Biology subjects

Bonaguidi, M. A.

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

8 recordsLinked to original sources

bioRxiv2026

Single cell profiling reveals GSM-15606 attenuates air pollution-induced inflammation and preserves hippocampal neurogenesis

1.IntroductionAir pollution (AirPoll) is a major environmental risk factor for age-related cognitive decline and dementia, yet we poorly understood the cellular and molecular mechanisms underlying its effects and their potential attenuation. MethodsWe combined single cell RNA sequencing with immunohistochemistry to determine transcriptional responses in microglia, astrocytes, neurons and neural stem cells in the hippocampus of mice following exposure to chronic diesel exhaust particle (DEP). Differential gene expression profiles were compared between filtered-air and DEP exposed animals. The gamma secretase modulator GSM-15606 (BPN) was used to probe selective rescue of inflammatory signatures across distinct cell populations. ResultsDEP exposure triggered robust inflammatory programs in microglia and astrocytes, including upregulation of cytokine signaling components, innate immune receptors, stress-responsive transcription factors, and markers of reactive glial phenotypes. In neural stem cells, DEP induced activation of gliosis-associated pathways, including Il6st, Stat3, and Txnip, consistent with a pro-inflammatory state that may bias lineage decisions. Immunostaining confirmed a significant reduction in immature neurons in the neurogenic niche after AirPoll exposure. GSM-15606 attenuated many DEP-induced transcriptional alterations in microglia and astrocytes, reducing expression of inflammatory mediators and reactive gliosis markers, but did not modulate the inflammatory profile of neural stem cells. ConclusionsAirPoll activates divergent inflammatory pathways across hippocampal cell populations and suppresses neurogenesis. Targeting inflammation with GSM-15606 selectively reverses glial but not neural stem cell responses, highlighting cell-type-specific mechanisms and potential therapeutic pathways to mitigate pollution-related cognitive vulnerability. These results support GSM-15606 as a protective agent against AirPoll-induced hippocampal dysfunction and amyloidogenic stress.

neuroscience↗

bioRxiv2024

Inactivation of a non-canonical gp130 signaling arm attenuates chronic systemic inflammation and multimorbidity induced by a high-fat diet.

Interleukin-6 (IL-6) is a major pro-inflammatory cytokine for which the levels in plasma demonstrate a robust correlation with age and body mass index (BMI) as part of the senescence-associated secretory phenotype. IL-6 cytokines also play a crucial role in metabolic homeostasis and regenerative processes, primarily via the canonical STAT3 pathway. Thus, selective modulation of IL-6 signaling may offer a unique opportunity for therapeutic interventions. Recently, we discovered that a non-canonical signaling pathway downstream of tyrosine (Y) 814 within the intracellular domain of gp130, the IL-6 co-receptor, is responsible for the recruitment and activation of SRC family of kinases (SFK). Mice with constitutive genetic inactivation of gp130 Y814 (F814 mice) show accelerated resolution of inflammatory response and superior regenerative outcomes in skin wound healing and posttraumatic models of osteoarthritis. The current study was designed to explore if selective genetic or pharmacological inhibition of the non-canonical gp130-Y814/SFK signaling reduces systemic chronic inflammation and multimorbidity in a high-fat diet (HFD)-induced model of accelerated aging. F814 mice showed significantly reduced inflammatory response to HFD in adipose and liver tissue, with significantly reduced levels of systemic inflammation compared to wild type mice. F814 mice were also protected from HFD-induced bone loss and cartilage degeneration. Pharmacological inhibition of gp130-Y814/SFK in mice on HFD mirrored the effects observed in F814 mice on HFD; furthermore, this pharmacological treatment also demonstrated a marked increase in physical activity levels and protective effects against inflammation-associated suppression of neurogenesis in the brain tissue compared to the control group. These findings suggest that selective inhibition of SFK signaling downstream of gp130 receptor represents a promising strategy to alleviate systemic chronic inflammation. Increased degenerative changes and tissue senescence are inevitable in obese and aged organisms, but we demonstrated that the systemic response and inflammation-associated multi-morbidity can be therapeutically mitigated.

