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At least 19 recordsLinked to original sources
PubMed2026

Altered ECM deposition and cell adhesion signaling in a human cortical organoid model of fragile X syndrome.

Fragile X Syndrome (FXS) is the most common inherited intellectual disability, and the most common monogenic cause of autism spectrum disorder (ASD). It is caused by epigenetic silencing of the FMR1 gene leading to the loss of FMRP, an RNA-binding protein that regulates local mRNA translation in neuronal dendrites, crucial for synapse development. Three-dimensional (3D) brain organoid models derived through in vitro differentiation of pluripotent stem cells offer a powerful tool to dissect the underlying mechanisms of neurodevelopmental disorders. Here, we generated human FXS and control organoids using isogenic human embryonic stem cell clones with and without the FXS mutation. Our results show that mature FXS cortical brain organoids can be derived by inhibiting the TGFβ and Wnt pathways. Moreover, expression analyses including immunofluorescence, qRT-PCR, proteomics and western blotting reveal altered levels of neuronal markers and ECM deposition along with modulated downstream signaling molecules. Interestingly, in silico analysis of proteomics revealed several altered pathways, such as cell adhesion, regulation of neurogenesis and cell cycle that are implicated in FXS. Collectively, our unique FXS-organoids derived from isogenic hESC lines may serve as a model for studying the pathology of FXS disorder and for developing therapeutical intervention.

Humans↗
PubMed1999

DNA-ploidy analysis correlates with the histogenetic classification of thymic epithelial tumours.

The ploidy values of the epithelial component were determined in a series of thymomas and organotypic thymic carcinomas using image cytometry and the results were compared with the histological tumour subtypes according to the histogenetic classification introduced by Marino, Müller Hermelink, and Kirchner (MMHK). Forty-six cases of thymic epithelial tumours were included in the study. After reclassification according to the MMHK classification, the distribution among the subtypes was as follows: three medullary, nine mixed type, five predominantly cortical (organoid), 16 cortical thymomas, and 13 well-differentiated thymic carcinomas. Single cell preparations were made from paraffin-embedded tumour tissue and stained according to Feulgen. Ploidy analysis was performed using an automated image analysis system. In five cases, DNA cytometry could not be performed, for technical reasons. The remaining 41 cases consisted of 11 diploid and 30 non-diploid tumours. The percentage of aneuploid tumours in the different subtypes increased from medullary (0 per cent) through mixed type (44.4 per cent), predominantly cortical (75 per cent), cortical (83.3 per cent) to well-differentiated thymic carcinomas (100 per cent). DNA-ploidy determination using image cytometry correlates with the concept of the MMHK classification of thymomas.

Humans↗
PubMed1998

Thymic epithelial tumor progression in an SV40T transgenic mouse model. Cortical thymoma-thymic carcinoma sequence.

There have been several reports that thymoma in human is a progressive disease, and that thymoma and thymic carcinoma form a continuum. We established a stable line of SV40T transgenic mice, which consistently produced thymic epithelial tumours progressing to thymic carcinoma within a predictable time span. Using this animal model and a morphological approach, thymic epithelial tumour progression was studied with reference to sequential changes at different time points in animals aged from 3 to 32 weeks. At all ages, SV40T was expressed in the nuclei of thymic epithelial cells; in these transgenic mice we observed the entire spectrum from cortical type thymoma to thymic carcinoma. Thymic size tended to increase with ageing in SV40T TG mice. While younger mice had predominantly cortical (organoid) or cortical thymoma, older mice had well-differentiated thymic carcinoma (WDTC) or poorly differentiated thymic carcinoma. When SV40T TG mice (248 line) reached a certain age, carcinoma of the thymus was present in all of them. Cortical-type thymoma became malignant within a predictable time span, suggesting a cortical thymoma-carcinoma sequence. When the mice were 9 weeks of age, the thymuses formed gross masses compatible with cortical thymoma. At 14 weeks of age, WDTC appeared against the background of cortical thymoma. Poorly differentiated thymic carcinoma was found after 15 weeks and affected all animals over 23 weeks of age. Most thymic carcinomas coexisted in varying proportions with cortical-type thymoma. Medullary thymomas did not develop in the mice, and no transition from medullary-type thymomas to thymic carcinomas was observed. In this SV40T transgenic mouse model, thymic carcinoma is clearly preceded by cortical-type thymoma. These transgenic mice may provide an interesting model for the progression from cortical thymoma to WDTC and/or high-grade carcinoma.

