting conserved and novel mechanisms of inflammation and tissue remodeling. Herein, we uncover disease-associated transcriptional changes conserved in human CD, presenting a translational platform for future mechanistic and therapeutic studies.

molecular biology↗

bioRxiv2024

Gut bacteria-derived succinate induces enteric nervous system regeneration

Enteric neurons control gut physiology by regulating peristalsis, nutrient absorption, and secretion1. Disruptions in microbial communities caused by antibiotics or enteric infections result in the loss of enteric neurons and long-term motility disorders2-5. However, the signals and underlying mechanisms of this microbiota-neuron communication are unknown. We studied the effects of microbiota on the recovery of the enteric nervous system after microbial dysbiosis caused by antibiotics. We found that both enteric neurons and glia are lost after antibiotic exposure, but recover when the pre-treatment microbiota is restored. Using murine gnotobiotic models and fecal metabolomics, we identified neurogenic bacterial species and their derived metabolite succinate as sufficient to rescue enteric neurons and glia. Unbiased single-nuclei RNA-seq analysis uncovered a novel neural precursor-like population marked by the expression of the neuronal gene Nav2. Genetic fate-mapping showed that Plp1+ enteric glia differentiate into neurons following antibiotic exposure. In contrast, Nav2+ neurons expand upon succinate treatment and indicate an alternative mode of neuronal regeneration under recovery conditions. Our findings highlight specific microbial species, metabolites, and the underlying cellular mechanisms involved in neuronal regeneration, with potential therapeutic implications for peripheral neuropathies.

neuroscience↗

bioRxiv2023

Enteric glial hub cells coordinate intestinal motility

The enteric nervous system is a complex network of neurons and glia within the gut that coordinate gut motility. By optimizing single nucleus RNA-sequencing methods and spatial transcriptomics, we generated maps of the mouse duodenum and identified distinct molecular classes of enteric glia across the intestine with unique morphological and spatial identities. Here we show enteric glial functional specialization, with one myenteric subtype directly sensing force and expressing the mechanosensory ion channel PIEZO2. Genetic reduction of PIEZO2 in enteric glial populations enriched for this mechanosensory subtype led to defects in gastrointestinal motility. These results provide insight into the multifaceted functions of distinct enteric glial cell subtypes in maintaining gut health, and emphasize the importance of considering subtype-specific roles of enteric glia in a wide range of diseases and disorders.

neuroscience↗

bioRxiv2022

Cellular Maturation of Oligodendrocytes is Governed by Transient Gene Melting

Pluripotent stem cells (PSCs) provide an unlimited source for generating somatic cell types. However, generating fully mature cells constitutes a bottleneck for realizing their full potential in research and medicine. Here, we report a transcriptional mechanism that governs the timing of cellular maturation in post-mitotic oligodendrocytes. During differentiation of PSCs to oligodendrocytes, the transcription factor SOX6 redistributes from nearly all super enhancers in proliferating oligodendrocyte progenitor cells to cluster across specific gene bodies in immature oligodendrocytes. These sites exhibit gene melting, a process of extensive chromatin decondensation and transcription, which abruptly turns off upon maturation. Suppression of SOX6 deactivates these immaturity loci, resulting in rapid transition to mature myelinating oligodendrocytes. Cells harboring this immature oligodendrocyte SOX6 gene signature are specifically enriched in multiple sclerosis patient brains, suggestive that failed maturation may contribute to limited myelin regeneration in disease. Collectively, our finding that maturation rate is controlled by transient transcriptional clusters may inform approaches to accelerate the generation and regeneration of mature cell types. HIGHLIGHTSO_LITranscription factors (TFs) can act as gatekeepers of post-mitotic cellular maturation C_LIO_LIIn oligodendrocytes, clustering of SOX6 controls the immaturity program through transient gene melting C_LIO_LISuppressing SOX6 deactivates immaturity genes and unlocks oligodendrocyte maturation C_LIO_LISOX6 immaturity signature is enriched in oligodendrocytes in multiple sclerosis patients C_LI

developmental biology↗

bioRxiv2020

Non-Canonical Targets of HIF1a Drive Cell-Type-Specific Dysfunction

All mammalian cells sense and respond to insufficient oxygen, or hypoxia, through the activity of hypoxia-inducible factors (HIFs), an evolutionarily conserved family of transcriptional regulators that promote oxygen-independent energy metabolism and angiogenesis. While HIF activation is transiently protective for all cells, prolonged HIF activity drives distinct pathological responses in different tissues. How HIF achieves this pleiotropic effect is largely unknown. Here, we demonstrate that non-canonical targets of HIF1a impair the function of oligodendrocyte progenitor cells (OPCs) to generate oligodendrocytes. Beyond the canonical gene targets shared between all cell types, HIF1a also bound to and activated a unique set of targets in OPCs including Ascl2 and Dlx3. Each of these targets, when ectopically expressed, was sufficient to block oligodendrocyte development through suppression of the key oligodendrocyte regulator Sox10. Chemical screening revealed that inhibition of MEK/ERK signaling overcame the HIF1a-mediated block in oligodendrocyte generation by restoring Sox10 expression without impacting canonical HIF1a activity. Collectively this work defines the mechanism by which chronic HIF1a suppresses oligodendrocyte formation. More broadly, we establish that cell-type-specific HIF1a targets, independent of the canonical hypoxia response, perturb cell function and drive disease in chronic hypoxia.

developmental biology↗

bioRxiv2019

NFIA regulates granule recruitment and exocytosis in the adult pancreas

After food ingestion, pancreatic cells secrete zymogen and hormone-containing granules to precisely control digestion and blood glucose levels. Identifying regulators of this process is paramount to combatting multiple pancreatic diseases. Here we show that pancreatic deletion of the transcription factor nuclear factor IA (NFIA) leads to hyperglycemia, hypoinsulinemia, and hypolipidemia. Surprisingly, insulin and digestive enzymes are produced in the absence of NFIA, however, they are not secreted properly and instead accumulate inside pancreatic cells. In NFIA-deficient mice we saw a reduction of insulin granules in the ready releasable pool and the first-phase insulin response was impaired. We found that NFIA binds to and activates Rab39b, a Rab GTPase critical for exocytosis. Re-expression of Rab39b in NFIA knockout islets restored glucose-stimulated insulin secretion. In sum, the NFIA-Rab39b axis regulates pancreatic physiology through granule recruitment and docking, linking NFIA to a new process with potential effects in diabetes, pancreatitis, and lipid disorders.

cell biology↗