cell biology↗

bioRxiv2023

Single cell transcriptomics reveals early photoreceptor trajectories and a cancer-predisposed cone precursor state

Human cone photoreceptors differ from rods and serve as the retinoblastoma cell-of-origin, yet the developmental basis for their distinct behaviors is poorly understood. Here, we used deep full-length single-cell RNA-sequencing (scRNA-seq) to distinguish post-mitotic cone and rod developmental states and identify cone-specific features that contribute to retinoblastomagenesis. The analyses revealed nascent, immediately post-mitotic cone- and rod precursor populations characterized by higher THRB or NRL regulon activities, immature and maturing cone and rod precursors with concurrent cone- and rod-related gene and regulon expression, and distinct early and late cone and rod maturation states distinguished by maturation-associated declines in RAX regulon activity. Cell-state-specific gene expression features inferred based on full-length scRNA-seq were consistent with past single nucleus 3 RNA-seq analyses. Beyond the cell state characterizations, full-length scRNAseq revealed that both L/M cone and rod precursors co-expressed NRL and THRB RNAs, yet they differentially expressed functionally antagonistic NRL and THRB isoforms and prematurely terminated THRB transcripts. Moreover, early L/M cone precursors exhibited successive expression of several lncRNAs along with MYCN, which composed the seventh most L/M-cone-specific regulon, and SYK, which was implicated in the cone precursors proliferative response to RB1 loss. These findings reveal previously unresolved photoreceptor precursor states and suggest a role for early cone-precursor-intrinsic SYK expression in retinoblastoma initiation. Impact StatementFeatures acquired by early post-mitotic retinal cells underlie the distinct behaviors of rods and the cone cells of origin of retinoblastoma tumors.

developmental biology↗

bioRxiv2022

A critical period for neurogenesis loss and cognitive decline in patients with mesial temporal lobe epilepsy patients

Mesial temporal lobe epilepsy (MTLE) is a syndromic disorder presenting with seizures and cognitive comorbidities. While seizure etiology is increasingly understood, the pathophysiological mechanisms contributing to cognitive decline and epilepsy progression remain less recognized. We have previously shown that adult hippocampal neurogenesis, a process contributing to visual spatial learning and memory in rodents, dramatically declines in MTLE patients with increased disease duration. Here, we investigate when multiple cognitive domains become effected by epilepsy disease duration and how human neurogenesis levels contribute to it. We find that intelligence, and verbal learning and memory decline at a critical period of 20 years disease duration. Surprisingly, the number of human immature neurons positively associate with auditory verbal, rather than visuospatial, learning and memory. Moreover, we uncover cognitive functions enriched to either immature or mature granule neurons and functions shared between them. Our study provides cellular evidence of how adult neurogenesis contributes to human cognition, and signifies an opportunity to advance regenerative medicine for patients with MTLE and other cognitive disorders. O_FIG O_LINKSMALLFIG WIDTH=108 HEIGHT=200 SRC="FIGDIR/small/507339v2_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@12d6c9forg.highwire.dtl.DTLVardef@13670aborg.highwire.dtl.DTLVardef@11efda3org.highwire.dtl.DTLVardef@19de537_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2020

Olfactory neuron turnover in adult Drosophila

Sustained neurogenesis occurs in the olfactory epithelium of several species, including humans, to support olfactory function throughout life. We recently developed a modified lineage tracing method to identify adult neurogenesis in Drosophila. By applying this technique, here we report on the continuous generation of Olfactory Sensory Neurons (OSN) in the antennae of adult Drosophila. New neurons develop sensory dendrites and project axons targeting diverse glomeruli of the antennal lobes in the brain. Furthermore, we identified sustained apoptosis of OSN in the antennae of adult flies, revealing unexpected turnover in the adult olfactory system. Our results substantiate Drosophila as a compelling platform to expedite research about mechanisms and compounds promoting neuronal regeneration, circuit remodeling and its contribution to behavior in the adult.

