Biology subjects

Chowdhury, K.

Publications and source records attributed to Chowdhury, K..

5 recordsLinked to original sources

bioRxiv2026

The p53-p21-Cyclin D2 regulatory axis drives metabolic reprogramming and a distinct senescent macrophage senotype during aging and MASLD.

Aging drives chronic disease in part through senescent cells, including macrophages, which fuel inflammation. Senescent macrophages are functionally heterogeneous: canonical p16-high macrophages promote tumorigenesis or, in other contexts, disease tolerance, whereas we previously identified a distinct p21-high, p16-low senotype that drives metabolic dysfunction-associated steatotic liver disease (MASLD). The molecular basis of this senotype has remained undefined. Using genetic and multi-omic approaches, we show that a p53-p21-dependent program actively represses p16 and is required for senescent macrophage viability. We identify Cyclin D2 as a non-canonical downstream effector that redistributes from the nucleus to mitochondria and lipid droplets, where it partners with MIC60 to drive metabolic reprogramming and modulates AKT1-mTORC1 signaling that sustains the SASP. Cyclin D2-p21 double-positive macrophages accumulate with aging and MASLD in mice and in human liver cirrhosis, and can be selectively depleted by senolytic treatment. Together, these findings define a druggable p53-p21-Cyclin D2 axis that specifies macrophage senotype.

immunology↗

bioRxiv2026

IFN-γ-Dependent Macrophage Reprogramming Coordinates Inflammatory Resolution and Matrix Remodeling in Heart Regeneration

Heart regeneration requires coordinated immune activation, timely inflammatory resolution, and dynamic extracellular matrix (ECM) remodeling in addition to cardiomyocyte (CM) proliferation. However, the cytokine signals that instruct immune cell functions during cardiac repair remain incompletely understood. Here, we identify interferon-gamma (IFN-{gamma}) as a critical regulator of macrophage plasticity in zebrafish heart regeneration. IFN-{gamma} signaling components are dynamically activated following cardiac injury, with early induction of ifng1 and temporally coordinated receptor expression. Genetic ablation of ifng1 impairs myocardial regeneration, resulting in reduced CM proliferation and persistent fibrotic scarring. Temporal transcriptional profiling reveals sustained inflammatory signatures, impaired efferocytosis, and abolished reparative programs, accompanied by aberrant immune cell dynamics and retention of injury-derived debris in mutant hearts. Transcriptomic analysis of cardiac macrophages further reveals that IFN-{gamma} deficiency disrupts the transition from an inflammatory state to a reparative, ECM-remodeling phenotype, leading to reduced collagen denaturation and diminished CM protrusion at the injury border zone. Inducible- and macrophage-specific blockade of IFN-{gamma} signaling phenocopies defects in global knockout, establishing a cell-autonomous requirement for IFN-{gamma} in coordinating regenerative immune function. Collectively, our findings define an IFN-{gamma}-dependent macrophage reprogramming axis that couples inflammatory resolution to ECM remodeling in heart regeneration, elucidating how cytokine signaling actively instructs tissue repair. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/712551v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@8cb384org.highwire.dtl.DTLVardef@15dd8d6org.highwire.dtl.DTLVardef@46dcc4org.highwire.dtl.DTLVardef@47e2ac_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2025

Scube2 Modulates Coronary Vessel Formation during Cardiac Growth and Regeneration in Zebrafish

Coronary vessel formation is essential for cardiac growth and regeneration, yet the mechanisms regulating these processes remain incompletely defined. In this study, we identified and characterized Scube2 as a novel regulator in coronary vessel formation and heart regeneration. Scube2 is expressed in the epicardium covering the coronary vasculature under homeostatic conditions in adult hearts and is strongly upregulated after cardiac injury. Zebrafish scube2 mutant exhibits reduced coronary vessel coverage during cardiac growth and pronounced myocardial defects, including abnormal vessel morphology, disorganized contractile fibers, and mitochondrial damage. Following injury, scube2 mutant hearts show impaired revascularization and persistent fibrosis, indicating defective regeneration. Mechanistically, transcriptomic profiling of scube2 mutant hearts reveals attenuated expression of angiogenic-related genes, including those mediated by vascular endothelial and platelet-derived growth factors, consistent with reduced proliferation of endothelial cells and cardiomyocytes during repair. In a gain-of-function setting, SCUBE2 enhances platelet-derived growth factor signaling by promoting receptor activation in HEK293 cells. These findings support a novel role for Scube2 in cardiac growth and regeneration by modulating coronary vessel formation. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/695032v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@7c5b5org.highwire.dtl.DTLVardef@451c40org.highwire.dtl.DTLVardef@141c88forg.highwire.dtl.DTLVardef@1d63765_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2022

Regulation of excitatory presynaptic activity by Ambra1 protein determines neuronal networks in sex-dimorphic manner

Heterozygous mutation of Ambra1, known as a positive autophagy regulator, produces autismlike behavior in mice and autistic phenotypes in humans in a female-specific manner. However, the substantial roles of the Ambra1 mutation in neurons are still unknown. We find that Ambra1 heterozygotes display a moderate decrease in excitatory synaptic release in-vitro and ex-vivo exclusively in females without autophagy activity, resulting in significant alterations in {gamma}-oscillation power and seizure susceptibility by excitatory/inhibitory (E/I) imbalance. Specifically, Ambra1 deficiency has no effect on neurogenesis and morphogenesis, but selectively decreases excitatory synaptic activity without changes in synapse number, quantal size, synaptic release probability, and synaptic plasticity. Therefore, the limited excitatory synaptopathy by Ambra1 expression levels ultimately determines E/I imbalance in global neural networks leading to the female-specific ASD.

neuroscience↗

bioRxiv2022

Comparative single-cell profiling reveals distinct cardiac resident macrophages essential for zebrafish heart regeneration

Zebrafish exhibit a robust ability to regenerate their hearts following injury, and the immune system plays a key role in this process. We previously showed that delaying macrophage recruitment by clodronate liposome (CL) treatment compromises neutrophil resolution and heart regeneration, even when the infiltrating macrophage number was restored within the first-week post injury (Lai et al., 2017). Here, we examined the molecular mechanisms underlying the cardiac repair of regenerative PBS-control hearts vs. non-regenerative CL-treated hearts. Bulk transcriptomic analyses revealed that CL-treated hearts exhibited disrupted inflammatory resolution and energy metabolism during cardiac repair. Temporal single-cell profiling of inflammatory cells in regenerative vs. non-regenerative conditions further identified heterogenous macrophages and neutrophils with distinct infiltration dynamics, gene expression, and cellular crosstalk. Among them, two residential macrophage subpopulations were enriched in regenerative hearts and barely recovered in non-regenerative hearts. Early CL treatment at 8 days or even 1 month before cryoinjury led to the depletion of resident macrophages without affecting the circulating macrophage recruitment to the injured area. Strikingly, these resident macrophage-deficient zebrafish still exhibited compromised neovascularization and scar resolution. Our results characterized the inflammatory cells of the zebrafish injured hearts and identified key resident macrophage subpopulations prerequisite for successful heart regeneration.

developmental biology↗