Biology subjects

D'Mello, C.

Publications and source records attributed to D'Mello, C..

4 recordsLinked to original sources

bioRxiv2025

Aging-enhanced accumulation of fibroblasts excludes oligodendrocytes in demyelinated lesions

Fibroblast dysregulation contributes to pathological fibrosis and aberrant repair. Emerging evidence suggest that fibroblasts accumulate in lesions following central nervous system injury, but whether and how they influence oligodendrocyte repair responses, including in aging, is uncertain. Here we report that fibroblasts accumulate in the parenchyma of spinal cord white matter lesions of 6 - 10 week old young mice after lysolecithin-induced demyelination. This was first observed through immunofluorescence microscopy that employed several markers attributed to fibroblasts, including platelet-derived growth factor-{beta}, collagen type 11, -smooth muscle actin, periostin and fibronectin; and by the use of platelet-derived growth factor-{beta} TdTomato reporter transgenic mice. Single-nucleus and spatial transcriptomics of lysolecithin lesions established the presence of fibroblasts in lysolecithin lesions and delineated them from closely related pericytes. CellChat ligand - receptor analyses highlight fibroblasts in the lysolecithin environment as a major source of input of signals for microglia/macrophages and oligodendrocyte precursor cells, with numerous reciprocal interactions. The infiltration of fibroblasts was promoted by microglia/macrophages, as anticipated by their temporal representation in lysolecithin lesions, and by tissue culture experiments where the migration of fibroblasts was enhanced by macrophages. Of particular relevance to spontaneous regenerative events in lysolecithin demyelination, areas of fibroblast accumulation were devoid of oligodendrocyte precursor cells. In tissue culture, oligodendrocyte precursor cells were excluded from fibroblast domains. Moreover, fibroblast accumulation after lysolecithin injury was enhanced with increasing age, a known detriment to the capacity to remyelinate after injury, and exclusion of oligodendrocyte precursor cells from fibroblast areas of 48 - 52 week mice exceeds that occurring in younger 6 - 10 weeks animals. Finally, by mining a publicly available single-nucleus RNA database of multiple sclerosis, we found fibroblasts in the edge of chronic active and chronic inactive lesions and in lesion core, and fewer in periplaque or normal white matter. We identified several communication networks between fibroblasts, microglia/macrophages and oligodendrocyte precursor cells in these MS lesions. Our collective results demonstrate a role of fibroblasts in demyelination-associated neuropathology, which is exacerbated by aging, and highlight the importance of regulating fibroblasts to promote effective CNS repair.

neuroscience↗

bioRxiv2024

EMMPRIN confers metabolic advantage for monocytes and macrophages to promote disease in a model of multiple sclerosis

Monocytes and monocyte-derived macrophages have important roles in the initiation and progression of multiple sclerosis (MS). These cells undergo metabolic reprogramming to generate immunophenotypes that promote leukocyte infiltration, axonal degeneration and demyelination, worsening MS pathology. The mechanisms that dictate metabolic programs in monocytes and macrophages in MS remain unclear. We previously reported that extracellular matrix metalloproteinase inducer (EMMPRIN, CD147), a glycoprotein that acts as a chaperone of monocarboxylate transporter 4 (MCT4), assisted with glycolysis-driven pro-inflammatory phenotype in macrophages in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Using newly-generated CCR2CreERT2:EMMPRINfl/fl (CCR2:EMMP) mice, we report that presymptomatic deletion of EMMPRIN in CCR2+ monocytes prevented or reduced clinical disability of EAE. This was correspondent with decreased infiltration of leukocytes into the CNS. Single cell RNA-seq of blood monocytes from EAE and proteomics analysis of macrophages from CCR2:EMMP-/- mice revealed significant alterations in metabolic programs, particularly reduced glycolysis and elevated mitochondrial electron transport and fatty acid oxidation, which were linked to their reduced pro-inflammatory traits. Our findings implicate EMMPRIN as a key regulator of metabolic pathways that exacerbate pro-inflammatory functions of monocytes in MS.

immunology↗

bioRxiv2023

Spatially resolved single-cell analysis uncovers protein kinase C-& expressing microglia with anti-tumor activity in glioblastoma

Glioblastoma (GBM) is a brain tumor that poses a formidable challenge to treatment options available. The tumor microenvironment (TME) in GBM is highly complex, marked by immunosuppression and cellular heterogeneity. Understanding the cellular interactions and their spatial organization within the TME is crucial for developing effective therapeutic strategies. In this study, we integrated single-cell RNA sequencing and spatial transcriptomics in a GBM mouse model to unravel the spatial landscape of the brain TME. We identified a previously unrecognized microglia subtype expressing protein kinase C{delta} (PKC{delta}) associated with potent anti-tumor functions. The presence of PKC{delta}-expressing microglia was confirmed in resected human GBM specimens. Elevating tumoral PKC{delta} expression using niacin or adeno-associated virus in mice enhanced the phagocytosis of GBM cells by microglia in culture and increased the lifespan of mice with intracranial GBM. These findings were corroborated in analyses of the TCGA GBM datasets where low PKC{delta} samples showed negative pathway enrichment for apoptosis, phagocytosis, and immune signaling pathways, as well as lower levels of immune cell infiltration overall. Our study underscores the importance of integrating spatial context to unravel the TME, resulting in the identification of previously unrecognized subsets of microglia with anti-tumor functions. These findings provide valuable insights for advancing innovative immunotherapeutic strategies in GBM.

immunology↗

bioRxiv2022

Single cell spatial analysis identifies regulators of brain tumor initiating cells

Glioblastomas (GBMs) are aggressive brain tumors with extensive intratumoral heterogeneity. Here, we used spatial transcriptomics and single-cell ATAC-seq to dissect the transcriptome of distinct anatomical regions of the tumor microenvironment. We identified numerous extracellular matrix (ECM) molecules including biglycan elevated in areas infiltrated with brain tumor-initiating cells (BTICs). Single-cell RNA sequencing showed that the ECM molecules were differentially expressed by cells including injury response versus developmental BTICs. Exogeneous biglycan or overexpression of biglycan resulted in a higher proliferation rate of BTICs, and this was associated mechanistically with LDL receptor-related protein 6 (LRP6) binding and activation of the Wnt/{beta}-catenin pathway. Biglycan-overexpressing BTICs grew to a larger tumor mass when implanted intracranially in mice. This study points to the spatial heterogeneity of ECM molecules in the GBM microenvironment and suggests biglycan-LRP6 axis as a therapeutic target to curb GBM growth.

cancer biology↗