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Single-cell transcriptomic profiling reveals distinct mechanical responses between normal and diseased tendon progenitor cells.

ABSTRACT: Regenerative medicine approaches utilizing stem cells offer a promising strategy to address tendinopathy, a class of common tendon disorders associated with pain and impaired function. Tendon progenitor cells (TPCs) are important in healing and maintaining tendon tissues. Here we provide a comprehensive single cell transcriptomic profiling of TPCs from three normal and three clinically classified tendinopathy samples in response to mechanical stimuli. Analysis reveals seven distinct TPC subpopulations including subsets that are responsive to the mechanical stress, highly clonogenic, and specialized in cytokine or growth factor expression. The single cell transcriptomic profiling of TPCs and their subsets serves as a foundation for further investigation into the pathology and molecular hallmarks of tendinopathy in mechanical stimulation conditions.

SUBMITTER: Still C

PROVIDER: S-EPMC8324492 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Single-cell transcriptomic profiling reveals distinct mechanical responses between normal and diseased tendon progenitor cells

Project description:Regenerative medicine approaches utilizing stem cells offer a promising strategy to address tendinopathy, a class of common tendon disorders associated with pain and impaired function. Tendon progenitor cells (TPCs) are important in healing and maintaining tendon tissues. Here we provide a comprehensive single cell transcriptomic profiling of TPCs from three normal and three clinically classified tendinopathy samples in response to mechanical stimuli. Analysis reveals seven distinct TPC subpopulations including subsets that are responsive to the mechanical stress, highly clonogenic, and specialized in cytokine or growth factor expression. The single cell transcriptomic profiling of TPCs and their subsets serves as a foundation for further investigation into the pathology and molecular hallmarks of tendinopathy in mechanical stimulation conditions.

2021-07-07 | GSE150482 | GEO

Single-cell transcriptomic profiling reveals distinct mechanical responses between normal and diseased tendon progenitor cells

Project description:Single-cell transcriptomic profiling reveals distinct mechanical responses between normal and diseased tendon progenitor cells

| PRJNA632551 | ENA

Single-cell STAT5 signal transduction profiling in normal and leukemic stem and progenitor cell populations reveals highly distinct cytokine responses.

Project description:BackgroundSignal Transducer and Activator of Transcription 5 (STAT5) plays critical roles in normal and leukemic hematopoiesis. However, the manner in which STAT5 responds to early-acting and lineage-restricted cytokines, particularly in leukemic stem/progenitor cells, is largely unknown.Methodology/principal findingsWe optimized a multiparametric flow cytometry protocol to analyze STAT5 phosphorylation upon cytokine stimulation in stem and progenitor cell compartments at a single-cell level. In normal cord blood (CB) cells, STAT5 phosphorylation was efficiently induced by TPO, IL-3 and GM-CSF within CD34(+)CD38(-) hematopoietic stem cells (HSCs). EPO- and SCF-induced STAT5 phosphorylation was largely restricted to the megakaryocyte-erythroid progenitor (MEP) compartment, while G-CSF as well IL-3 and GM-CSF were most efficient in inducing STAT5 phosphorylation in the myeloid progenitor compartments. Strikingly, mobilized adult peripheral blood (PB) CD34(+) cells responded much less efficiently to cytokine-induced STAT5 activation, with the exception of TPO. In leukemic stem and progenitor cells, highly distinct cytokine responses were observed, differing significantly from their normal counterparts. These responses could not be predicted by the expression level of cytokine receptors. Also, heterogeneity existed in cytokine requirements for long-term expansion of AML CD34(+) cells on stroma.Conclusions/significanceIn conclusion, our optimized multiparametric flow cytometry protocols allow the analysis of signal transduction at the single cell level in normal and leukemic stem and progenitor cells. Our study demonstrates highly distinctive cytokine responses in STAT5 phosphorylation in both normal and leukemic stem/progenitor cells.

| S-EPMC2776352 | biostudies-literature

Metabolomic and transcriptomic profiling reveals distinct nutritional properties of cassavas with different flesh colors.

Project description:Cassava is a significant food security crop in several developing countries. Metabolites in cassava roots provide numerous nutrients essential for human health. Exploiting the diversity of nutritional ingredients present in cassavas is vital for improving its nutritional value. To address this problem, root metabolomes of three cassava cultivars with white-flesh, light-yellow-flesh and yellow-flesh were comprehensively measured, respectively. A total of 508 metabolites were detected in cassava roots, including 300 primary metabolites and 185 secondary metabolites. There were 22.6% to 34.1% metabolites exhibiting significant variations among the three cassava cultivars. The light-yellow-flesh cassava contained higher contents of secondary metabolites, especially flavone, phenylpropanoids and alkaloids, and lower contents of primary metabolites except lipids, alcohols, vitamins and derivatives. Compared with light-yellow-flesh cassava, the yellow-flesh cassava contained higher contents of amino acid and derivatives, but lower contents of phenylpropanoids, nucleotide and derivates. White-flesh cassava contained higher contents of primary metabolites, especially amino acid and derivatives, but lower contents of secondary metabolites except flavonoid and indole derivatives. Transcriptome analyses were parallelly performed to decipher the potential mechanisms regulating the accumulations of related metabolites. Several pathways were both enriched by differentially expressed genes and differentially accumulated metabolites, supporting that metabolisms of these metabolites were regulated at transcriptional level. These results expand the knowledge on metabolite compositions in cassava roots and provide substantial information for genetic improvement of cassavas with high nutritional values.

