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Transcriptomic Analysis of Mineralized Adipose-Derived Stem Cell Tissues for Calcific Valve Disease Modelling.

ABSTRACT: Calcific aortic valve disease (CAVD) is characterized by the fibrosis and mineralization of the aortic valve, which leads to aortic stenosis and heart failure. At the cellular level, this is due to the osteoblastic-like differentiation of valve interstitial cells (VICs), resulting in the calcification of the tissue. Unfortunately, human VICs are not readily available to study CAVD pathogenesis and the implicated mechanisms in vitro; however, adipose-derived stromal/stem cells (ASCs), carrying the patient's specific genomic features, have emerged as a promising cell source to model cardiovascular diseases due to their multipotent nature, availability, and patient-specific characteristics. In this study, we describe a comprehensive transcriptomic analysis of tissue-engineered, scaffold-free, ASC-embedded mineralized tissue sheets using bulk RNA sequencing. Bioinformatic and gene set enrichment analyses revealed the up-regulation of genes associated with the organization of the extracellular matrix (ECM), suggesting that the ECM could play a vital role in the enhanced mineralization observed in these tissue-engineered ASC-embedded sheets. Upon comparison with publicly available gene expression datasets from CAVD patients, striking similarities emerged regarding cardiovascular diseases and ECM functions, suggesting a potential link between ECM gene expression and CAVDs pathogenesis. A matrisome-related sub-analysis revealed the ECM microenvironment promotes the transcriptional activation of the master gene runt-related transcription factor 2 (RUNX2), which is essential in CAVD development. Tissue-engineered ASC-embedded sheets with enhanced mineralization could be a valuable tool for research and a promising avenue for the identification of more effective aortic valve replacement therapies.

SUBMITTER: Brodeur A

PROVIDER: S-EPMC10889332 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Transcriptomic Analysis of Mineralized Adipose-Derived Stem Cell Tissues for Calcific Valve Disease Modelling.

Brodeur Alyssa A Roy Vincent V Touzel-Deschênes Lydia L Bianco Stéphanie S Droit Arnaud A Fradette Julie J Ruel Jean J Gros-Louis François F

International journal of molecular sciences 20240214 4

Calcific aortic valve disease (CAVD) is characterized by the fibrosis and mineralization of the aortic valve, which leads to aortic stenosis and heart failure. At the cellular level, this is due to the osteoblastic-like differentiation of valve interstitial cells (VICs), resulting in the calcification of the tissue. Unfortunately, human VICs are not readily available to study CAVD pathogenesis and the implicated mechanisms in vitro; however, adipose-derived stromal/stem cells (ASCs), carrying th ...[more]

PMID: 38396969

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Project description:Calcific Aortic Valve Disease (CAVD) is the most frequent valvular heart disease in developed countries. It is characterized by a progressive calcification of aortic valve leaflets mediated by myeloid cells, such as monocytes and macrophages. However, the molecular mechanisms involved in their recruitment and activity are still poorly understood and limit the development of a pharmacological treatments. Previous studies have already demonstrated the role of macrophages in CAVD development. However, little is known about the implication of their precursors, monocytes. Thus, we hypothesized that circulating monocytes from CAVD patients have higher pro-calcific and pro-inflammatory capacities. We aimed first to assess the pro-calcifying potential of circulating monocytes from patients with CAVD and second to better understand the molecular mechanisms of this pro-calcific effect through a whole transcriptomic study. Methods : We first characterized monocytes sub-population, from PBMCs isolated from peripheral blood of healthy volunteers (Vol) and patients with CAVD or without CAVD (NCAVD), with flow cytometry. Then we analyzed the whole transcriptome of these monocytes by RNA sequencing (RNAseq) to identify dysregulated genes expression, further confirmed by RT-qPCR. Finally, after evaluation of monocytes secretome with multiplex analysis, we evaluated CAVD monocytes capacities to induce myofibroblastic transdifferenciation and osteoblastic differencitation of human valvular interstitial cells (hVIC) with immunocytochemistry (ICC) and O-cresolphtalein assay. Results : In CAVD (calcific aortic valve disease) monocytes, we observe a shift in their sub-populations, with an increased frequency of classical monocytes (CD14+CD16-) and a decreased frequency of non-classical monocytes (CD14+CD16++). Interestingly, we found specific upregulation of genes linked to both inflammation (PDK4) and calcification (ATP2B1), alongside the downregulation of immunomodulatory genes (DDR1, IKBKE) in monocytes from CAVD patients. Additionally, CAVD monocytes produce lower levels of immunomodulatory and anti-osteoblastogenic cytokines (IL3, CCL3), which promote myofibroblastic transdifferentiation (TIMP1, TNC) and osteoblastic differentiation (ALPL, OPG). This correlates with an increase in αsma+ and opn+ cells and a doubling of hVIC calcifications. Conclusions : We demonstrated for the first time that circulating monocytes from CAVD patients have higher pro-inflammatory and pro-calcific capacities that might promote CAVD development. Likewise, we identify dysregulated genes, which could be used as new therapeutic targets.

Dataset Information

Transcriptomic Analysis of Mineralized Adipose-Derived Stem Cell Tissues for Calcific Valve Disease Modelling.

Publications

Transcriptomic Analysis of Mineralized Adipose-Derived Stem Cell Tissues for Calcific Valve Disease Modelling.

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