Age-related epithelial defects limit thymic function and regeneration.

The thymus is essential for establishing adaptive immunity yet undergoes age-related involution that leads to compromised immune responsiveness. The thymus is also extremely sensitive to acute insult and although capable of regeneration, this capacity declines with age for unknown reasons. We applied single-cell and spatial transcriptomics, lineage-tracing and advanced imaging to define age-related changes in nonhematopoietic stromal cells and discovered the emergence of two atypical thymic epithelial cell (TEC) states. These age-associated TECs (aaTECs) formed high-density peri-medullary epithelial clusters that were devoid of thymocytes; an accretion of nonproductive thymic tissue that worsened with age, exhibited features of epithelial-to-mesenchymal transition and was associated with downregulation of FOXN1. Interaction analysis revealed that the emergence of aaTECs drew tonic signals from other functional TEC populations at baseline acting as a sink for TEC growth factors. Following acute injury, aaTECs expanded substantially, further perturbing trophic regeneration pathways and correlating with defective repair of the involuted thymus. These findings therefore define a unique feature of thymic involution linked to immune aging and could have implications for developing immune-boosting therapies in older individuals.

The bidirectional relationship between periodontitis and diabetes: New prospects for stem cell-derived exosomes.

Periodontitis and diabetes have a bidirectional link, making therapeutic treatment of periodontitis and diabetes challenging. Numerous factors, including microbes, inflammatory cytokines, immune cell activity, glucose levels, and metabolic disorders, contribute to the bidirectional relationship of periodontitis and diabetes. Basic periodontal treatment, medication, surgical treatment, and combined treatment are the most widely used treatments, but their efficacy are limited. Because of their capacity to support bone remodeling and tissue regeneration and restoration, reduce blood glucose levels, restore islet function, and ameliorate local and systemic inflammation, stem cell-derived exosomes have emerged as a possible therapeutic. In this review, we summarize the utilization of stem cell-derived exosomes in periodontitis and diabetes，discuss their potential mechanisms in periodontitis and diabetes bidirectional promoters. It provides some theoretical basis for using stem cell-derived exosomes to regulate the bidirectional link between periodontitis and diabetes.

Potential angiogenic, immunomodulatory, and antifibrotic effects of mesenchymal stem cell-derived extracellular vesicles in systemic sclerosis.

Systemic sclerosis (SSc) is an intricate systemic autoimmune disease with pathological features such as vascular injury, immune dysregulation, and extensive fibrosis of the skin and multiple organs. Treatment options are limited; however, recently, mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have been acknowledged in preclinical and clinical trials as being useful in treating autoimmune diseases and are likely superior to MSCs alone. Recent research has also shown that MSC-EVs can ameliorate SSc and the pathological changes in vasculopathy, immune dysfunction, and fibrosis. This review summarizes the therapeutic effects of MSC-EVs on SSc and the mechanisms that have been discovered to provide a theoretical basis for future studies on the role of MSC-EVs in treating SSc.

The acetyltransferase KAT7 is required for thymic epithelial cell expansion, expression of AIRE target genes, and thymic tolerance.

The autoimmune regulator (AIRE) induces the transcription of thousands of peripheral tissue genes (PTGs) in thymic epithelial cells (TECs) to mediate immunological tolerance. The chromatin state required for optimal AIRE function in TECs and how this state is induced remains unclear. We tested the role of the histone acetyltransferase, KAT7 (also known as HBO1 or MYST2), which is essential for acetylation of histone 3 lysine 14, in TEC differentiation, AIRE-mediated PTG expression, and thymic tolerance. We find that KAT7 is required for optimal expansion of medullary TEC and has a major role in the expression of AIRE-dependent PTGs, associated with enhanced chromatin accessibility at these gene loci in TECs. Mice with TEC-specific Kat7 deletion develop organ-specific autoimmunity with features resembling those observed in Aire-deficient mice. These findings highlight critical roles for KAT7-mediated acetylation in promoting a chromatin state at PTG loci that enables AIRE function and the establishment of immunological tolerance.

Dual roles for LUBAC signaling in thymic epithelial cell development and survival.

Thymic epithelial cells (TECs) form a unique microenvironment that orchestrates T cell differentiation and immunological tolerance. Despite the importance of TECs for adaptive immunity, there is an incomplete understanding of the signalling networks that support their differentiation and survival. We report that the linear ubiquitin chain assembly complex (LUBAC) is essential for medullary TEC (mTEC) differentiation, cortical TEC survival and prevention of premature thymic atrophy. TEC-specific loss of LUBAC proteins, HOIL-1 or HOIP, severely impaired expansion of the thymic medulla and AIRE-expressing cells. Furthermore, HOIL-1-deficiency caused early thymic atrophy due to Caspase-8/MLKL-dependent apoptosis/necroptosis of cortical TECs. By contrast, deficiency in the LUBAC component, SHARPIN, caused relatively mild defects only in mTECs. These distinct roles for LUBAC components in TECs correlate with their function in linear ubiquitination, NFκB activation and cell survival. Thus, our findings reveal dual roles for LUBAC signaling in TEC differentiation and survival.