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Combined multidimensional single-cell protein and RNA profiling dissects the cellular and functional heterogeneity of thymic epithelial cells.

ABSTRACT: The network of thymic stromal cells provides essential niches with unique molecular cues controlling T cell development and selection. Recent single-cell RNA sequencing studies have uncovered previously unappreciated transcriptional heterogeneity among thymic epithelial cells (TEC). However, there are only very few cell markers that allow a comparable phenotypic identification of TEC. Here, using massively parallel flow cytometry and machine learning, we deconvoluted known TEC phenotypes into novel subpopulations. Using CITEseq, these phenotypes were related to corresponding TEC subtypes defined by the cells' RNA profiles. This approach allowed the phenotypic identification of perinatal cTEC and their physical localisation within the cortical stromal scaffold. In addition, we demonstrate the dynamic change in the frequency of perinatal cTEC in response to developing thymocytes and reveal their exceptional efficiency in positive selection. Collectively, our study identifies markers that allow for an unprecedented dissection of the thymus stromal complexity, as well as physical isolation of TEC populations and assignment of specific functions to individual TEC subtypes.

SUBMITTER: Klein F

PROVIDER: S-EPMC10333192 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Combined multidimensional single-cell protein and RNA profiling dissects the cellular and functional heterogeneity of thymic epithelial cells.

Klein Fabian F Veiga-Villauriz Clara C Börsch Anastasiya A Maio Stefano S Palmer Sam S Dhalla Fatima F Handel Adam E AE Zuklys Saulius S Calvo-Asensio Irene I Musette Lucas L Deadman Mary E ME White Andrea J AJ Lucas Beth B Anderson Graham G Holländer Georg A GA

Nature communications 20230710 1

The network of thymic stromal cells provides essential niches with unique molecular cues controlling T cell development and selection. Recent single-cell RNA sequencing studies have uncovered previously unappreciated transcriptional heterogeneity among thymic epithelial cells (TEC). However, there are only very few cell markers that allow a comparable phenotypic identification of TEC. Here, using massively parallel flow cytometry and machine learning, we deconvoluted known TEC phenotypes into no ...[more]

PMID: 37429879

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Project description:ObjectiveCurrent concepts highlight the neurological and psychological heterogeneity of functional/dissociative seizures (FDS). However, it remains uncertain whether it is possible to distinguish between a limited number of subtypes of FDS disorders. We aimed to identify profiles of distinct FDS subtypes by cluster analysis of a multidimensional dataset without any a priori hypothesis.MethodsWe conducted an exploratory, prospective multicenter study of 169 patients with FDS. We collected biographical, trauma (childhood and adulthood traumatic experiences), semiological (seizure characteristics), and psychopathological data (psychiatric comorbidities, dissociation, and alexithymia) through psychiatric interviews and standardized scales. Clusters were identified by the Partitioning Around Medoids method. The similarity of patients was computed using Gower distance. The clusters were compared using analysis of variance, chi-squared, or Fisher exact tests.ResultsThree patient clusters were identified in this exploratory, hypothesis-generating study and named on the basis of their most prominent characteristics: A "No/Single Trauma" group (31.4%), with more male patients, intellectual disabilities, and nonhyperkinetic seizures, and a low level of psychopathology; A "Cumulative Lifetime Traumas" group (42.6%), with clear female predominance, hyperkinetic seizures, relatively common comorbid epilepsy, and a high level of psychopathology; and A "Childhood Traumas" group (26%), commonly with comorbid epilepsy, history of childhood sexual abuse (75%), and posttraumatic stress disorder, but also with a high level of anxiety and dissociation.SignificanceAlthough our cluster analysis was undertaken without any a priori hypothesis, the nature of the trauma history emerged as the most important differentiator between three common FDS disorder subtypes. This subdifferentiation of FDS disorders may facilitate the development of more specific therapeutic programs for each patient profile.

Dataset Information

Combined multidimensional single-cell protein and RNA profiling dissects the cellular and functional heterogeneity of thymic epithelial cells.

Publications

Combined multidimensional single-cell protein and RNA profiling dissects the cellular and functional heterogeneity of thymic epithelial cells.

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