Aging↗
PubMed2023

Unraveling Neuronal Identities Using SIMS: A Deep Learning Label Transfer Tool for Single-Cell RNA Sequencing Analysis.

Large single-cell RNA datasets have contributed to unprecedented biological insight. Often, these take the form of cell atlases and serve as a reference for automating cell labeling of newly sequenced samples. Yet, classification algorithms have lacked the capacity to accurately annotate cells, particularly in complex datasets. Here we present SIMS (Scalable, Interpretable Machine Learning for Single-Cell), an end-to-end data-efficient machine learning pipeline for discrete classification of single-cell data that can be applied to new datasets with minimal coding. We benchmarked SIMS against common single-cell label transfer tools and demonstrated that it performs as well or better than state of the art algorithms. We then use SIMS to classify cells in one of the most complex tissues: the brain. We show that SIMS classifies cells of the adult cerebral cortex and hippocampus at a remarkably high accuracy. This accuracy is maintained in trans-sample label transfers of the adult human cerebral cortex. We then apply SIMS to classify cells in the developing brain and demonstrate a high level of accuracy at predicting neuronal subtypes, even in periods of fate refinement, shedding light on genetic changes affecting specific cell types across development. Finally, we apply SIMS to single cell datasets of cortical organoids to predict cell identities and unveil genetic variations between cell lines. SIMS identifies cell-line differences and misannotated cell lineages in human cortical organoids derived from different pluripotent stem cell lines. When cell types are obscured by stress signals, label transfer from primary tissue improves the accuracy of cortical organoid annotations, serving as a reliable ground truth. Altogether, we show that SIMS is a versatile and robust tool for cell-type classification from single-cell datasets.

Brain organoids↗
PubMed2026

Metabolic atlas of early human cortex reveals glycolytic remodeling and pentose phosphate pathway control of cell fate transitions.

Cortical development involves rapid progenitor expansion and cell diversification supported by tightly regulated metabolic programs, yet these programs remain largely uncharacterized in human development. Here, we generated a metabolic atlas of the early human cortex using primary tissue and stem cell-derived cortical organoids. We observed dynamic changes in core metabolic functions, including an unexpected increase in glycolysis and pentose phosphate pathway (PPP) activity during late neurogenesis. Manipulation of glucose availability in cortical organoids altered cell-type composition, increasing outer radial glia (oRG) and inhibitory neuron populations. Pharmacological and genetic inhibition of PPP enzymes recapitulated these cell fate changes. Ribose was sufficient to rescue radial glia (RG) gene expression changes, revert organoid cell-type composition, and restore levels of ATP and hypotaurine. These data identify a critical role for the PPP in modulating RG cell fate specification and generate a resource for future exploration of additional metabolic pathways in human cortical development.

cell fate↗
PubMed1993

Thymoma--morphologic subclassification correlates with invasiveness and immunohistologic features: a study of 122 cases.