| S-EPMC8991741 | biostudies-literature

Genomic and Transcriptomic Profiling of Combined Hepatocellular and Intrahepatic Cholangiocarcinoma Reveals Distinct Molecular Subtypes.

Project description:We performed genomic and transcriptomic sequencing of 133 combined hepatocellular and intrahepatic cholangiocarcinoma (cHCC-ICC) cases, including separate, combined, and mixed subtypes. Integrative comparison of cHCC-ICC with hepatocellular carcinoma and intrahepatic cholangiocarcinoma revealed that combined and mixed type cHCC-ICCs are distinct subtypes with different clinical and molecular features. Integrating laser microdissection, cancer cell fraction analysis, and single nucleus sequencing, we revealed both mono- and multiclonal origins in the separate type cHCC-ICCs, whereas combined and mixed type cHCC-ICCs were all monoclonal origin. Notably, cHCC-ICCs showed significantly higher expression of Nestin, suggesting Nestin may serve as a biomarker for diagnosing cHCC-ICC. Our results provide important biological and clinical insights into cHCC-ICC.

| S-EPMC8317046 | biostudies-literature

Asymptomatic Hyperuricemia Is Associated with Achilles Tendon Rupture through Disrupting the Normal Functions of Tendon Stem/Progenitor Cells.

Project description:Hyperuricemia is a metabolic disorder that is essential to the development of inflammatory gout, with increasing prevalence over recent years. Emerging clinical findings has evidenced remarkable tendon damage in individuals with longstanding asymptomatic hyperuricemia, yet the impact of hyperuricemia on tendon homeostasis and associated repercussions is largely unknown. Here, we investigated whether asymptomatic hyperuricemia was associated with spontaneous ruptures in the Achilles tendon and the pathological effect of hyperuricemia on the tendon stem/progenitor cells (TSPCs). Significantly higher serum uric acid (SUA) levels were found in 648 closed Achilles tendon rupture (ATR) patients comparing to those in 12559 healthy volunteers. In vitro study demonstrated that uric acid (UA) dose dependently reduced rat Achilles TSPC viability, decreased the expressions of tendon collagens, and deformed their structural organization while significantly increased the transcript levels of matrix degradative enzymes and proinflammatory factors. Consistently, marked disruptions in Achilles tendon tissue structural and functional integrity were found in a rat model of hyperuricemia, together with enhanced immune cell infiltration. Transcriptome analysis revealed a significant elevation in genes involved in metabolic stress and tissue degeneration in TSPCs challenged by hyperuricemia. Specifically, reduced activity of the AKT-mTOR pathway with enhanced autophagic signaling was confirmed. Our findings indicate that asymptomatic hyperuricemia may be a predisposition of ATR by impeding the normal functions of TSPCs. This information may provide theoretical and experimental basis for exploring the early prevention and care of ATR.

| S-EPMC9731760 | biostudies-literature

Genomic and transcriptomic profiling reveals distinct molecular subsets associated with outcomes in mantle cell lymphoma.

Project description:Mantle cell lymphoma (MCL) is a phenotypically and genetically heterogeneous malignancy in which the genetic alterations determining clinical indications are not fully understood. Here, we performed a comprehensive whole-exome sequencing analysis of 152 primary samples derived from 134 MCL patients, including longitudinal samples from 16 patients and matched RNA-Seq data from 48 samples. We classified MCL into 4 robust clusters (C1-C4). C1 featured mutated immunoglobulin heavy variable (IGHV), CCND1 mutation, amp(11q13), and active B cell receptor (BCR) signaling. C2 was enriched with del(11q)/ATM mutations and upregulation of NF-κB and DNA repair pathways. C3 was characterized by mutations in SP140, NOTCH1, and NSD2, with downregulation of BCR signaling and MYC targets. C4 harbored del(17p)/TP53 mutations, del(13q), and del(9p), and active MYC pathway and hyperproliferation signatures. Patients in these 4 clusters had distinct outcomes (5-year overall survival [OS] rates for C1-C4 were 100%, 56.7%, 48.7%, and 14.2%, respectively). We also inferred the temporal order of genetic events and studied clonal evolution of 16 patients before treatment and at progression/relapse. Eleven of these samples showed drastic clonal evolution that was associated with inferior survival, while the other samples showed modest or no evolution. Our study thus identifies genetic subsets that clinically define this malignancy and delineates clonal evolution patterns and their impact on clinical outcomes.

| S-EPMC8803323 | biostudies-literature

Genomic and transcriptomic profiling of peripheral T cell lymphoma reveals distinct molecular and microenvironment subtypes.

