LEFTY-PITX2 signaling pathway is critical for generation of mature and ventricular cardiac organoids in human pluripotent stem cell-derived cardiac mesoderm cells

Myeong Hwa Song, Seung Cheol Choi, Ji Min Noh, Hyung Joon Joo, Chi Yeon Park, Jung Joon Cha, Tae Hoon Ahn, Tae Hee Ko, Jong Il Choi, Ji Eun Na, Im Joo Rhyu, Yongjun Jang, Yongdoo Park, Jeong An Gim, Jong Hoon Kim, Do Sun Lim

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

The generation of mature ventricular cardiomyocytes (CMs) resembling adult CMs from human pluripotent stem cells (hPSCs) is necessary for disease modeling and drug discovery. To investigate the effect of self-organizing capacity on the generation of mature cardiac organoids (COs), we generated cardiac mesoderm cell-derived COs (CMC-COs) and CM-derived COs (CM-COs) and evaluated COs. CMC-COs exhibited more organized sarcomere structures and mitochondria, well-arranged t-tubule structures, and evenly distributed intercalated discs. Increased expressions of ventricular CM, cardiac metabolic, t-tubule formation, K+ ion channel, and junctional markers were confirmed in CMC-COs. Mature ventricular-like function such as faster motion vector speed, decreased beats per min, increased peak-to-peak duration, and prolonged APD50 and APD90 were observed in CMC-COs. Transcriptional profiling revealed that extracellular matrix-integrin, focal adhesion, and LEFTY-PITX2 signaling pathways are upregulated in CMC-COs. LEFTY knockdown affected ECM-integrin-FA signaling pathways in CMC-COs. Here, we found that high self-organizing capacity of CMCs is critical for the generation of mature and ventricular COs. We also demonstrated that LEFTY-PITX2 signaling plays key roles for CM maturation and specification into ventricular-like CM subtype in CMC-COs. CMC-COs are an attractive resource for disease modeling and drug discovery.

Original languageEnglish
Article number121133
JournalBiomaterials
Volume278
DOIs
Publication statusPublished - 2021 Nov

Keywords

  • Cardiac maturation
  • Cardiac mesoderm cells
  • ECM-integrins
  • Focal adhesion signaling
  • LEFTY-PITX2 signaling
  • Ventricular cardiac organoid

ASJC Scopus subject areas

  • Biophysics
  • Bioengineering
  • Ceramics and Composites
  • Biomaterials
  • Mechanics of Materials

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