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Minimal contribution of IP3R2 in cardiac differentiation and derived ventricular-like myocytes from human embryonic stem cells

Abstract

Type 2 inositol 1,4,5-trisphosphate receptor (IP3R2) regulates the intracellular Ca2+ release from endoplasmic reticulum in human embryonic stem cells (hESCs), cardiovascular progenitor cells (CVPCs), and mammalian cardiomyocytes. However, the role of IP3R2 in human cardiac development is unknown and its function in mammalian cardiomyocytes is controversial. hESC-derived cardiomyocytes have unique merits in disease modeling, cell therapy, and drug screening. Therefore, understanding the role of IP3R2 in the generation and function of human cardiomyocytes would be valuable for the application of hESC-derived cardiomyocytes. In the current study, we investigated the role of IP3R2 in the differentiation of hESCs to cardiomyocytes and in the hESC-derived cardiomyocytes. By using IP3R2 knockout (IP3R2KO) hESCs, we showed that IP3R2KO did not affect the self-renewal of hESCs as well as the differentiation ability of hESCs into CVPCs and cardiomyocytes. Furthermore, we demonstrated the ventricular-like myocyte characteristics of hESC-derived cardiomyocytes. Under the α1-adrenergic stimulation by phenylephrine (10 μmol/L), the amplitude and maximum rate of depolarization of action potential (AP) were slightly affected in the IP3R2KO hESC-derived cardiomyocytes at differentiation day 90, whereas the other parameters of APs and the Ca2+ transients did not show significant changes compared with these in the wide-type ones. These results demonstrate that IP3R2 has minimal contribution to the differentiation and function of human cardiomyocytes derived from hESCs, thus provide the new knowledge to the function of IP3R2 in the generation of human cardiac lineage cells and in the early cardiomyocytes.

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Fig. 1: The expression pattern of IP3R2 during cardiomyocyte differentiation of hESCs.
Fig. 2: The comparison of self-renewal properties of undifferentiated wt, IP3R2KO-6, and IP3R2KO-12 hESCs.
Fig. 3: Effects of IP3R2 deficiency on the differentiation of hESCs into CVPCs and cardiomyocytes.
Fig. 4: Effects of IP3R2 deficiency on the APs of wt and IP3R2KO hESC-derived cardiomyocytes at differentiation day 90 with or without phenylephrine (PE) treatment.
Fig. 5: Effects of IP3R2 deficiency on Ca2+ transients of wt and IP3R2KO hESC-derived cardiomyocytes at differentiation day 90 with or without phenylephrine (PE) treatment.

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Acknowledgements

This work was supported by grants from National Key R&D Program of China (2017YFA0103700 and 2016YFC1301204 to HTY), National Natural Science Foundation of China (81520108004, 81470422 to HTY), the Strategic Priority Research Program of the CAS (No. XDA16010201 to HTY), Shanghai Natural Science Foundation (17ZR1435500 to JJH), and the Shenzhen Basic Research Foundation (KQJSCX20170330155020267). The authors thank WiCell Research Institute for providing the H7 hESCs, Dr. Hua-jun Bai (Shanghai Institute of Nutrition and Health) for the assistance in hESC culture, and Prof. Ping Liang from Zhejiang University for the constructive discussion and suggestions.

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HTY and PZ contributed to the concept and experiment design; PZ, JJH, HL and YJW contributed to the data collection; PZ, HTY, KFOY and MLL contributed to the data analysis; HTY and PZ contributed to the data interpretation and manuscript writing; HTY approved the manuscript and provided the funding support.

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Correspondence to Huang-tian Yang.

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Zhang, P., Huang, Jj., Ou-yang, Kf. et al. Minimal contribution of IP3R2 in cardiac differentiation and derived ventricular-like myocytes from human embryonic stem cells. Acta Pharmacol Sin 41, 1576–1586 (2020). https://doi.org/10.1038/s41401-020-00528-w

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Keywords

  • IP3R2
  • human embryonic stem cells
  • differentiation
  • cardiovascular progenitor cells
  • cardiomyocytes
  • function

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