Project description:Peripheral T cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin's lymphomas varying in clinical, phenotypic, and genetic features. The molecular pathogenesis and the role of the tumor microenvironment in PTCL are poorly understood, with limited biomarkers available for genetic subtyping and targeted therapies. Through an integrated genomic and transcriptomic study of 221 PTCL patients, we delineate the genetic landscape of PTCL, enabling molecular and microenvironment classification. According to the mutational status of RHOA, TET2, histone-modifying, and immune-related genes, PTCL is divided into 4 molecular subtypes with discrete patterns of gene expression, biological aberrations, and vulnerabilities to targeted agents. We also perform an unsupervised clustering on the microenvironment transcriptional signatures and categorize PTCL into 4 lymphoma microenvironment subtypes based on characteristic activation of oncogenic pathways and composition of immune communities. Our findings highlight the potential clinical rationale of future precision medicine strategies that target both molecular and microenvironment alterations in PTCL.

| S-EPMC10897627 | biostudies-literature

Gene expression markers of tendon fibroblasts in normal and diseased tissue compared to monolayer and three dimensional culture systems.

Project description:BackgroundThere is a paucity of data regarding molecular markers that identify the phenotype of the tendon cell. This study aims to quantify gene expression markers that distinguish between tendon fibroblasts and other mesenchymal cells which may be used to investigate tenogenesis.MethodsExpression levels for 12 genes representative of musculoskeletal tissues, including the proposed tendon progenitor marker scleraxis, relative to validated reference genes, were evaluated in matched samples of equine tendon (harvested from the superficial digital flexor tendon), cartilage and bone using quantitative PCR (qPCR). Expression levels of genes associated with tendon phenotype were then evaluated in healthy, including developmental, and diseased equine tendon tissue and in tendon fibroblasts maintained in both monolayer culture and in three dimensional (3D) collagen gels.ResultsSignificantly increased expression of scleraxis was found in tendon compared with bone (P = 0.002) but not compared to cartilage. High levels of COL1A2 and scleraxis and low levels of tenascin-C were found to be most representative of adult tensional tendon phenotype. While, relative expression of scleraxis in developing mid-gestational tendon or in acute or chronically diseased tendon did not differ significantly from normal adult tendon, tenascin-C message was significantly upregulated in acutely injured equine tendon (P = 0.001). Relative scleraxis gene expression levels in tendon cell monolayer and 3D cultures were significantly lower than in normal adult tendon (P = 0.002, P = 0.02 respectively).ConclusionThe findings of this study indicate that high expression of both COL1A2 and scleraxis, and low expression of tenascin-C is representative of a tensional tendon phenotype. The in vitro culture methods used in these experiments however, may not recapitulate the phenotype of normal tensional tendon fibroblasts in tissues as evidenced by gene expression.

| S-EPMC2651848 | biostudies-literature

Large-Scale Profiling of Signaling Pathways Reveals a Distinct Demarcation between Normal and Extended Liver Resection.

Project description:Despite numerous studies addressing normal liver regeneration, we still lack comprehensive understanding of the biological processes underlying failed liver regeneration. Therefore, we analyzed the activity of 271 intracellular signaling pathways (ISPs) by genome wide profiling of differentially expressed RNAs in murine liver tissue biopsies after normal hepatectomy (nHx; 68% of liver removed) and extended hepatectomy (eHx; 86% of liver removed). Comprehensive, genome-wide transcriptome profiling using RNAseq was performed in liver tissue obtained from mice (sham, nHx, and eHx) harvested 1, 8, 16, 32, and 48 h after operation (n = 3 per group) and the OncoFinder toolkit was used for an unsupervised, unbiased identification of intracellular signaling pathways (ISP) activity. We observed that the normal regenerative process requires a transient activation and silencing of approximately two dozen of ISPs. After nHx, the Akt Pathway represented with 13 branches, the Chromatin Pathway and the DDR Pathways dominated. After eHx, the ATM main pathway and two of its branches (Cell Survival; G2_M Checkpoint Arrest) dominated, as well as the Hypoxia Pathways. Further, 14 ISPs demonstrated a strong inverse regulation, with the Hedgehog and the Brca1 Main Pathways as chief activators after nHx, and the ATM Pathway (G2_M Checkpoint Arrest) as the dominating constraining response after eHx.

| S-EPMC7290735 | biostudies-literature

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