Construction of sinusoid-scale microvessels in perfusion culture of a decellularized liver
Open accessAbstract
There is a great deal of demand for the construction of transplantable liver grafts. Over the last decade, decellularization techniques have been developed to construct whole liver tissue grafts as potential biomaterials. However, the lack of intact vascular networks, especially sinusoids, in recellularized liver scaffolds leads to hemorrhage and thrombosis after transplantation, which is a major obstacle to the development of transplantable liver grafts. In the present study, we hypothesized that both mechanical (e.g., fluid shear stress) and chemical factors (e.g., fibronectin coating) can enhance the formation of hierarchical vascular networks including sinusoid-scale microvessels. We demonstrated that perfusion culture promoted formation of sinusoid-scale microvessels in recellularized liver scaffolds, which was not observed in static culture. In particular, perfusion culture at 4.7 ml/min promoted the formation of sinusoid-scale microvessels compared to perfusion culture at 2.4 and 9.4 ml/min. In addition, well-aligned endothelium was observed in perfusion culture, suggesting that endothelial cells sensed the flow-induced shear stress. Moreover, fibronectin coating of decellularized liver scaffolds enhanced the formation of sinusoid-scale microvessels in perfusion culture at 4.7 ml/min. This study represents a critical step in the development of functional recellularized liver scaffolds, which can be used not only for transplantation but also for drug screening and disease-modeling studies. STATEMENT OF SIGNIFICANCE: Decellularized liver scaffolds are promising biomaterials that allow production of large-scale tissue-engineered liver grafts. However, it is difficult to maintain recellularized liver grafts after transplantation due to hemorrhage and thrombosis. To overcome this obstacle, construction of an intact vascular network including sinusoid-scale microvessels is essential. In the present study, we succeeded in constructing sinusoid-scale microvessels in decellularized liver scaffolds via a combination of perfusion culture and surface coating. We further confirmed that endothelial cells in decellularized liver scaffolds responded to flow-derived mechanical stress by aligning actin filaments. Our strategy to construct sinusoid-scale microvessels is critical for the development of intact vascular networks, and addresses the limitations of recellularized liver scaffolds after transplantation.
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Watanabe et al. adjusted the perfusion rate to simulate various hemodynamic conditions and observed their effects on the formation of microvascular structures within recellularized liver scaffolds.
“In the research conducted by Watanabe et al., adjusting the perfusion rate enabled the simulation of various hemodynamic conditions, and their effects on the formation of microvascular structures within recellularized liver scaffolds were observed [32].”
From Decellularized liver scaffolds for constructing drug-metabolically functional ex vivo human liver models (2025) · cites this paper as [32]
Fluid shear stress regulates the morphology, functionality, and intercellular interactions of endothelial cells.
“Specifically, fluid shear stress (FSS) has been shown to regulate the morphology, functionality, and intercellular interactions of endothelial cells.”
From Decellularized liver scaffolds for constructing drug-metabolically functional ex vivo human liver models (2025) · cites this paper as [32]
Optimal levels of fluid shear stress can promote the proliferation and migration of endothelial cells, which are crucial for the formation of vascular networks.
“For instance, optimal levels of FSS can promote the proliferation and migration of endothelial cells, which are crucial for the formation of vascular networks.”
From Decellularized liver scaffolds for constructing drug-metabolically functional ex vivo human liver models (2025) · cites this paper as [32]
ECM components, especially collagen present in the scaffold, can stimulate the activation pathway upon contact with circulating platelets in the bloodstream.
“The ECM components, especially collagen present in the scaffold, can stimulate the activation pathway upon contact with circulating platelets in the bloodstream [150,220,221].”
From Liver tissue engineering using decellularized scaffolds: Current progress, challenges, and opportunities (2024) · cites this paper as [150]
Platelet aggregation and coagulation are expected to occur immediately after in vivo transplantation of the liver scaffold, potentially impeding the blood supply to the organ and causing cell death.
“As a result, platelet aggregation and coagulation are expected to occur immediately after in vivo transplantation of the liver scaffold, potentially impeding the blood supply to the organ and causing cell death.”
From Liver tissue engineering using decellularized scaffolds: Current progress, challenges, and opportunities (2024) · cites this paper as [150]
Perfusion at 4.7 ml/min facilitated generation of sinusoid-scale microvessels, unlike perfusion rates of 2.4 and 9.4 ml/min.
“Perfusion at a rate of 4.7 ml/min was noted to facilitate the generation of sinusoid-scale microvessels, unlike perfusion rates of 2.4 and 9.4 ml/min.”
From Liver tissue engineering using decellularized scaffolds: Current progress, challenges, and opportunities (2024) · cites this paper as [150]
Fibronectin is a major component present in decellularized tissues and has been extensively used for conjugation with biomaterial surfaces to accelerate attachment, spreading, and differentiation of ECs.
“Fibronectin, a large adhesive glycoprotein, is considered a major component present in decellularized tissues and has been extensively used for conjugation with biomaterial surfaces to accelerate the attachment, spreading, and differentiation of ECs [150,230,231].”
From Liver tissue engineering using decellularized scaffolds: Current progress, challenges, and opportunities (2024) · cites this paper as [150]
Incorporation of fibronectin coating onto decellularized liver scaffolds facilitated development of sinusoid-scale microvessels during perfusion culture at 4.7 ml/min.
“Furthermore, the incorporation of fibronectin coating onto decellularized liver scaffolds was found to facilitate the development of sinusoid-scale microvessels during perfusion culture at 4.7 ml/min.”
From Liver tissue engineering using decellularized scaffolds: Current progress, challenges, and opportunities (2024) · cites this paper as [150]
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- Authors
- Watanabe, M., Yano, K., Okawa, K., Yamashita, T., Tajima, K., Sawada, K., Yagi, H., Kitagawa, Y., Tanishita, K., & Sudo, R.
- Affiliations
- Keio University (JP)
- Waseda University (JP)
- Corresponding author
- Sudo, Ryo
- ORCID
- Venue
- Acta Biomaterialia
- Publisher
- Elsevier BV
- Published
- 2019-09
- Volume
- 95
- Pages
- 307-318
- ISSN
- 1742-7061 (ISSN-L)
- OpenAlex
- W2905867585
- Cited by
- 38
- References
- 55
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 8 · 2023: 7 · 2022: 7 · 2021: 4 · 2020: 2 · 2019: 2
- FWCI
- 2.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Acta Biomaterialia (acceptedVersion)
- PubMed (publishedVersion)
- Funders
- Keio University
- Japan Agency for Medical Research and Development
- Japan Society for the Promotion of Science (16H03173)
- Topics
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- decellularized liver scaffold, perfusion culture, vascular network formation, endothelial cell alignment, fluid shear stress, fibronectin coating, actin filament alignment
- MeSH terms
- Animals, Fibronectins, Humans, Liver, Male, Perfusion, Stress, Mechanical, Rats, Sprague-Dawley, Neovascularization, Physiologic, Green Fluorescent Proteins, Tissue Scaffolds, Microvessels, Human Umbilical Vein Endothelial Cells
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