We applied the classification system of Marino and Müller-Hermelink (Virchows Arch A Pathol Anat Histopathol 407:119-149, 1985) and Kirchner and Müller-Hermelink (Prog Surg Pathol 10: 167-189, 1989) to 122 thymic epithelial tumors to evaluate the utility of this classification and to determine its correlation with invasiveness, follicular lymphoid hyperplasia, myasthenia gravis, and immunophenotype. The majority of cases could be classified according to this scheme: eight cases (7%) were medullary thymoma, 34 cases (28%) were mixed thymoma, 20 cases (16%) were predominantly cortical (organoid) thymoma, 22 cases (18%) were cortical thymoma, 32 cases (26%) were well-differentiated carcinoma (WDC), two cases (2%) were high-grade carcinoma, and four cases (3%) were unclassifiable. We report a detailed histologic analysis of these subtypes, with criteria for diagnosis. We propose that the term "organoid thymoma" be replaced by "predominantly cortical thymoma." We also observed a previously unrecognized subtype of WDC with spindle-shaped epithelial cells, which must be distinguished from medullary thymoma. There was a strong correlation between histologic subtype and invasion (P < .0001). All medullary and mixed thymomas were either completely encapsulated (64%) or had only invasion through the capsule (36%). Organoid and cortical thymomas showed an intermediate degree of invasiveness, with 36% invasive into mediastinal fat and 14% into adjacent structures. All the cases of WDC were invasive either through the capsule (19%) or into adjacent structures (81%); five cases (16%) also showed distant spread in the form of pleural seeding (four cases) or lymph node metastasis (one case). Microscopic evaluation disclosed invasion in a substantial number of cases (28.5%) thought by the surgeon to be encapsulated. The presence of follicular lymphoid hyperplasia, either within the tumor, in the residual normal thymus, or in both, was a significant predictor of myasthenia gravis (P < .0015); there was an increased association of myasthenia gravis and thymomas with cortical type epithelium (organoid thymoma, cortical thymoma, and WDC). There was no correlation between epithelial cell morphology and antigen expression; however, the immunophenotype of the associated lymphocytes corresponded closely to the morphologic classification of the thymomas. The Müller-Hermelink morphologic classification can be applied to most cases of thymoma and strongly predicts invasive behavior. The correlation of lymphocyte immunophenotype with the morphologic classification of the epithelial cells suggests that it is biologically accurate.

Adolescent↗
PubMed2024

SIMS: A deep-learning label transfer tool for single-cell RNA sequencing analysis.

Cell atlases serve as vital references for automating cell labeling in new samples, yet existing classification algorithms struggle with accuracy. Here we introduce SIMS (scalable, interpretable machine learning for single cell), a low-code data-efficient pipeline for single-cell RNA classification. We benchmark SIMS against datasets from different tissues and species. We demonstrate SIMS's efficacy in classifying cells in the brain, achieving high accuracy even with small training sets (<3,500 cells) and across different samples. SIMS accurately predicts neuronal subtypes in the developing brain, shedding light on genetic changes during neuronal differentiation and postmitotic fate refinement. Finally, we apply SIMS to single-cell RNA datasets of cortical organoids to predict cell identities and uncover genetic variations between cell lines. SIMS identifies cell-line differences and misannotated cell lineages in human cortical organoids derived from different pluripotent stem cell lines. Altogether, we show that SIMS is a versatile and robust tool for cell-type classification from single-cell datasets.

Single-Cell Analysis↗
PubMed2026

Cross-tissue immune profiling of APOE &#x3b5;4 reveals early dysregulation in Alzheimer's disease.

INTRODUCTION: Apolipoprotein E (APOE) &#x3b5;4 is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), but its contribution to disease pathogenesis remains incompletely understood. METHODS: Here, we integrate proteomic profiling of plasma (n&#xa0;=&#xa0;9028), cerebrospinal fluid (n&#xa0;=&#xa0;1099), dorsolateral prefrontal cortex (n&#xa0;=&#xa0;720), and superior temporal gyrus (n&#xa0;=&#xa0;105) to define the immune phenotype associated with APOE &#x3b5;4. RESULTS: We identify a conserved, allele dose-dependent pro-inflammatory immune protein signature across peripheral and central tissues independent of AD diagnosis. This signature also emerges in patient-derived cortical organoids prior to amyloid beta and tau pathology, supporting a genotype-driven mechanism. Cross-tissue comparisons reveal shared innate and antiviral responses alongside tissue-specific immune signaling. Notably, a 12-week medical ketogenic diet partially reversed the APOE &#x3b5;4 immune signature. DISCUSSION: These findings position immune dysregulation as an early and tractable driver of AD risk in APOE &#x3b5;4 carriers with direct implications for targeted prevention strategies.

