Biology subjects

Bueno, M.

Publications and source records attributed to Bueno, M..

7 recordsLinked to original sources

bioRxiv2026

Mesothelial Plasticity Specifies a Pleural Immune Circuit that Orchestrates Lung Regeneration

Following injury, predisposition towards regenerative repair and away from degenerative remodeling is central to organismal health, yet the upstream determinants that instruct this fate choice remain poorly understood. Here, we identify mesothelial cell plasticity as a central determinant between regeneration and degeneration by comparing mouse models of pneumonectomy (PNX) versus chronic lung allograft dysfunction (CLAD). While mesothelial cells expand in both settings, following PNX, these cells undergo differentiation through multiple transitional states, culminating in an inflammatory population that orchestrates monocyte recruitment and subsequent tissue regeneration. In contrast, in CLAD, mesothelial cells enrich in an extracellular matrix-enriched state that lacks pro-regenerative signaling capacity. Using single cell epigenomic profiling and in vivo genetics, we define a mesothelium-specific TWIST1-CCL2 axis that governs mesothelium plasticity and signaling, monocyte recruitment and lung regrowth. Together, these findings demonstrate that context-dependent reprogramming of a pleural population, known to protect organs, can be leveraged to drive regeneration.

Developmental Biology↗

bioRxiv2026

Alveolar Epithelial Cell Loss of the Mitochondrial Regulator TFAM Drives Progressive Lung Fibrosis

Idiopathic pulmonary fibrosis (IPF) is characterized by failed alveolar epithelial repair and progressive fibrotic remodeling. Although aberrant reprogramming of alveolar type 2 (AT2) cells and accumulation of transitional AT2 states are increasing recognized as central features of IPF, the epithelial-intrinsic mechanisms that initiate these pathogenic states remain incompletely understood. Here, we identify mitochondrial transcription factor A (TFAM), a regulator of mitochondrial DNA maintenance, as a critical regulator of AT2 cell homeostasis. TFAM expression was reduced in AT2 cells from human IPF lungs. Inducible AT2 cell-specific Tfam deletion in mice caused spontaneous fibrotic remodeling and increased susceptibility to bleomycin-induced lung injury. TFAM-deficient AT2 cells acquired KRT8+ transitional and p21+ senescence-associated features before the onset of fibrotic transformation, accompanied by impaired oxidative phosphorylation, redox imbalance, mitochondrial superoxide accumulation, repression of mtDNA-encoded respiratory genes, and disrupted mitochondrial ultrastructure. TFAM-deficient AT2 cells developed a profibrotic secretory program that promoted extracellular matrix deposition and fibroblast activation. We further identified insulin-like growth factor-binding protein 2 (IGFBP2) as a secreted mediator induced in TFAM-deficient AT2 cells. IGFBP2 was elevated in AT2 cells in human IPF lung tissue and bronchoalveolar lavage fluid (BALF) from patients with IPF. IGFBP2 was detected in supernatants from fibrotic human precision-cut lung slices (hPCLS). IGFBP2 neutralization attenuated profibrotic remodeling in fibrotic hPCLS. Collectively, our findings identify TFAM-dependent mitochondrial homeostasis as an epithelial checkpoint linking AT2 cell-state stability to impaired epithelial-mesenchymal crosstalk driving pulmonary fibrosis.

pathology↗

bioRxiv2025

Can a history of crop rotations improve the prediction of soil organic carbon in the Andes? integrating machine learning multi-annual crop classification as a proxy of soil management