neuroscience↗

bioRxiv2019

Generation of mechanosensory neurons in adult Drosophila

Auditory and vestibular mechanosensory hair cells do not regenerate following injury or aging in the adult mammalian inner ear, inducing irreversible hearing loss and balance disorders for millions of people. Research on model systems showing replacement of mechanosensory cells can provide mechanistic insights into developing new regenerative therapies. Here, we developed lineage tracing systems to reveal, for the first time, the generation of mechanosensory neurons in the Johnstons Organ (JO) of intact adult Drosophila, which are the functional counterparts to hair cells in vertebrates. New JO neurons develop cilia, express an essential mechano-transducer gene and target central brain circuitry. Furthermore, we identified self-replication of JO neurons as an unexpected mechanism of neuronal plasticity, which is enhanced upon treatment with experimental and ototoxic compounds. Our findings introduce a new platform to expedite research about mechanisms and compounds mediating mechanosensory cell regeneration, with implications for hearing and balance restoration in humans. SUMMARY STATEMENTUsing refined lineage tracing and live imaging, we identified self-renewal of mechanosensory neurons in adult Drosophila, the functional counterparts to vertebrate hair cells, and their enhanced regeneration through pharmacological administration.

developmental biology↗

bioRxiv2019

Early Stem Cell Aging in the Mature Brain

Stem cell dysfunction drives many age-related disorders. Identifying mechanisms that initially compromise stem cell function represent early targets to enhance stem cell behavior later in life. Here, we pinpoint multiple factors that disrupt neural stem cells (NSC) in the adult hippocampus. We find that NSCs exhibit asynchronous maintenance by identifying short-term (ST-NSC) and intermediate-term NSCs (IT-NSCs). ST-NSC divide rapidly to generate neurons and deplete in the young brain. Meanwhile, multipotent IT-NSCs persist for months, but are pushed out of homeostasis by lengthening quiescence. Single cell transcriptome analysis of deep NSC quiescence revealed several hallmarks of biological aging in the mature brain and identified tyrosine-protein kinase Abl1 as an NSC pro-aging factor. Treatment with the Abl-inhibitor Imatinib increased NSC proliferation without impairing NSC maintenance in the middle-aged brain. Further intersectional analysis of mature NSC with old epidermal, hematopoietic and muscle stem cell transcriptomes identified consensus changes in stem cell aging. Our study elucidates multiple origins of adult neurogenesis decline and reveals that hippocampal NSCs are particularly vulnerable to a shared stem cell aging signature.

neuroscience↗

bioRxiv2017

Genome-Wide Analysis of Facial Regionalization in Zebrafish

Patterning of the facial skeleton involves the precise deployment of thousands of genes in distinct regions of the pharyngeal arches. Despite the significance for craniofacial development, how genetic programs drive this regionalization remains incompletely understood. Here we use combinatorial labeling of zebrafish cranial neural crest-derived cells (CNCCs) to define global gene expression along the dorsoventral axis of the developing arches. Intersection of region-specific transcriptomes with expression changes in response to signaling perturbations demonstrates complex roles for Endothelin1 (Edn1) signaling in the intermediate joint-forming region yet a surprisingly minor role in ventral-most regions. Analysis of co-variance across multiple sequencing experiments further reveals clusters of coregulated genes, with in situ hybridization confirming the domain-specific expression of novel genes. We then performed mutational analysis of a number of these genes, which uncovered antagonistic functions of two new Edn1 targets, follistatin a (fsta) and emx2, in regulating cartilaginous joints in the hyoid arch. Our unbiased discovery and functional analysis of genes with regional expression in zebrafish arch CNCCs reveals complex regulation by Ednl and points to novel candidates for craniofacial disorders.\n\nSummary StatementUsing zebrafish to purify distinct groups of embryonic cells, Askary et al. have created a detailed map of how thousands of genes are deployed to shape the developing face.

developmental biology↗