American Journal of Pathology最新文献

Clear cell morphology is an uncommon finding in human tumors and reflects the distinctive appearance of the cytoplasm under standard histopathologic examination. Granular cell morphology appears to be a closely related phenomenon and reflects an abundant eosinophilic cytoplasm. Accumulating evidence suggests a central role for the MITF/TFE family of transcription factors in diverse clear cell and granular cell neoplasms. A principal function of these transcription factors concerns cytoplasmic organellar biogenesis: TFEB is the master regulator of lysosome biogenesis while MITF controls the biogenesis of lysosome-related organelles known as melanosomes which are responsible for melanin pigment production. Here we review the role of MITF/TFE pathway activation in a variety of benign and malignant tumors, with an emphasis on the diverse oncogenic mechanisms that activate this pathway and the resulting altered cell biology that contributes to the distinctive histomorphologic features.

Spinal muscular atrophy (SMA) is an inherited neurodegenerative disorder caused by a deficiency of the survival motor neuron (SMN) protein. Traditionally, it has been classified as a motor neuron disease. Over the past decade, however, numerous non-motor neuronal and non-neural pathologies reported in both SMA patients and mouse models have led to its redefinition as a systemic disorder. Although SMN protein expression outside the central nervous system (CNS) is well-established, it remains controversial whether its functional loss in non-neuronal cells/tissues merely represents a comorbidity or actively contributes to driving motor neuron degeneration. This review summarizes key evidence supporting the non-cell-autonomous death of motor neurons in SMA. Based on these lines of evidence, we propose three potential pathways for pathological transmission: (1) neuroinflammatory and neurotoxicity signaling mediated by glial cells, (2) aberrant retrograde signaling from the neuromuscular junction, and (3) modulation of the CNS by peripheral factors via the circulatory system. Future studies should focus on identifying critical peripheral tissues involved in SMA pathogenesis, elucidating the molecular mechanisms by which SMN deficiency leads to dysfunction in these tissues, and characterizing key mediators that influence motor neuron survival. In the current era where SMN-enhancing therapies have significantly improved patient survival, a deeper understanding of non-cell-autonomous mechanisms, and targeting them, represents a crucial step toward achieving curative strategies for SMA.

Glaucoma is a leading cause of irreversible blindness, characterized by retinal ganglion cell (RGC) degeneration and neuroinflammation. Retinal microglia are key modulators of this pathology. Using single-cell transcriptomic analysis of human glaucomatous retinas, we identified a distinct population of disease-associated microglia (DAM), defined by elevated TREM2 and other neurodegeneration-related genes. DAM exhibited enriched transcriptional programs associated with phagocytosis, antigen presentation, and immune regulation, with TREM2^high microglia predominating. In a mouse model of retinal ischemia-reperfusion (IR) injury, Trem2 knockout (Trem2^-/^-) mice exhibited exacerbated retinal neurodegeneration and neuroinflammation, impaired microglial phagocytosis and antigen presentation relative to WT controls. Furthermore, Trem2^-/^- microglia failed to acquire a DAM-like or anti-inflammatory (M2) phenotype, instead adopting a pro-inflammatory (M1)-skewed state. Flow cytometry and immunofluorescence analyses of cervical lymph nodes revealed increased frequencies of CD8⁺ T cells and CD19⁺ B cells, along with a reduction in FOXP3⁺ regulatory T cells (Tregs) in Trem2^-/^- mice. CD8⁺ T cells displayed heightened proliferation and diminished exhaustion, indicating sustained effector function. Transcriptomic profiling further confirmed enhanced lymphocyte activation, inflammasome signaling, and suppression of immunoregulatory pathways, including TGF-β and IL-2 signaling critical for Treg induction. Collectively, these findings establish TREM2 as a central regulator of disease-associated microglial activation and immune homeostasis in glaucoma. Loss of TREM2 compromises both innate and adaptive immune regulation, leading to sustained inflammation and exacerbated retinal neurodegeneration.

