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Generation of Quiescent Cardiac Fibroblasts From Human Induced Pluripotent Stem Cells for In Vitro Modeling of Cardiac Fibrosis
- Source :
- Circulation research, vol 125, iss 5, Circ Res
- Publication Year :
- 2019
- Publisher :
- eScholarship, University of California, 2019.
-
Abstract
- Rationale: Activated fibroblasts are the major cell type that secretes excessive extracellular matrix in response to injury, contributing to pathological fibrosis and leading to organ failure. Effective anti-fibrotic therapeutic solutions, however, are not available due to the poorly defined characteristics and unavailability of tissue-specific fibroblasts. Recent advances in single-cell RNA-sequencing fill such gaps of knowledge by enabling delineation of the developmental trajectories and identification of regulatory pathways of tissue-specific fibroblasts among different organs. Objective: This study aims to define the transcriptome profiles of tissue-specific fibroblasts using recently reported mouse single-cell RNA-sequencing atlas and to develop a robust chemically defined protocol to derive cardiac fibroblasts (CFs) from human induced pluripotent stem cells for in vitro modeling of cardiac fibrosis and drug screening. Methods and Results: By analyzing the single-cell transcriptome profiles of fibroblasts from 10 selected mouse tissues, we identified distinct tissue-specific signature genes, including transcription factors that define the identities of fibroblasts in the heart, lungs, trachea, and bladder. We also determined that CFs in large are of the epicardial lineage. We thus developed a robust chemically defined protocol that generates CFs from human induced pluripotent stem cells. Functional studies confirmed that iPSC-derived CFs preserved a quiescent phenotype and highly resembled primary CFs at the transcriptional, cellular, and functional levels. We demonstrated that this cell-based platform is sensitive to both pro- and anti-fibrosis drugs. Finally, we showed that crosstalk between human induced pluripotent stem cell-derived cardiomyocytes and CFs via the atrial/brain natriuretic peptide-natriuretic peptide receptor-1 pathway is implicated in suppressing fibrogenesis. Conclusions: This study uncovers unique gene signatures that define tissue-specific identities of fibroblasts. The bona fide quiescent CFs derived from human induced pluripotent stem cells can serve as a faithful in vitro platform to better understand the underlying mechanisms of cardiac fibrosis and to screen anti-fibrotic drugs.
- Subjects :
- Cell type
Physiology
Cardiac fibrosis
induced pluripotent stem cells
1.1 Normal biological development and functioning
Cells
Clinical Sciences
Cardiorespiratory Medicine and Haematology
Regenerative Medicine
Cardiovascular
Article
Transcriptome
Extracellular matrix
Mice
Fibrosis
Underpinning research
Genetics
Medicine
2.1 Biological and endogenous factors
Animals
Humans
Human Induced Pluripotent Stem Cells
Stem Cell Research - Embryonic - Human
Aetiology
Induced pluripotent stem cell
Myocytes
Cultured
Stem Cell Research - Induced Pluripotent Stem Cell
Stem Cell Research - Induced Pluripotent Stem Cell - Human
business.industry
fibrosis
RNA-Binding Proteins
Heart
Fibroblasts
medicine.disease
Stem Cell Research
In vitro
Antifibrinolytic Agents
Cell biology
Heart Disease
Cardiovascular System & Hematology
Cardiology and Cardiovascular Medicine
business
Cardiac
transcriptome
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Circulation research, vol 125, iss 5, Circ Res
- Accession number :
- edsair.doi.dedup.....c7a1633e0c3cd7fd92ea94685da40f11