Soil organic carbon (SOC) is a crucial component related to various processes that ensure soil health and function. Its modeling is vital for assessing and monitoring soil degradation caused by the potential impact of agricultural activities. This study aimed to model SOC in the Northern highlands of Peru, characterized by a high amount of SOC, which is being affected by crop expansion. Crop rotation (CR) was incorporated into a modeling exercise using remote sensing data, fieldwork, and farmer surveys. A multi-year classification model with seven cropland classes was developed using data collected from 534 fields across 2022-2024, including 189 soil samples. Each cropland field was represented as a polygon delineating its boundaries and indicating its dominant crop cover. Time series of multispectral Sentinel-2 Level-2A Top of Canopy imagery were used to derive phenological features--such as the timing of maximum canopy cover and the length of the growing period--based on Normalized Difference Vegetation Index (NDVI) time series. A Random Forest classifier was used as the baseline model. The cropland classification model demonstrated strong overall performance, with F1 scores ranging from 0.81 to 0.98 across the different classes. The model performed well for lupin and pasture but scored lower for beans and potatoes. Predictions of cropland classes from 2019 to 2022 were created, resulting in frequency layers that represent crop rotations. Four feature configurations were evaluated: (i) including all features as a benchmark, (ii) excluding climatology, (iii) excluding crop rotation history, and (iv) excluding soil properties. Configurations including all features and excluding crop rotation history showed the highest performance (R2 = 0.63), while those excluding climatology or soil properties performed worse (R2 {approx} 0.52-0.53). Although soil features were the most important, fallow frequency emerged as the most critical predictor of SOC in crop rotations. When soil data were excluded, fallow frequency, combined with climatic features, explained over half of the SOC variability. The findings emphasize the importance of incorporating CR into SOC mapping efforts.

biophysics↗

bioRxiv2024

SenSet, a novel human lung senescence cell gene signature, identifies cell-specific senescence mechanisms

Cellular senescence is a major hallmark of aging. Senescence is defined as an irreversible growth arrest observed when cells are exposed to a variety of stressors including DNA damage, oxidative stress, or nutrient deprivation. While senescence is a well-established driver of aging and age-related diseases, it is a highly heterogeneous process with significant variations across organisms, tissues, and cell types. The relatively low abundance of senescence in healthy aged tissues represents a major challenge to studying senescence in a given organ, including the human lung. To overcome this limitation, we developed a Positive-Unlabeled (PU) learning framework to generate a comprehensive senescence marker gene list in human lungs (termed SenSet) using the largest publicly available single-cell lung dataset, the Human Lung Cell Atlas (HLCA). We validated SenSet in a highly complex ex vivo human 3D lung tissue culture model subjected to the senescence inducers bleomycin, doxorubicin, or irradiation, and established its sensitivity and accuracy in characterizing senescence. Using SenSet, we identified and validated cell-type specific senescence signatures in distinct lung cell populations upon aging and environmental exposures. Our study presents the first comprehensive analysis of senescent cells in the healthy aging lung and uncovers cell-specific gene signatures of senescence, presenting fundamental implications for our understanding of major lung diseases, including cancer, fibrosis, chronic obstructive pulmonary disease, or asthma.

genomics↗

bioRxiv2024

Mitochondrial sites of contact with the nucleus aid in chemotherapy evasion of glioblastoma cells