Cutaneous dermal microvascular responses are critical to common inflammatory skin conditions and effective wound healing. However, few laboratory models effectively recreate the spatially intact microenvironment essential for genesis and function of the human dermal microcirculation. Recently, stem cell-derived skin organoids (SKOs) have been developed that possess many microanatomical and cellular features of native human skin, including hair-forming epidermis and an underlying dermal layer containing endothelial-lined channels. Here, we profiled temporal dynamics of human SKO vasculogenesis and interrogated organoid responses to inflammatory and traumatic stimuli. SKOs generated from IPSCs expressing endothelial-specific GFP develop vasculogenic foci by post-differentiation day 6 that evolved into extensive microvascular networks that persisted beyond 4 months in culture. Multiplex antibody arrays provided mechanistic insight into secreted effectors supporting early events in SKO vasculogenesis, including VEGFA and placental growth factor. Over time, SKO microvasculature became ensheathed by αSMA-positive (+), PDGFRβ+ mural cells producing collagen IV-rich basement membranes, while endothelium retained markers of proliferative activation/immaturity, including nestin. Functionally, SKOs treated with pro-inflammatory cytokines expressed endothelial and perivascular VCAM1 and ICAM1, with concomitant release of endogenous inflammatory mediators. Finally, wounding of SKOs via sharp dissection provided the first demonstration of angiogenic healing responses that were further augmented by exogenous VEGF. Overall, this advanced human culture system represents a highly relevant model for understanding biological responses by the dermal microvasculature.

Recent studies have shown that cancer-associated fibroblasts (CAFs), a key component of the tumor microenvironment, are heterogeneous and can be divided into distinct subsets. While all CAFs were believed to promote tumor progression, recent studies have identified a distinguished subset of tumor-restraining CAFs (rCAFs). We previously demonstrated that the upregulation of Meflin (Immunoglobulin Superfamily Containing Leucine-Rich Repeat) expression confers a tumor-restraining role on CAFs in pancreatic, colon, urothelial, and lung cancers. Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer with a poor prognosis. In this study, we showed that Meflin can be a candidate marker for rCAFs in TNBC. In co-culture experiments with tumor cells and fibroblasts, Meflin overexpression in fibroblasts inhibited tumor cell growth in a three-dimensional culture model and shifted their gene expression profile toward that characteristic of universal or normal fibroblasts. Meflin overexpression in fibroblasts significantly reduced the expression of the chemokine receptor ACKR3 and enhanced that of the prostaglandin synthase PTGDS. This is suggestive of the involvement of these proteins in tumor microenvironment regulation. Furthermore, Meflin deficiency reduced the area of tumor vessels in a TNBC mouse model, highlighting its role in CAF-mediated inhibition of TNBC progression and improvement of drug delivery. Accordingly, Meflin plays a role as a potential functional marker of rCAFs in TNBC.

Having the ability to objectively index dopamine levels in the brain with a peripheral biomarker of brain dopamine would enable the objective monitoring of the progression of Parkinson's disease (PD) and other dopamine-dependent disorders. This study investigates this potential biomarker using a dopamine-depletion approach, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin model and PD subjects, which are well-known models of dopamine depletion in the midbrain of rodents and humans, respectively. MPTP-induced dopamine depletion in the substantia nigra compacta (SNc) resulted in a significant decrease in dopamine and norepinephrine levels in the blood. The proportion of dopamine D2-subtype receptor (D2R)-expressing leukocytes progressively decreased (specifically B cells and T cells) during the DA depletion. Parkinson's subjects displayed significantly decreased D2R expression in B and T cells, and increased levels in epinephrine, dopamine, norepinephrine, and levodopa, compared to control subjects. We found a significant negative correlation between blood levodopa and D2R expression in classical monocytes which correlated mildly with blood dopamine levels. The modulation of peripheral D2Rs in PD and MPTP seen in this study demonstrate that SNc dopamine depletion in humans and rodents does manifest in the periphery. Although this study didn't provide a clear narrative of how nigral and peripheral dopamine system mirror each other, the results give evidence that peripheral D2Rs may be both biomarkers and important substrates for treatment of dopamine-dependent disorders.