Humans↗
PubMed2025

Single-cell analysis of dup15q syndrome reveals developmental and postnatal molecular changes in autism.

Duplication 15q (dup15q) syndrome is a leading genetic cause of autism spectrum disorder, offering a key model for studying autism-related mechanisms. Using single-cell and single-nucleus RNA sequencing of cortical organoids from dup15q patient-derived iPSCs and post-mortem brain samples, we identify increased glycolysis, disrupted layer-specific marker expression, and aberrant morphology in deep-layer neurons during fetal-stage organoid development. In adolescent-adult postmortem brains, upper-layer neurons exhibit heightened transcriptional burden related to synaptic signaling, a pattern shared with idiopathic autism. Using spatial transcriptomics, we confirm these cell-type-specific disruptions in brain tissue. By gene co-expression network analysis, we reveal disease-associated modules that are well preserved between postmortem and organoid samples, suggesting metabolic dysregulation that may lead to altered neuron projection, synaptic dysfunction, and neuron hyperexcitability in dup15q syndrome.

Humans↗
PubMed1994

Thymoma. Histologic subclassification is an independent prognostic factor.

BACKGROUND: Several histologic classifications of thymomas have been proposed, and attempts have been made to correlate the different histologic subtypes to clinical behavior and prognosis. Recently, Marino and Müller-Hermelink and Kirchner et al. proposed a new morphologic classification of thymomas based on the resemblance of the neoplastic cells to subtypes of the normal thymic epithelial cells. In this classification, six categories of thymic epithelial tumors are recognized. They define four categories of thymoma: medullary, mixed, organoid (predominantly cortical), and cortical, and two subgroups of thymic carcinomas: well differentiated thymic carcinoma and high grade carcinomas. METHODS: The authors studied 116 patients with thymic epithelial tumors classified according to the proposals of Marino and Müller-Hermelink and Kirchner et al. to assess the effect of histologic classification and other factors (stage, size of tumor, lymphoid hyperplasia, myasthenia gravis, age, sex, and treatment) on survival, and freedom from relapse. RESULTS: Eight cases (7%) were medullary, 32 cases (28%) mixed, 20 cases (17%) organoid (predominantly cortical), 21 cases (18%) cortical, 29 cases (25%) well differentiated carcinoma (WDTC), two cases (2%) high grade carcinoma, and four cases (3%) unclassifiable. Fifty-two patients were in stage I, 32 stage II (16 IIA, 16 IIB), 28 stage III, and four Stage IVA. Only stage (P = 0.0001; hazard ratio = 5.36) and histology (P = 0.0019; hazard ratio = 8.010) were significant in predicting recurrence. Histology was highly correlated with stage, but by multivariate analysis was an independent factor in predicting relapse (P = 0.0281; hazard ratio = 5.92). None of the medullary or mixed thymomas recurred, even though 30% were invasive. Patients with WDTC recurred more often and earlier than patients with organoid and cortical thymoma (log rank, P = 0.0001). The actuarial freedom from relapse for patients with WDTC was 58% at 5 years and 46% at 10 years compared with 100% for other subtypes. Both advanced stage (III and IV) and the WDTC histologic subtype significantly increased the risk of death from thymoma (log rank, P = 0.0001). The actuarial survival of patients with WDTC was 80% at 5 years and 54% at 10 years, whereas that of patients with the other subtypes was 100% at 5 and 10 years. Five of seven relapses and six of seven deaths from thymoma occurred in patients with WDTC. In Stage II patients, one of 16 minimally invasive (Stage IIA) tumors recurred, compared with 3 of 16 grossly invasive (Stage IIB) tumors, indicating that microscopic assessment of invasion is important in staging. CONCLUSIONS: The histologic classification of Marino and Müller-Hermelink has prognostic significance, independent of tumor stage. Medullary and mixed thymomas were benign tumors with no risk of recurrence, even when capsular invasion was present. Organoid and cortical thymoma showed intermediate invasiveness and a low, but significant, risk of late relapse, even with minimal invasion. WDTC were always invasive and had a significantly increased risk of relapse and death, even for Stage II patients. Adjuvant therapy appears unnecessary for medullary and mixed thymomas, even when invasive.