Glioblastoma (GBM) is the most common form of a malignant primary brain tumour in adults for which therapeutic options are minimal. The rapid onset of the resistance mechanisms against the chemotherapeutic agent Temozolomide (TMZ), the first line of pharmacological care for patients, prevents the long-term validity of this approach. The underpinning biology for this remains poorly understood thus compromising the efficacy of this approach. The Translocator Protein (TSPO) is an 18kDa ubiquitous cholesterol-binding molecule on the outer membrane of mitochondria (OMM). Upregulated in cancers TSPO is required to form contacts between mitochondria and the nucleus termed: Nucleus Associated Mitochondria (NAM). In GBM tissues as well as in 2D and 3D cell cultures we assayed patterns of TSPO expression (i), autophagy/mitophagy (ii), transcription factors (iii) and susceptibility to TMZ-induced demise (iv). Confocal and ultrastructural imaging detailed the organization and redistribution of the mitochondrial network (v). Our findings show that TMZ exploits mitochondria via TSPO to aid the formation of NAM which couples the expression of the nuclear transcription factor Sterol regulatory element-binding transcription factor 1 (SREBP1) and the stabilization of YAP/TAZ. Pharmacological modulation of TSPO counteracts all the above and re-instates susceptibility to TMZ-induced demise. NAM is therefore proposed as a variable in the engagement and execution of pro-survival mechanisms in GBM thus offering a means to both insight into the pathophysiology of this disease and offer novel therapeutic strategies. Key PointsO_LITMZ exploits TSPO to curb mitochondrial quality control in glioblastoma cells. C_LIO_LITMZ-mediated MRR is associated with the relocation of mitochondria to the nucleus and modulation of transcriptional factors involved in cholesterol metabolism and adaptation to aggressive growth. C_LIO_LITSPO represents a pharmacological target to revert chemoresistance in glioblastoma cells. C_LI Importance of the StudyThis study elucidates a mitochondrion-driven mechanism of chemoresistance in human glioblastoma cells, which depends on the mitochondrial translocator protein TSPO. The administration of TSPO ligands restores susceptibility to TMZ by influencing the dynamics of transcriptional factors associated with cholesterol metabolism and mechanical transduction.

cancer biology↗

bioRxiv2023

Optimal transport for mapping senescent cells in spatial transcriptomics

Spatial transcriptomics (ST) provides a unique opportunity to study cellular organization and cell-cell interactions at the molecular level. However, due to the low resolution of the sequencing data additional information is required to utilize this technology, especially for cases where only a few cells are present for important cell types. To enable the use of ST to study senescence we developed scDOT, which combines ST and single cell RNA-Sequencing (scRNA-Seq) to improve the ability to reconstruct single cell resolved spatial maps. scDOT integrates optimal transport and expression deconvolution to learn non-linear couplings between cells and spots and to infer cell placements. Application of scDOT to existing and new lung ST data improves on prior methods and allows the identification of the spatial organization of senescent cells, the identification of their neighboring cells and the identification of novel genes involved in cell-cell interactions that may be driving senescence.

cell biology↗

bioRxiv2018

MicroRNA-223 protects neurons from degeneration in Experimental Autoimmune Encephalomyelitis

Multiple sclerosis (MS) is an autoimmune disease characterized by demyelination and neurodegeneration in the brain, spinal cord and optic nerve. Neuronal degeneration and death underlie progressive forms of MS and cognitive dysfunction. Neuronal damage is triggered by numerous harmful factors in the brain that engage diverse signalling cascades in neurons thus therapeutic approaches to protect neurons will need to focus on agents that can target broad biological processes. To target the broad spectrum of signaling events that mediate neurodegeneration in MS we have focused on non-coding small microRNAs (miRNAs). microRNAs are epigenetic regulators of protein expression, targeting messenger RNAs (mRNAs) and inhibiting their translation. Dysregulation of miRNAs has been described in many neurodegenerative diseases including MS. In this study we identified two miRNAs, miR-223-3p and miR-27a-3p, that were upregulated in neurons in the experimental autoimmune encephalomyelitis (EAE) mouse model of CNS inflammation and in active MS lesions. Overexpression of miR-27a-3p or miR-223-3p protected dissociated cortical neurons from degeneration in response to peripheral blood mononuclear cell conditioned media (PBMC-CM). Introduction of miR-223-3p in vivo in mouse retinal ganglion cells (RGCs) protected RGC axons from degeneration in the EAE model. By in silico analysis we found that mRNAs in the glutamate receptor (GluR) pathway are enriched in miR-27a-3p and miR-223-3p targets. Antagonism of the GluR pathway protected neurons from PBMC-CM-dependent degeneration. Our results suggest that miR-223-3p and miR-27a-3p are upregulated in response to inflammation to mediate a compensatory neuroprotective gene expression program that desensitizes neurons to glutamate by downregulating mRNAs involved in GluR signalling.

neuroscience↗