APOE-NOTCH axis governs elastogenesis during human cardiac valve remodeling

doi:10.1038/s44161-024-00510-3

. 2024 Aug;3(8):933-950.

doi: 10.1038/s44161-024-00510-3. Epub 2024 Jul 24.

APOE-NOTCH axis governs elastogenesis during human cardiac valve remodeling

Ziyi Liu^#^{1

2

3}, Yu Liu^#^{4

5}, Zhiyun Yu^#^{1

2

3}, Cheng Tan^{1

2

3}, Nicole Pek^{1

2

3}, Anna O'Donnell^{3

6}, Angeline Wu⁷, Ian Glass⁸, David S Winlaw^{9

10}, Minzhe Guo^{1

3}, Jason R Spence^{7

11

12}, Ya-Wen Chen^{13

14

15

16}, Katherine E Yutzey^{3

6}, Yifei Miao^{17

18

19

20

21}, Mingxia Gu^{22

23

24

25

26}

Affiliations

¹ Perinatal Institute, Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
² Center for Stem Cell and Organoid Medicine (CuSTOM), Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
³ Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, OH, USA.
⁴ Cardiovascular Institute, Stanford School of Medicine, Stanford, CA, USA.
⁵ Division of Cardiovascular Medicine, Department of Medicine, Stanford School of Medicine, Stanford, CA, USA.
⁶ The Heart Institute, Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
⁷ Department of Internal Medicine, Gastroenterology, University of Michigan Medical School, Ann Arbor, MI, USA.
⁸ Department of Pediatrics, Genetic Medicine, University of Washington, Seattle, WA, USA.
⁹ Cardiothoracic Surgery, Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
¹⁰ Department of Surgery, University of Cincinnati School of Medicine, Cincinnati, OH, USA.
¹¹ Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, USA.
¹² Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI, USA.
¹³ Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁴ Department of Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁵ Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁶ Institute for Airway Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁷ Perinatal Institute, Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. Yifei.Miao@cchmc.org.
¹⁸ Center for Stem Cell and Organoid Medicine (CuSTOM), Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. Yifei.Miao@cchmc.org.
¹⁹ Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, OH, USA. Yifei.Miao@cchmc.org.
²⁰ Cardiovascular Institute, Stanford School of Medicine, Stanford, CA, USA. Yifei.Miao@cchmc.org.
²¹ Division of Pediatric Cardiology, Department of Pediatrics, Stanford School of Medicine, Stanford, CA, USA. Yifei.Miao@cchmc.org.
²² Perinatal Institute, Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. Mingxia.Gu@cchmc.org.
²³ Center for Stem Cell and Organoid Medicine (CuSTOM), Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. Mingxia.Gu@cchmc.org.
²⁴ Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, OH, USA. Mingxia.Gu@cchmc.org.
²⁵ Cardiovascular Institute, Stanford School of Medicine, Stanford, CA, USA. Mingxia.Gu@cchmc.org.
²⁶ Division of Pediatric Cardiology, Department of Pediatrics, Stanford School of Medicine, Stanford, CA, USA. Mingxia.Gu@cchmc.org.

^# Contributed equally.

PMID: 39196035
DOI: 10.1038/s44161-024-00510-3

APOE-NOTCH axis governs elastogenesis during human cardiac valve remodeling

Ziyi Liu et al. Nat Cardiovasc Res. 2024 Aug.

. 2024 Aug;3(8):933-950.

doi: 10.1038/s44161-024-00510-3. Epub 2024 Jul 24.

Authors

Affiliations

¹ Perinatal Institute, Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
² Center for Stem Cell and Organoid Medicine (CuSTOM), Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
³ Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, OH, USA.
⁴ Cardiovascular Institute, Stanford School of Medicine, Stanford, CA, USA.
⁵ Division of Cardiovascular Medicine, Department of Medicine, Stanford School of Medicine, Stanford, CA, USA.
⁶ The Heart Institute, Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
⁷ Department of Internal Medicine, Gastroenterology, University of Michigan Medical School, Ann Arbor, MI, USA.
⁸ Department of Pediatrics, Genetic Medicine, University of Washington, Seattle, WA, USA.
⁹ Cardiothoracic Surgery, Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
¹⁰ Department of Surgery, University of Cincinnati School of Medicine, Cincinnati, OH, USA.
¹¹ Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, USA.
¹² Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI, USA.
¹³ Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁴ Department of Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁵ Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁶ Institute for Airway Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁷ Perinatal Institute, Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. Yifei.Miao@cchmc.org.
¹⁸ Center for Stem Cell and Organoid Medicine (CuSTOM), Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. Yifei.Miao@cchmc.org.
¹⁹ Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, OH, USA. Yifei.Miao@cchmc.org.
²⁰ Cardiovascular Institute, Stanford School of Medicine, Stanford, CA, USA. Yifei.Miao@cchmc.org.
²¹ Division of Pediatric Cardiology, Department of Pediatrics, Stanford School of Medicine, Stanford, CA, USA. Yifei.Miao@cchmc.org.
²² Perinatal Institute, Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. Mingxia.Gu@cchmc.org.
²³ Center for Stem Cell and Organoid Medicine (CuSTOM), Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. Mingxia.Gu@cchmc.org.
²⁴ Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, OH, USA. Mingxia.Gu@cchmc.org.
²⁵ Cardiovascular Institute, Stanford School of Medicine, Stanford, CA, USA. Mingxia.Gu@cchmc.org.
²⁶ Division of Pediatric Cardiology, Department of Pediatrics, Stanford School of Medicine, Stanford, CA, USA. Mingxia.Gu@cchmc.org.

