Regulating the Cell Differentiation Trajectory of Progenitor Cells in Adipose Tissue Fibrosis
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PROVIDER: PRJNA1260036 | ENA |
REPOSITORIES: ENA
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Project description:Adipose tissue heterogeneity has emerged as a central factor in regulating adipose tissue function in physiology and pathophysiology, yet tools to model and study this diversity in vitro remain limited. Here, we performed single-cell RNA sequencing on cultured primary white and brown preadipocytes to assess how in vitro conditions impact progenitor identity. We identified two major subpopulations in both depots: committed adipogenic precursors (CAPs) and fibro-adipogenic progenitor-like cells (FAPLs). Remarkably, FAPLs were also present in brown adipose tissue, expanding the known landscape of progenitor populations in this depot. Trajectory and regulon analyses revealed that both white and brown FAPLs exhibit similar pro-fibrotic, stress-responsive signatures and diverge early from proliferating progenitor states. Integration of datasets showed that FAPLs from both depots cluster together, emphasizing their conserved identity, while CAPs remain depot-specific. Comparison to previously published in vivo single-cell datasets revealed that these in vitro populations, including brown adipose FAPLs, correspond to adipose-resident progenitor subtypes, validating the physiological relevance of this model for studying adipose tissue heterogeneity and development.
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Project description:Defining the trajectory of cells during differentiation and disease is key for uncovering the mechanisms driving cell fate and identity. However, trajectories of human cells remain largely unexplored due to the challenges of studying them with human samples. In this study, we investigated the proteome trajectory of iPSCs differentiation to hepatic stellate cells (diHSCs) and identified RORA as a key transcription factor governing the metabolic reprogramming of HSCs necessary for HSCs’ commitment, identity, and activation. Using RORA deficient iPSCs and pharmacologic interventions, we showed that RORA is required for early differentiation and prevents diHSCs activation by reducing the high energetic state of the cells. While RORA knockout mice had enhanced fibrosis, whereas RORA agonists rescued multi-organ fibrosis in in vivo models. Notably, RORA expression was consistently found to be negatively correlated with liver fibrosis and HSCs activation markers in patients with liver disease. This study reveals that RORA regulates cell metabolic plasticity, crucial for mesoderm differentiation, pericyte quiescence, and fibrosis, influencing cell commitment and disease.
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Project description:White adipose tissue (WAT) harbors functionally diverse subpopulations of adipose progenitor cells that differentially impact tissue plasticity in a sex- and depot-dependent manner. To date, the molecular basis of this cellular heterogeneity has not been fully defined. Here, we describe a multilayered omics approach to dissect adipose progenitor cell heterogeneity from in three dimensions: progenitor subpopulation, sex, and anatomical localization. We applied state-of-the-art mass spectrometry methods to quantify 4870 proteins in eight different stromal cell populations from perigonadal and inguinal WAT of male and female mice and acquired transcript expression levels of 15477 genes using RNA-seq. Notably, our data highlight the molecular signatures defining sex differences in PDGFR+ preadipocyte differentiation and identify regulatory pathways that functionally distinguish adipose tissue PDGFRb+ subpopulations. The data are freely accessible as a resource at "Pread Profiler. Together, the multilayered omics analysis provides unprecedented insights into adipose stromal cell heterogeneity.
2023-03-11 | PXD023829 | Pride
Project description:Analysis of PPARg targets in adipose progenitor cells at gene expression level. The hypothesis tested in the present study was that PPARg control adipose nichenenesis and niche occupancy through regulating downstream targets in adipose progenitors. Results provide important information of the response of PPARg deletion in adipose progenitor cells, such as specific up- or down-regulated genes involved in cellular adhesion, chemotaxis and mural cell to endothelial interactions.
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Project description:Fibrosis disrupts adipose tissue (AT) homeostasis in response to chronic caloric excess, exacerbating metabolic dysfunction. The molecular mechanisms linking adipocyte plasticity to AT fibrosis are largely unknown. Here we show that the Hippo pathway is coupled with TGFbeta signaling to orchestrate a functional adipocyte-to-myofibroblast transition in AT fibrosis. We found that Lats1/2-knockout adipocytes could dedifferentiate into DPP4+ progenitor cells and convert to DPP4- myofibroblasts upon TGFbeta stimulation. Macrophages recruited by CCL2 served as a major cell source of TGFbeta. YAP and TAZ, the Hippo downstream effectors, enhanced SMAD2 stability to promote fibrotic responses. Importantly, inhibition of YAP/TAZ activity in obese mice markedly relieved AT fibrosis and improved metabolic homeostasis. Together, our findings identify the Hippo pathway as a molecular switch in the initiation and development of AT fibrosis, implying it as a therapeutic target.
2022-08-11 | GSE184826 | GEO
Project description:Defining the trajectory of cells during differentiation and disease is key for uncovering the mechanisms driving cell fate and identity. However, trajectories of human cells remain largely unexplored due to the challenges of studying them with human samples. In this study, we investigated the proteome trajectory of iPSCs differentiation to hepatic stellate cells (diHSCs) and identified RORA as a key transcription factor governing the metabolic reprogramming of HSCs necessary for HSCs’ commitment, identity, and activation. Using RORA deficient iPSCs and pharmacologic interventions, we showed that RORA is required for early differentiation and prevents diHSCs activation by reducing the high energetic state of the cells. While RORA knockout mice had enhanced fibrosis, whereas RORA agonists rescued multi-organ fibrosis in in vivo models. Notably, RORA expression was consistently found to be negatively correlated with liver fibrosis and HSCs activation markers in patients with liver disease. This study reveals that RORA regulates cell metabolic plasticity, crucial for mesoderm differentiation, pericyte quiescence, and fibrosis, influencing cell commitment and disease.
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Project description:Human adipose stem and progenitor cells (ASPCs) develop into heterogenous cultures of adipogenic and Structural Wnt-regulated Adipose Tissue resident (SWAT) cells upon induction of adipogenic differentiation. In vitro proliferating ASPC and differentiating adipocytes were collected from multiple timepoints to identify the trajectory of cells. Cells from two white depots (subcutaneous abdominal & visceral abdominal) and two brown depots (supraclavicular & perirenal) were used for the study. Progenitors from all 4 depots show similar differentiation trajectories during early differentiation.
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Project description:Fibulin-7 in progenitor cells promotes adipose tissue fibrosis and disrupts metabolic homeostasis in obesity [RNA-seq]
| PRJNA1329204 | ENA