Long non-coding RNAs (lncRNAs) are emerging as critical regulators of acute kidney injury (AKI). In this study, we investigated the pathological role of pseudogene derived lncRNA GSTM3P1(human)/Gstm2-ps1(mouse) in sepsis-associated AKI (SA-AKI). GSTM3P1/Gstm2-ps1 was transiently upregulated in kidney proximal tubular cells at the early stage of SA-AKI in mice treated with lipopolysaccharide (LPS) or cecal ligation and puncture (CLP), as well as in LPS-treated proximal tubular cells. Functionally, overexpression of GSTM3P1/gstm2-ps1 exacerbated LPS-induced proximal tubular cell apoptosis and oxidative stress. In contrast, proximal tubule-specific gstm2-ps1 knockout mice were significantly protected from LPS-induced AKI, as evidenced by improved renal function and reduced apoptosis, kidney injury markers, and reactive oxygen species. Similarly, these mice showed renal protective effects against CLP-induced AKI. Mechanistically, overexpression of GSTM3P1/Gstm2-ps1 in proximal tubular cells markedly suppressed parent gene GSTM3/GSTM2 protein but not mRNA expression, indicating a translational repression. Restoration of GSTM3/GSTM2 rescued proximal tubular cells from LPS-induced apoptosis. Furthermore, RNA pulldown assay revealed that Gstm2-ps1 bind to Human antigen R (HuR), a known post-transcriptional regulator for mRNA stability and translation. Overexpression of HuR antagonized Gstm2-ps1-mediated repression of GSTM2, associated with increased cell survival after LPS injury. In conclusion, the early induction of GSTM3P1/Gstm2-ps1 in SA-AKI exacerbates kidney injury by a novel mechanism to sequester HuR and inhibit the translation of parent gene GSTM3/gstm2 for oxidative stress detoxification.

Acute ischemic stroke is a complex disorder in which the damage goes beyond neuronal loss and involves dynamic responses from glial, vascular, stromal, and immune cells. Spatial transcriptomics (ST) has become a powerful tools to study these processes by preserving tissue architecture while revealing detailed gene expression patterns. This review describes how ST advanced the understanding of cellular changes after stroke, focusing on microglia, astrocytes, and oligodendrocytes to showcase the complexity of stroke pathobiology. Research shows that the glial cells adopt different states depending on location and time, influencing both harmful and protective outcomes, such as inflammation, blood-brain barrier (BBB) damage, remyelination, and tissue repair. By combining ST with single-cell and multi-omics approaches, new therapeutic targets have been identified, including different types of activated glial states and key signalling pathways involved in glial communication. Despite the recent progress in ST, challenges remain, particularly the need for multi-timepoint analyses, 3D reconstructions and standardized datasets that can move the field closer to clinical applications. Future reference atlases, together with experimental validation, will be essential for developing precise, cell-targeted therapies. The goal is to provide a review that helps researchers at all levels to summarize results from the most recent ST studies and to highlight the possible applications of spatial approaches for improving stroke research and therapy.

Spatial profiling technologies are transforming our understanding of tissue organization by enabling high-resolution mapping of molecular features in situ. Spatial multi-omics platforms ranging from spot-based to single-cell and subcellular resolution are increasingly being integrated into pathobiological workflows, offering unprecedented insights into novel cellular states, the tissue microenvironment, cell-cell communication, drug resistance niches and disease heterogeneity. In this article, we discuss recent experimental and computational advances in spatial biology, highlighting how multimodal integration enables a more comprehensive understanding of tissue function and its dysregulation. We explore the challenges and opportunities that arise in 3D spatial mapping, the impact on biomarker discovery, therapeutic decision-making, and the translational implications of large-scale pathological foundational models trained on spatial omics data. Finally, we highlight that refined biological questions, combined with artificial intelligence, can unlock the full potential of spatial omics and reshape diagnostic workflows towards more precise clinical decision-making.

Retinal detachment (RD) is an ocular emergency that can lead to irreversible vision loss. However, due to the cellular heterogeneity within the retina, the pathological alterations following RD remain insufficiently elucidated. In this study, single-cell RNA sequencing (scRNA-Seq) was performed on retinal tissues from patients with RD, and the data were analyzed using the single-cell graphical Gaussian model (SingleCellGGM), a gene co-expression network analysis algorithm developed by our team. SingleCellGGM analysis revealed several cell-type-specific gene modules (GMs) following RD, which were further validated. We observed a GM associated with the glycolytic process that was upregulated across most cell clusters, and further confirmed that anaerobic glycolytic in the retina was markedly increased following RD. In addition, a GM associated with apoptosis regulation was significantly enriched in rod cells. In Müller cells, the GM related to extracellular matrix (ECM) organization was downregulated. In microglia, GM related to leukocyte migration were upregulated, potentially involving the Fibronectin 1 (FN1) pathway, and limited evidence suggested T-cell infiltration into the retina following RD, with both findings remaining preliminary and requiring further validation. Overall, this study reveals cell-type-specific pathological changes following RD, providing deeper insight into the pathological mechanisms underlying visual dysfunction following RD.