^# Contributed equally.

PMID: 39196035
DOI: 10.1038/s44161-024-00510-3

Abstract

Valve remodeling is a process involving extracellular matrix organization and elongation of valve leaflets. Here, through single-cell RNA sequencing of human fetal valves, we identified an elastin-producing valve interstitial cell (VIC) subtype (apolipoprotein E (APOE)⁺, elastin-VICs) spatially located underneath valve endothelial cells (VECs) sensing unidirectional flow. APOE knockdown in fetal VICs resulted in profound elastogenesis defects. In valves with pulmonary stenosis (PS), we observed elastin fragmentation and decreased expression of APOE along with other genes regulating elastogenesis. Cell-cell interaction analysis revealed that jagged 1 (JAG1) from unidirectional VECs activates elastogenesis in elastin-VICs through NOTCH2. Similar observations were made in VICs cocultured with VECs under unidirectional flow. Notably, a drastic reduction of JAG1-NOTCH2 was also observed in PS valves. Lastly, we found that APOE controls JAG1-induced NOTCH activation and elastogenesis in VICs through the extracellular signal-regulated kinase pathway. Our study suggests important roles of both APOE and NOTCH in regulating elastogenesis during human valve remodeling.

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References

1. Aikawa, E. et al. Human semilunar cardiac valve remodeling by activated cells from fetus to adult: implications for postnatal adaptation, pathology, and tissue engineering. Circulation 113, 1344–1352 (2006). - PubMed - DOI
1. Hinton, R. B. Jr. et al. Extracellular matrix remodeling and organization in developing and diseased aortic valves. Circ. Res. 98, 1431–1438 (2006). - PubMed - DOI
1. Votteler, M. et al. Elastogenesis at the onset of human cardiac valve development. Development 140, 2345–2353 (2013). - PubMed - PMC - DOI
1. Lindsey, S. E., Butcher, J. T. & Yalcin, H. C. Mechanical regulation of cardiac development. Front. Physiol. 5, 318 (2014). - PubMed - PMC - DOI
1. Stuart, A. G. & Williams, A. Marfan’s syndrome and the heart. Arch. Dis. Child. 92, 351–356 (2007). - PubMed - PMC - DOI

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[1] Aikawa, E. et al. Human semilunar cardiac valve remodeling by activated cells from fetus to adult: implications for postnatal adaptation, pathology, and tissue engineering. Circulation 113, 1344–1352 (2006). - PubMed - DOI

[2] Aikawa, E. et al. Human semilunar cardiac valve remodeling by activated cells from fetus to adult: implications for postnatal adaptation, pathology, and tissue engineering. Circulation 113, 1344–1352 (2006). - PubMed - DOI

[3] Hinton, R. B. Jr. et al. Extracellular matrix remodeling and organization in developing and diseased aortic valves. Circ. Res. 98, 1431–1438 (2006). - PubMed - DOI

[4] Hinton, R. B. Jr. et al. Extracellular matrix remodeling and organization in developing and diseased aortic valves. Circ. Res. 98, 1431–1438 (2006). - PubMed - DOI

[5] Votteler, M. et al. Elastogenesis at the onset of human cardiac valve development. Development 140, 2345–2353 (2013). - PubMed - PMC - DOI

[6] Votteler, M. et al. Elastogenesis at the onset of human cardiac valve development. Development 140, 2345–2353 (2013). - PubMed - PMC - DOI

[7] Lindsey, S. E., Butcher, J. T. & Yalcin, H. C. Mechanical regulation of cardiac development. Front. Physiol. 5, 318 (2014). - PubMed - PMC - DOI

[8] Lindsey, S. E., Butcher, J. T. & Yalcin, H. C. Mechanical regulation of cardiac development. Front. Physiol. 5, 318 (2014). - PubMed - PMC - DOI

[9] Stuart, A. G. & Williams, A. Marfan’s syndrome and the heart. Arch. Dis. Child. 92, 351–356 (2007). - PubMed - PMC - DOI

[10] Stuart, A. G. & Williams, A. Marfan’s syndrome and the heart. Arch. Dis. Child. 92, 351–356 (2007). - PubMed - PMC - DOI

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APOE-NOTCH axis governs elastogenesis during human cardiac valve remodeling

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APOE-NOTCH axis governs elastogenesis during human cardiac valve remodeling

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