ArticleStem cell research & therapy2022
Chemically defined and small molecules-based generation of sinoatrial node-like cells.
Article in Stem cell research & therapy, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 22 citations in OpenAlex.
- Coordination of cardiogenesis in vivo and in vitro.Nature reviews. Molecular cell biology · 2026Review
- Promoting differentiation of human-induced pluripotent stem cells into sinoatrial node-like cells through programmed regulation of AMPK signalling pathway.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2025Article
- Pluripotent stem cell-derived cardiomyocyte transplantation: marching from bench to bedside.Science China. Life sciences · 2025Review
- Effect of CDM3 on co-culture of human-induced pluripotent stem cells with Matrigel-covered polycaprolactone to prepare cardiac patches.In vitro cellular & developmental biology. Animal · 2023Article
- Three-dimensional human bile duct formation from chemically induced human liver progenitor cells.Frontiers in bioengineering and biotechnology · 2023Article
- Novel Insights into the Sinoatrial Node in Single-Cell RNA Sequencing: From Developmental Biology to Physiological Function.Journal of cardiovascular development and disease · 2022Review
- RA signaling pathway combined with Wnt signaling pathway regulates human-induced pluripotent stem cells (hiPSCs) differentiation to sinus node-like cells.Stem cell research & therapy · 2022Article
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Authors and funding
11 authors at 5 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
backgroundExisting methods for in vitro differentiation of human pluripotent stem cells (hPSCs) into sinoatrial node-like cells (SANLCs) require complex and undefined medium constituents. This might hinder the elucidation of the molecular mechanisms involved in cardiac subtype specification and prevent translational application. In our study, we aimed to establish a chemically defined differentiation methods to generate SANLCs effectively and stably.
methodsWe induced human embryonic stem cells (hESCs)/induced PSCs (hiPSCs) to pan-cardiomyocytes by temporal modulation of the WNT/β-catenin (WNT) signaling pathway with GSK3 inhibitor and WNT inhibitor. During cardiac mesoderm stage of the differentiation process, signaling of WNT, retinoid acid (RA), and fibroblast growth factor (FGF) was manipulated by three specific molecules. Moreover, metabolic selection was designed to improve the enrichment of SANLCs. Finally, RT-PCR, immunofluorescence, flow cytometry, and whole cell patch clamp were used to identify the SANLCs.
resultsWNT, RA, and FGF signaling promote the differentiation of hPSCs into SANLCs in a concentration- and time window-sensitive manner, respectively. Synergetic modulation of WNT, FGF, and RA signaling pathways enhance the pacemaker phenotype and improve the differentiation efficiency of SANLCs (up to 45%). Moreover, the purification based on lactate metabolism and glucose starvation further reached approximately 50% of SANLCs. Finally, the electrophysiological data demonstrate that cells differentiated with the proposed protocol produce a considerable number of SANLCs that display typical electrophysiological characteristics of pacemaker cells in vitro.
conclusionWe provide an optimized and chemically defined protocol to generate SANLCs by combined modulation of WNT, RA, and FGF signaling pathways and metabolic selection by lactate enrichment and glucose starvation. This chemically defined method for generating SANLCs might provide a platform for disease modeling, drug discovery, predictive toxicology, and biological pacemaker construction.
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