Adolescent↗
PubMed1992

Thymoma in childhood: a clinicopathological study of five cases.

The histological and clinical findings in five cases of thymoma arising in paediatric patients have been studied. The age range was 11-15 years and no patient was affected by myasthenia gravis. All tumours were macroscopically encapsulated, but two of them displayed evidence of microscopic capsular invasion. Histologically, four cases were of the predominantly cortical type (organoid thymoma) with prominent areas of medullary differentiation and Hassall's bodies; one case was of the cortical type. All patients are alive and disease-free 3 months to 9 years after surgery. These findings suggest that thymoma in the paediatric age group may be characterized by fairly uniform clinicopathological features, with a low rate of association with myasthenia gravis and a favourable prognosis.

Adolescent↗
PubMed1999

Thymic tumours in Denmark. A retrospective study of 213 cases from 1970-1993.

Histological slides of 213 thymic tumours were reviewed twice and classified according to Kirchner and Müller-Hermelink into 122 thymomas (syn. organotypic thymic epithelial tumours (TET)), 58 thymic carcinomas (syn. non-organotypic TET) and 16 lymphomas. Tumour heterogeneity (i.e. features of two subtypes in one tumour) appeared in 38% of the organotypic TET. The overall diagnostic correspondence between the reviews of the 122 organotypic TET was 48%. By reducing the five diagnostic groups to three: organotypic TET benign (medullary and mixed thymomas), organotypic TET low-grade (organoid and cortical thymomas and well-differentiated thymic carcinoma (WDTC)) and non-organotypic TET (usually high-grade thymic carcinomas), and minimising the effect of tumour heterogeneity in this way, the diagnostic correspondence increased to 82%. Correlating histological type with stage, we found that 80% of medullary and 87% of mixed thymomas were stage I, that 85% of cortical and 81% of WDTC were stage II or III, and that non-organotypic TET were stage II or III (86%) or stage IV (14%), respectively. It is suggested to report on the heterogeneity of a given case of thymic epithelial tumour in the pathology reports and give the approximate percentage of each component, telling the clinician which component may determine the prognosis.

Cysts↗
PubMed1995

Thymomas and thymic carcinomas. A retrospective investigation with histological reclassification.

The morphological heterogeneity of thymomas has caused much confusion respecting their classification. Recently Kirchner & Müller-Hermelink (4) proposed a histological subclassification which has been claimed to represent an independent prognostic factor: medullary and mixed thymomas are benign; organoid and cortical type as well as well-differentiated thymic carcinomas are low-grade malignant tumors, which have the capacity to recur and spread, even if they are clinically benign. High-grade malignant thymomas are always malignant. We present the clinicopathological data on 10 clinically benign and 14 clinically malignant thymomas. Having reclassified the thymomas, we found four low-grade malignant examples among the clinically benign thymomas. It is important to identify this group of patients as they are at risk of tumor recurrence. However, further investigation is needed to support the validity of this subclassification system.

Aged↗
PubMed1994

The clinicopathological correlation of epithelial subtyping in thymoma: a study of 112 consecutive cases.

The clinicopathological features of 112 thymomas collected from the surgical pathological files of Taipei Veterans General Hospital from 1961 to 1991 were investigated to determinate the clinical efficacy of epithelial subtyping. All thymomas were categorized based on the Müller-Hermelink system into three subtypes: cortical thymoma, mixed thymoma, and medullary thymoma. The former was further subclassified into organoid thymoma, conventional cortical thymoma, and well differentiated thymic carcinoma (WDTC) according to the systems of Pescarmona and Kirchner. The association of each subtype with sex, age at diagnosis, clinical stage, presence of myasthenia gravis, and length of survival was studied. As classified by the Müller-Hermelink system, the cortical thymomas as a whole tended to occur in younger patients and were more frequently associated with myasthenia gravis than the medullary thymomas. The cortical thymomas also showed a propensity to be invasive in nature, whereas the medullary thymomas generally behaved as benign tumors. Further subclassification of cortical thymomas into organoid thymoma, conventional thymoma, and WDTC did not provide more information about clinical behavior. By Kaplan-Meier's actuarial survival analyses none of the epithelial subtypes displayed a statistically significant influence on prognosis. It is concluded that staging remains the most important factor affecting the patient's outcome. Because of the existence of many intermediate forms and the deficiency of clinical relevance, the subclassification of cortical thymomas should be interpreted as a morphological continuum rather than as distinct histological variants.

