Sustained perfusion of revascularized bioengineered livers heterotopically transplanted into immunosuppressed pigs
Open accessAbstract
Implanted bioengineered livers have not exceeded three days of continuous perfusion. Here we show that decellularized whole porcine livers revascularized with human umbilical vein endothelial cells and implanted heterotopically into immunosuppressed pigs whose spleens had been removed can sustain perfusion for up to 15 days. We identified peak glucose consumption rate as a main predictor of the patency of the revascularized bioengineered livers (rBELs). Heterotopic implantation of rBELs into pigs in the absence of anticoagulation therapy led to sustained perfusion for three days, followed by a pronounced immune responses directed against the human endothelial cells. A 10 day steroid-based immunosuppression protocol and a splenectomy at the time of rBEL implantation reduced the immune responses and resulted in continuous perfusion of the rBELs for over two weeks. We also show that the human endothelial cells in the perfused rBELs colonize the liver sinusoids and express sinusoidal endothelial markers similar to those in normal liver tissue. Revascularized liver scaffolds that can maintain blood perfusion at physiological pressures might eventually help to overcome the chronic shortage of transplantable human livers.
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Using allograft-derived scaffolds is more clinically relevant, but only a limited number of human organs can be obtained; organs from other species have also been utilized.
“Using allograft-derived scaffolds would be more clinically relevant, but only a very limited number of human organs can be obtained; hence, organs from other species have also been utilized6,7.”
From Bioengineered liver crosslinked with nano-graphene oxide enables efficient liver regeneration via MMP suppression and immunomodulation (2023) · cites this paper as [7]
The Discussion reports a shortage of transplantable human livers, and the Results describe making scaffolds from porcine livers. The paper does not say that allograft-derived scaffolds would be more clinically relevant or explicitly give limited human-scaffold availability as the reason for using another species. (LLM, conf=0.85)
Experimental — accuracy not yet measuredOver the last two decades, livers from mice, rats, ferrets, rabbits, sheep, pigs, and humans have been used for decellularization.
“Over the last two decades, livers from mice, rats, ferrets, rabbits, sheep, pigs, and humans have been used for decellularization [[8], [9], [10], [11],[13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27]].”
From Liver tissue engineering using decellularized scaffolds: Current progress, challenges, and opportunities (2024) · cites this paper as [8]
Several published studies have demonstrated promising results in generating bioengineered livers.
“Several published studies have demonstrated promising results in generating bioengineered livers [[8], [9], [10], [11], [12], [13], [14]].”
From Liver tissue engineering using decellularized scaffolds: Current progress, challenges, and opportunities (2024) · cites this paper as [8]
Several studies have been conducted to evaluate the feasibility of recellularizing decellularized livers, primarily on rodent liver initially, and researchers have continued to scale it up using whole porcine and human livers.
“Several studies have been conducted to evaluate the feasibility of recellularizing decellularized livers, primarily on rodent liver initially, and researchers have continued to scale it up using whole porcine and human livers (Table 1) [8,14,101,110,[193], [194], [195]].”
From Liver tissue engineering using decellularized scaffolds: Current progress, challenges, and opportunities (2024) · cites this paper as [8]
With immunosuppression withdrawal, graft thrombosis occurred similar to the non-immunosuppressed group, indicating that xenogeneic immune response against HUVECs played a critical role in thrombosis and graft loss.
“Interestingly, with immunosuppression withdrawal, graft thrombosis occurred similar to non-immunosuppressed group, indicating that xenogeneic immune response against HUVECs played a critical role in thrombosis and graft loss.”
From Liver tissue engineering using decellularized scaffolds: Current progress, challenges, and opportunities (2024) · cites this paper as [8]
In pigs, immunosuppression by splenectomy and methylprednisolone before transplanting decellularized liver reendothelialized with HUVECs led to a significant reduction in immune responses and resulted in longer graft perfusion and vascular patency for over 14 days compared to the group without immunosuppression.
“We observed that immunosuppression led to a significant reduction in immune responses and resulted in longer graft perfusion and vascular patency of the graft for over 14 days compared to the group without immunosuppression.”
From Liver tissue engineering using decellularized scaffolds: Current progress, challenges, and opportunities (2024) · cites this paper as [8]
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- Authors
- Shaheen, M. F., Joo, D. J., Ross, J. J., Anderson, B. D., Chen, H. S., Huebert, R. C., Li, Y., Amiot, B., Young, A., Zlochiver, V., Nelson, E., Mounajjed, T., Dietz, A. B., Michalak, G., Steiner, B. G., Davidow, D. S., Paradise, C. R., van Wijnen, A. J., Shah, V. H., Liu, M., & Nyberg, S. L.
- Affiliations
- Mayo Clinic (US)
- Miromatrix Medical (United States) (US)
- Corresponding author
- Ross, Jeffrey J.
- Nyberg, Scott L.
- ORCID
- Venue
- Nature Biomedical Engineering
- Published
- 2019-10-14
- Volume
- 4
- Issue
- 4
- Pages
- 437-445
- ISSN
- 2157-846X (ISSN-L)
- PMC
- PMC7153989
- OpenAlex
- W2979432487
- Cited by
- 75
- References
- 44
- Citations by year
- 2026: 4 · 2025: 16 · 2024: 10 · 2023: 18 · 2022: 10 · 2021: 10 · 2020: 6 · 2019: 1
- FWCI
- 6.45
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-11-05)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Biomedical Engineering (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
- Funders
- U.S. Department of Health & Human Services | NIH | Center for Information Technology (R01DK117861, R03DK113339, R01DK106667)
- Topics
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
- Keywords
- heterotopic liver transplantation, human umbilical vein endothelial cells, revascularization, immunosuppression, splenectomy, glucose utilization, immune response, xenotransplantation
- MeSH terms
- Animals, Biomedical Engineering, Glucose, Humans, Immunosuppression Therapy, Kinetics, Liver, Perfusion, Spleen, Swine, Vascular Patency, Liver Transplantation, Transplantation, Heterotopic, Cell Culture Techniques, Bioreactors, Endothelial Cells, Tissue Scaffolds
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