Stem cell antigen-1+cell-derived fibroblasts are crucial for cardiac fibrosis during heart failure

Tao, Tingting; Du, Luping; Teng, Peng; Guo, Yan; Wang, Xuyang; Hu, Yanhua; Zhao, Haige; Xu, Qingbo; Ma, Liang

doi:10.1007/s00018-023-04957-8

Cited by 2 publications

(1 citation statement)

References 57 publications

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“…While there is little doubt that myofibroblasts are specialized cells for ECM production and play a central role in fibrotic diseases of the heart and other organs, the origin of myofibroblasts is still highly debated. Tamoxifen-inducible Cre-loxP based lineage tracing systems have been utilized in the study of ECM producing cells in the setting of fibrosis [42][43][44] . Kramann et.…”

Section: Discussionmentioning

confidence: 99%

KLF4 in smooth muscle cell-derived progenitor cells is essential for angiotensin II-induced cardiac inflammation and fibrosis

Lu,

Jolly,

Dubner

et al. 2024

Preprint

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Cardiac fibrosis is defined by the excessive accumulation of extracellular matrix (ECM) material resulting in cardiac tissue scarring and dysfunction. While it is commonly accepted that myofibroblasts are the major contributors to ECM deposition in cardiac fibrosis, their origin remains debated. By combining lineage tracing and RNA sequencing, our group made the paradigm-shifting discovery that a subpopulation of resident vascular stem cells residing within the aortic, carotid artery, and femoral aartery adventitia (termed AdvSca1-SM cells) originate from mature vascular smooth muscle cells (SMCs) through anin situreprogramming process. SMC-to-AdvSca1-SM reprogramming and AdvSca1-SM cell maintenance is dependent on induction and activity of the transcription factor, KLF4. However, the molecular mechanism whereby KLF4 regulates AdvSca1-SM phenotype remains unclear. In the current study, leveraging a highly specific AdvSca1-SM cell reporter system, single-cell RNA-sequencing (scRNA-seq), and spatial transcriptomic approaches, we demonstrate the profibrotic differentiation trajectory of coronary artery-associated AdvSca1-SM cells in the setting of Angiotensin II (AngII)-induced cardiac fibrosis. Differentiation was characterized by loss of stemness-related genes, includingKlf4, but gain of expression of a profibrotic phenotype. Importantly, these changes were recapitulated in human cardiac hypertrophic tissue, supporting the translational significance of profibrotic transition of AdvSca1-SM-like cells in human cardiomyopathy. Surprisingly and paradoxically, AdvSca1-SM-specific genetic knockout ofKlf4prior to AngII treatment protected against cardiac inflammation and fibrosis, indicating thatKlf4is essential for the profibrotic response of AdvSca1-SM cells. Overall, our data reveal the contribution of AdvSca1-SM cells to myofibroblasts in the setting of AngII-induced cardiac fibrosis. KLF4 not only maintains the stemness of AdvSca1-SM cells, but also orchestrates their response to profibrotic stimuli, and may serve as a therapeutic target in cardiac fibrosis.

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Section: Discussionmentioning

confidence: 99%

KLF4 in smooth muscle cell-derived progenitor cells is essential for angiotensin II-induced cardiac inflammation and fibrosis

Lu,

Jolly,

Dubner

et al. 2024

Preprint

View full text Add to dashboard Cite

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From Cell to Gene: Deciphering the Mechanism of Heart Failure With Single‐Cell Sequencing

Zhang,

Wen,

Zhang

et al. 2024

Advanced Science

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Heart failure (HF) is a prevalent cardiovascular disease with significant morbidity and mortality rates worldwide. Due to the intricate structure of the heart, diverse cell types, and the complex pathogenesis of HF, further in‐depth investigation into the underlying mechanisms is required. The elucidation of the heterogeneity of cardiomyocytes and the intercellular communication network is particularly important. Traditional high‐throughput sequencing methods provide an average measure of gene expression, failing to capture the “heterogeneity” between cells and impacting the accuracy of gene function knowledge. In contrast, single‐cell sequencing techniques allow for the amplification of the entire genome or transcriptome at the individual cell level, facilitating the examination of gene structure and expression with unparalleled precision. This approach offers valuable insights into disease mechanisms, enabling the identification of changes in cellular components and gene expressions during hypertrophy associated with HF. Moreover, it reveals distinct cell populations and their unique roles in the HF microenvironment, providing a comprehensive understanding of the cellular landscape that underpins HF pathogenesis. This review focuses on the insights provided by single‐cell sequencing techniques into the mechanisms underlying HF and discusses the challenges encountered in current cardiovascular research.

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Stem cell antigen-1+cell-derived fibroblasts are crucial for cardiac fibrosis during heart failure

Cited by 2 publications

References 57 publications

KLF4 in smooth muscle cell-derived progenitor cells is essential for angiotensin II-induced cardiac inflammation and fibrosis

KLF4 in smooth muscle cell-derived progenitor cells is essential for angiotensin II-induced cardiac inflammation and fibrosis

From Cell to Gene: Deciphering the Mechanism of Heart Failure With Single‐Cell Sequencing

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