Adolescent↗
PubMed1998

Thymomas and thymic carcinomas. Evaluation of the Müller-Hermelink classification.

In the present study the Müller-Hermelink classification was used to analyze 39 thymomas and 4 thymic carcinomas collected over 20 years at the Chair and Department of Pathomorphology CM UJ. Our series consisted of 10 medullary thymomas (25.6%), 13 mixed (33.3%), 7 organoid (17.9%) and 9 cortical thymomas (23.0%). The mean age of the patients was 50.3 and it was the highest in patients with mixed thymomas-58.4 years and the lowest in patients with organoid thymomas-38.9 years, the difference being statistically significant. In the present series women were predominant (24:15). Myasthenia gravis was observed in 10 patients (25.6%), 5 women and 5 men, in 7 of them it was associated with cortical and organoid thymomas. Medullary, mixed and organoid thymomas were usually of lower stage (I and II), having a better prognosis than cortical thymomas and thymic carcinomas. One organoid thymoma recurring after 7 years evolved into cortical thymoma. Two thymic carcinomas were diagnosed as anaplastic, low differentiated, one as sarcomatous and one as well differentiated squamous carcinoma. The mean age of the patients was 39.7 years. The prognosis in all the patients with thymic carcinoma was poor. Based upon personal experience the authors regard the Müller-Hermelink classification as useful, easy to apply, reproducible and providing important prognostic information.

Adult↗
PubMed2026

Thalamic NRXN1-mediated input to human cortical progenitors drives excitatory neurogenesis.

The human cerebral cortex develops through coordinated signals from within the cortex and from other brain regions, including the thalamus. However, how thalamic neuronal projections influence early human cortical development remains less well-understood. In this study, we fused cortical and thalamic organoids to investigate how thalamic input shapes the maturation of human cortical cells. Using single-nuclei RNA-sequencing and cellular imaging, we found that thalamic input increases the production of cortical excitatory neurons. We identify neurexin-1 (NRXN1) as a mediator of physical contact between thalamic axons and cortical outer radial glia. Genetic knockout of thalamic NRXN1 reduced these contacts and attenuated the production of upper-layer excitatory neurons. These findings reveal a mechanism by which thalamic input regulates human cortical progenitors and shapes excitatory neuron production during development.

Animals↗
PubMed2025

A mouse organoid platform for modeling cerebral cortex development and cis-regulatory evolution in vitro.

Natural selection has shaped the gene regulatory networks that orchestrate cortical development, leading to structural and functional variation across mammals, but the molecular and cellular mechanisms underpinning these changes have only begun to be characterized. Here, we develop a reproducible protocol for cerebral cortex organoid generation from mouse epiblast stem cells (EpiSCs), which recapitulates the timing and cellular differentiation programs of the embryonic cortex. We generated cortical organoids from F1 hybrid EpiSCs derived from crosses between laboratory mice (C57BL/6J) and four wild-derived inbred strains spanning &#x223c;1 M years of evolutionary divergence to comprehensively map cis-acting transcriptional regulatory variation across developing cortical cell types, using single-cell RNA sequencing (scRNA-seq). We identify hundreds of genes that exhibit dynamic allelic imbalances, providing the first insight into the developmental mechanisms underpinning changes in cortical structure and function between subspecies. These experimental methods and cellular resources represent a powerful platform for investigating gene regulation in the developing cerebral cortex.

Organoids↗