TY - JOUR
T1 - Transplantation of bioengineered liver capable of extended function in a preclinical liver failure model
AU - Higashi, Hisanobu
AU - Yagi, Hiroshi
AU - Kuroda, Kohei
AU - Tajima, Kazuki
AU - Kojima, Hideaki
AU - Nishi, Kotaro
AU - Morisaku, Toshinori
AU - Hirukawa, Kazuya
AU - Fukuda, Kazumasa
AU - Matsubara, Kentaro
AU - Kitago, Minoru
AU - Shinoda, Masahiro
AU - Obara, Hideaki
AU - Adachi, Shungo
AU - Nishimura, Kumiko
AU - Natsume, Tohru
AU - Tomi, Masatoshi
AU - Soto-Gutierrez, Alejandro
AU - Kitagawa, Yuko
N1 - Funding Information:
The authors thank R. Kinoshita, N. Murakawa, M. Takahashi, M. Otomo, M. Kawamura, H. Shibutani, S. Yamaguchi, and H. Kushige for technical laboratory support and T. Otake, K. Matsumoto, and K. Kumagai for assistance with the surgery and animal-rearing during the experimental period. This study was supported by grants from the Japan Agency for Medical Research and Development (AMED) (No. 17bm0404004h0005 and 18bm0404038h0001) awarded to H. Yagi. This work was supported by grants from NIH, DK099257, DK117881, DK119973, DK096990, TR002383, and TR003289 to A.S.-G. This study was also partially supported by Pilot and Feasibility program supported by NIH/NIDDK Digestive Disease Research Core Center grant P30DK120531 awarded to A.S.-G. H.Y. and A.S.-G. are the inventors on a patent application that involves some perfusion technologies used in this work (WO/2011/002926). They have an international patent related to this work that describes the methods for preparing artificial organs and related compositions for transplantation and regeneration (WO/2015/168254). A.S.-G. is a co-founder and has a financial interest in Von Baer Wolff, Inc. This company focuses on the biofabrication of autologous human hepatocytes from stem cells technology and on the programming of liver failure. Their interests are managed by the Conflict-of-Interest Office at the University of Pittsburgh in accordance with their policies.
Funding Information:
The authors thank R. Kinoshita, N. Murakawa, M. Takahashi, M. Otomo, M. Kawamura, H. Shibutani, S. Yamaguchi, and H. Kushige for technical laboratory support and T. Otake, K. Matsumoto, and K. Kumagai for assistance with the surgery and animal‐rearing during the experimental period. This study was supported by grants from the Japan Agency for Medical Research and Development (AMED) (No. 17bm0404004h0005 and 18bm0404038h0001) awarded to H. Yagi. This work was supported by grants from NIH, DK099257, DK117881, DK119973, DK096990, TR002383, and TR003289 to A.S.‐G. This study was also partially supported by Pilot and Feasibility program supported by NIH/NIDDK Digestive Disease Research Core Center grant P30DK120531 awarded to A.S.‐G. H.Y. and A.S.‐G. are the inventors on a patent application that involves some perfusion technologies used in this work (WO/2011/002926). They have an international patent related to this work that describes the methods for preparing artificial organs and related compositions for transplantation and regeneration (WO/2015/168254). A.S.‐G. is a co‐founder and has a financial interest in Von Baer Wolff, Inc. This company focuses on the biofabrication of autologous human hepatocytes from stem cells technology and on the programming of liver failure. Their interests are managed by the Conflict‐of‐Interest Office at the University of Pittsburgh in accordance with their policies.
Publisher Copyright:
© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons
PY - 2022/3
Y1 - 2022/3
N2 - Unlimited organ availability would represent a paradigm shift in transplantation. Long-term in vivo engraftment and function of scaled-up bioengineered liver grafts have not been previously reported. In this study, we describe a human-scale transplantable liver graft engineered on a porcine liver-derived scaffold. We repopulated the scaffold parenchyma with primary hepatocytes and the vascular system with endothelial cells. For in vivo functional testing, we performed auxiliary transplantation of the repopulated scaffold in pigs with induced liver failure. It was observed that the auxiliary bioengineered liver graft improved liver function for 28 days and exhibited upregulation of liver-specific genes. This study is the first of its kind to present 28 days of posttransplant evaluation of a bioengineered liver graft using a preclinical large animal model. Furthermore, it provides definitive evidence for the feasibility of engineering human-scale transplantable liver grafts for clinical applications.
AB - Unlimited organ availability would represent a paradigm shift in transplantation. Long-term in vivo engraftment and function of scaled-up bioengineered liver grafts have not been previously reported. In this study, we describe a human-scale transplantable liver graft engineered on a porcine liver-derived scaffold. We repopulated the scaffold parenchyma with primary hepatocytes and the vascular system with endothelial cells. For in vivo functional testing, we performed auxiliary transplantation of the repopulated scaffold in pigs with induced liver failure. It was observed that the auxiliary bioengineered liver graft improved liver function for 28 days and exhibited upregulation of liver-specific genes. This study is the first of its kind to present 28 days of posttransplant evaluation of a bioengineered liver graft using a preclinical large animal model. Furthermore, it provides definitive evidence for the feasibility of engineering human-scale transplantable liver grafts for clinical applications.
KW - artificial organs/support devices
KW - bioengineering
KW - liver transplantation/hepatology
KW - regenerative medicine
KW - tissue/organ engineering
KW - translational research/science
UR - http://www.scopus.com/inward/record.url?scp=85122318663&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85122318663&partnerID=8YFLogxK
U2 - 10.1111/ajt.16928
DO - 10.1111/ajt.16928
M3 - Article
C2 - 34932270
AN - SCOPUS:85122318663
VL - 22
SP - 731
EP - 744
JO - American Journal of Transplantation
JF - American Journal of Transplantation
SN - 1600-6135
IS - 3
ER -