American Journal of Pathology最新文献

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. This article discusses recent experimental and computational advances in spatial biology, highlighting how multimodal integration enables a more comprehensive understanding of tissue function and its dysregulation. The challenges and opportunities that arise in three-dimensional spatial mapping, the impact on biomarker discovery, therapeutic decision-making, and the translational implications of large-scale pathology foundation models trained on spatial omics data are explored. Finally, it's highlighted that refined biological questions, combined with artificial intelligence, can unlock the full potential of spatial omics and reshape diagnostic workflows toward more precise clinical decision-making.

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. This article reviews 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 nonmotor neuronal and nonneural pathologies reported in both patients with SMA and mouse models have led to its redefinition as a systemic disorder. Although SMN protein expression outside the central nervous system is well established, it remains controversial whether its functional loss in nonneuronal 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. On the basis of these lines of evidence, three potential pathways for pathologic transmission are proposed: i) neuroinflammatory and neurotoxicity signaling mediated by glial cells, ii) aberrant retrograde signaling from the neuromuscular junction, and iii) modulation of the central nervous system 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.

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 microanatomic and cellular features of native human skin, including hair-forming epidermis and an underlying dermal layer containing endothelial-lined channels. Here, temporal dynamics of human SKO vasculogenesis are profiled and organoid responses to inflammatory and traumatic stimuli are interrogated. SKOs generated from induced pluripotent stem cells expressing endothelial-specific green fluorescent protein 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. Over time, SKO microvasculature became ensheathed by mural cells producing collagen IV-rich basement membranes, whereas endothelium retained signatures of proliferative activity/immaturity. Functionally, SKOs treated with proinflammatory cytokines expressed markers of endothelial and perivascular vascular activation, 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 vascular endothelial growth factor. 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. Although all CAFs were believed to promote tumor progression, recent studies have identified a distinguished subset of tumor-restraining CAFs (rCAFs). It was previously demonstrated that the up-regulation 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, it was shown 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.