Muscarinic agonism restores degenerated salivary glands through a calcium-ATP metabolic axis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1138700 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29914343_1.fastq.gz | Fastqsanger.gz | |||
| SRR29914343_2.fastq.gz | Fastqsanger.gz | |||
| SRR29914344_1.fastq.gz | Fastqsanger.gz | |||
| SRR29914344_2.fastq.gz | Fastqsanger.gz | |||
| SRR29914345_1.fastq.gz | Fastqsanger.gz |
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Project description:Chronic damage to tissues and organs is deemed irreversible. This has led to a focus on the development of regenerative therapies that replace tissues. Here, we break with this dogma by demonstrating that the chronically injured degenerating salivary gland can be functionally and structurally restored through a nerve-associated mechanism. Extensive disruption of the chronically injured secretory acinar-nerve niche can be reversed by muscarinic agonism, with the tissue maintaining a homeostatic-like state months after treatment ends. In addition, the proportion of de-differentiated acinar cell types that appear with chronic damage are greatly reduced by muscarinic stimulation, suggesting recovery of cells critical for function. This reversal is due, in part, to re-balancing a calcium-dependent metabolic pathway that enables cell replacement. Finally, we show that radiation damaged hair follicles also benefit from muscarinic stimulation through a similar mechanism. Thus, these data challenge the concept that chronic damage is irreversible and provide a new avenue for the development of restorative treatments, a paradigm shift that can be explored more broadly.
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Project description:Background: Low back pain is a leading cause of disability worldwide and is frequently attributed to intervertebral disc (IVD) degeneration. Though the contributions of the adjacent cartilage endplates (CEP) to IVD degeneration are well documented, the phenotype and functions of the resident CEP cells are critically understudied. To better characterize CEP cell phenotype and possible mechanisms of CEP degeneration, bulk and single-cell RNA-Sequencing of non-degenerated and degenerated CEP cells were performed. Methods: Human lumbar CEP cells from degenerated (Thompson Grade ≥ 4) and non-degenerated (Thompson Grade ≤ 2) discs were expanded for bulk (N=4 non-degenerated, N=4 degenerated) and single-cell (N=1 non-degenerated, N=1 degenerated) RNA-Sequencing. Genes identified from bulk RNA-Sequencing were categorized by function and their expression in non-degenerated and degenerated CEP cells were compared. A PubMed literature review was also performed to determine which genes were previously identified and studied in the CEP, IVD, and other cartilaginous tissues. For single-cell RNA-Sequencing, different cell clusters were resolved using unsupervised clustering and functional annotation. Differential gene expression analysis and Gene Ontology, respectively, were used to compare gene expression and functional enrichment between cell clusters, as well as between non-degenerated and degenerated CEP samples. Results: Bulk RNA-Sequencing revealed 38 genes were significantly upregulated and 15 genes were significantly downregulated in degenerated CEP cells relative to non-degenerated cells (|Fold change| ≥ 1.5). Of these, only 2 genes were previously studied in CEP cells and 31 were previously studied in the IVD and other cartilaginous tissues. Single-cell RNA-Sequencing revealed 11 unique cell clusters, including multiple chondrocyte and progenitor subpopulations with distinct gene expression and functional profiles. Analysis of genes in the bulk RNA-Sequencing dataset showed that progenitor cell clusters from both samples were enriched in “non-degenerated” genes, but not “degenerated” genes. For both bulk- and single-cell analyses, gene expression and pathway enrichment analyses highlighted several pathways that may regulate CEP degeneration, including transcriptional regulation, translational regulation, intracellular transport, and mitochondrial dysfunction. Conclusions: This thorough analysis using RNA-Sequencing methods highlighted numerous differences between non-degenerated and degenerated CEP cells, the phenotypic heterogeneity of CEP cells, and several pathways of interest that may be relevant in CEP degeneration.
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Project description:Background: Low back pain is a leading cause of disability worldwide and is frequently attributed to intervertebral disc (IVD) degeneration. Though the contributions of the adjacent cartilage endplates (CEP) to IVD degeneration are well documented, the phenotype and functions of the resident CEP cells are critically understudied. To better characterize CEP cell phenotype and possible mechanisms of CEP degeneration, bulk and single-cell RNA-Sequencing of non-degenerated and degenerated CEP cells were performed. Methods: Human lumbar CEP cells from degenerated (Thompson Grade ≥ 4) and non-degenerated (Thompson Grade ≤ 2) discs were expanded for bulk (N=4 non-degenerated, N=4 degenerated) and single-cell (N=1 non-degenerated, N=1 degenerated) RNA-Sequencing. Genes identified from bulk RNA-Sequencing were categorized by function and their expression in non-degenerated and degenerated CEP cells were compared. A PubMed literature review was also performed to determine which genes were previously identified and studied in the CEP, IVD, and other cartilaginous tissues. For single-cell RNA-Sequencing, different cell clusters were resolved using unsupervised clustering and functional annotation. Differential gene expression analysis and Gene Ontology, respectively, were used to compare gene expression and functional enrichment between cell clusters, as well as between non-degenerated and degenerated CEP samples. Results: Bulk RNA-Sequencing revealed 38 genes were significantly upregulated and 15 genes were significantly downregulated in degenerated CEP cells relative to non-degenerated cells (|Fold change| ≥ 1.5). Of these, only 2 genes were previously studied in CEP cells and 31 were previously studied in the IVD and other cartilaginous tissues. Single-cell RNA-Sequencing revealed 11 unique cell clusters, including multiple chondrocyte and progenitor subpopulations with distinct gene expression and functional profiles. Analysis of genes in the bulk RNA-Sequencing dataset showed that progenitor cell clusters from both samples were enriched in “non-degenerated” genes, but not “degenerated” genes. For both bulk- and single-cell analyses, gene expression and pathway enrichment analyses highlighted several pathways that may regulate CEP degeneration, including transcriptional regulation, translational regulation, intracellular transport, and mitochondrial dysfunction. Conclusions: This thorough analysis using RNA-Sequencing methods highlighted numerous differences between non-degenerated and degenerated CEP cells, the phenotypic heterogeneity of CEP cells, and several pathways of interest that may be relevant in CEP degeneration.
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