2. Academic Validation
  3. Employment of diverse in vitro systems for analyzing multiple aspects of disease, hereditary hemorrhagic telangiectasia (HHT)

Employment of diverse in vitro systems for analyzing multiple aspects of disease, hereditary hemorrhagic telangiectasia (HHT)

  • Cell Biosci. 2024 May 22;14(1):65. doi: 10.1186/s13578-024-01247-z.
Hyebin Koh # 1 2,  Woojoo Kang # 3 4,  Ying-Ying Mao 3 5,  Jisoo Park 3 6,  Sangjune Kim 6,  Seok-Ho Hong 7 8,  Jong-Hee Lee 9 10
Affiliations

Affiliations

  • 1 Futuristic Animal Resource & Research Center (FARRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, Republic of Korea.
  • 2 Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Republic of Korea.
  • 3 National Primate Research Center (NPRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, Republic of Korea.
  • 4 Department of Internal Medicine, School of Medicine, Kangwon National University, Chuncheon, Republic of Korea.
  • 5 Department of Animal Science and Biotechnology, College of Agriculture and Life Science, Chungnam National University, Daejeon, Republic of Korea.
  • 6 Department of Biological Sciences and Biotechnology, Chungbuk National University, Cheongju, Republic of Korea.
  • 7 Department of Internal Medicine, School of Medicine, Kangwon National University, Chuncheon, Republic of Korea. shhong@kangwon.ac.kr.
  • 8 KW-Bio Co., Ltd, Chuncheon, South Korea. shhong@kangwon.ac.kr.
  • 9 Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Republic of Korea. jonglee@kribb.re.kr.
  • 10 National Primate Research Center (NPRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, Republic of Korea. jonglee@kribb.re.kr.
  • # Contributed equally.
PMID: 38778363 DOI: 10.1186/s13578-024-01247-z
Abstract

Background: In vitro disease modeling enables translational research by providing insight into disease pathophysiology and molecular mechanisms, leading to the development of novel therapeutics. Nevertheless, in vitro systems have limitations for recapitulating the complexity of tissues, and a single model system is insufficient to gain a comprehensive understanding of a disease.

Results: Here we explored the potential of using several models in combination to provide mechanistic insight into hereditary hemorrhagic telangiectasia (HHT), a genetic vascular disorder. Genome editing was performed to establish hPSCs (H9) with ENG haploinsufficiency and several in vitro models were used to recapitulate the functional aspects of the cells that constitute blood vessels. In a 2D culture system, endothelial cells showed early senescence, reduced viability, and heightened susceptibility to apoptotic insults, and smooth muscle cells (SMCs) exhibited similar behavior to their wild-type counterparts. Features of HHT were evident in 3D blood-vessel Organoid systems, including thickening of capillary structures, decreased interaction between ECs and surrounding SMCs, and reduced cell viability. Features of ENG haploinsufficiency were observed in arterial and venous EC subtypes, with arterial ECs showing significant impairments. Molecular biological approaches confirmed the significant downregulation of Notch signaling in HHT-ECs.

Conclusions: Overall, we demonstrated refined research strategies to enhance our comprehension of HHT, providing valuable insights for pathogenic analysis and the exploration of innovative therapeutic interventions. Additionally, these results underscore the importance of employing diverse in vitro systems to assess multiple aspects of disease, which is challenging using a single in vitro system.

Keywords

ENDOGLIN; Blood vessel organoid; Endothelial cell; Hereditary hemorrhagic telangiectasia; High susceptibility; Inflammatory response; Smooth muscle cell; hPSC modeling.

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