臨床外科75巻9号

2020年09月発行

特集 変貌する肝移植—適応拡大・ドナー選択・治療戦略の最先端を知る 肝移植における挑戦

移植可能な再生肝臓グラフトの実用化に向けて

著者： 八木洋¹ 北川雄光¹

所属機関： ¹慶應義塾大学医学部外科学（一般・消化器）

ページ範囲：P.1116 - P.1123

【ポイント】
◆再生医療を支える最も重要な要素は，組織や臓器をつくるための「細胞」，細胞の動きを指示するシグナル因子となる「生理活性物質」，細胞生着し生理活性物質が有効に作用するための「足場」の存在である．
◆「脱細胞化」というのは，組織や臓器から細胞を破壊して洗い出し，細胞周囲環境を構成する線維性のタンパクからなる屋台骨（骨格）を残す技術である．
◆移植可能な実質臓器の再生という困難な課題を実現化するために，脱細胞化処理を施した臓器骨格を用いる方法は一つの解決策として有用である．

参考文献

1）Verfaillie CM：Biliary cells to the rescue of Prometheus. Gastroenterology 146：611-614, 2014

2）Michalopoulos GK, Bowen WC, Zajac VF, et al：Morphogenetic events in mixed cultures of rat hepatocytes and nonparenchymal cells maintained in biological matrices in the presence of hepatocyte growth factor and epidermal growth factor. Hepatology 29：90-100, 1999

3）Ohashi K, Yokoyama T, Yamato M, et al：Engineering functional two- and three-dimensional liver systems in vivo using hepatic tissue sheets. Nat Med 13：880-885, 2007

4）Rozga J, Williams F, Ro MS, et al：Development of a bioartificial liver：properties and function of a hollow-fiber module inoculated with liver cells. Hepatology 17：258-265, 1993

5）Tanimizu N, Kaneko K, Itoh T, et al：Intrahepatic bile ducts are developed through formation of homogeneous continuous luminal network and its dynamic rearrangement in mice. Hepatology 64：175-188, 2016

6）Lee SG, Hwang S, Kim KH, et al：Toward 300 liver transplants a year. Surg Today 39：367-373, 2009

7）Woo DH, Kim SK, Lim HJ, et al：Direct and indirect contribution of human embryonic stem cell-derived hepatocyte-like cells to liver repair in mice. Gastroenterology 142：602-611, 2012

8）Takahashi K, Yamanaka S：Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126：663-676, 2006

9）Wu SM, Hochedlinger K：Harnessing the potential of induced pluripotent stem cells for regenerative medicine. Nat Cell Biol 13：497-505, 2011

10）Collin de l'Hortet A, Takeishi K, Guzman-Lepe J, et al：Liver-regenerative transplantation：regrow and reset. Am J Transplant 16：1688-1696, 2016

11）Fox IJ, Chowdhury JR, Kaufman SS, et al：Treatment of the Crigler-Najjar syndrome type Ⅰ with hepatocyte transplantation. N Engl J Med 338：1422-1426, 1998

12）Demetriou AA, Holzman M, Moscioni AD, et al：Hepatic cell transplantation. Adv Vet Sci Comp Med 37：313-332, 1993

13）Whiting JF, Delmonico F, Morrissey P, et al：Clinical results of an organ procurement organization effort to increase utilization of donors after cardiac death. Transplantation 81：1368-1371, 2006

14）Park JK, Lee DH：Bioartificial liver systems：current status and future perspective. J Biosci Bioeng 99：311-319, 2005

15）Kajiwara M, Aoi T, Okita K, et al：Donor-dependent variations in hepatic differentiation from human-induced pluripotent stem cells. Proc Natl Acad Sci USA 109：12538-12543, 2012

16）Discher DE, Mooney DJ, Zandstra PW：Growth factors, matrices, and forces combine and control stem cells. Science 324：1673-1677, 2009

17）Wells RG：The role of matrix stiffness in regulating cell behavior. Hepatology 47：1394-1400, 2008

18）Ott HC, Clippinger B, Conrad C, et al：Regeneration and orthotopic transplantation of a bioartificial lung. Nat Med 16：927-933, 2010

19）Uygun BE, Soto-Gutierrez A, Yagi H, et al：Organ reengineering through development of a transplantable recellularized liver graft using decellularized liver matrix. Nat Med 16：814-820, 2010

20）Song JJ, Guyette JP, Gilpin SE, et al：Regeneration and experimental orthotopic transplantation of a bioengineered kidney. Nat Med 19：646-651, 2013

21）Badylak SF：The extracellular matrix as a biologic scaffold material. Biomaterials 28：3587-3593, 2007

22）Yagi H, Fukumitsu K, Fukuda K, et al：Human-scale whole-organ bioengineering for liver transplantation：a regenerative medicine approach. Cell Transplant 22：231-242, 2013

23）Yu YL, Shao YK, Ding YQ, et al：Decellularized kidney scaffold-mediated renal regeneration. Biomaterials 35：6822-6828, 2014

24）Shimoda H, Yagi H, Higashi H, et al：Decellularized liver scaffolds promote liver regeneration after partial hepatectomy. Sci Rep 9：12543, 2019

25）Kadota Y, Yagi H, Inomata K, et al：Mesenchymal stem cells support hepatocyte function in engineered liver grafts. Organogenesis 10：268-277, 2014

26）Inomata K, Tajima K, Yagi H, et al：A pre-clinical large animal model of sustained liver injury and regeneration stimulus. Sci Rep 8：14987, 2018

27）Kadota Y, Yagi H, Inomata K, et al：Mesenchymal stem cells support hepatocyte function in engineered liver grafts. Organogenesis 10：268-277, 2014

28）Mendez JJ, Ghaedi M, Steinbacher D, et al：Epithelial cell differentiation of human mesenchymal stromal cells in decellularized lung scaffolds. Tissue Eng Part A 20：1735-1746, 2014

29）Godier-Furnemont AF, Martens TP, Koeckert MS, et al：Composite scaffold provides a cell delivery platform for cardiovascular repair. Proc Natl Acad Sci USA 108：7974-7979, 2011

30）Simpson DL, Wehman B, Galat Y, et al：Engineering patient-specific valves using stem cells generated from skin biopsy specimens. Ann Thorac Surg 98：947-954, 2014

31）Caralt M, Uzarski JS, Iacob S, et al：Optimization and critical evaluation of decellularization strategies to develop renal extracellular matrix scaffolds as biological templates for organ engineering and transplantation. Am J Transplant 15：64-75, 2015

32）Yagi H, Parekkadan B, Suganuma K, et al：Long-term superior performance of a stem cell/hepatocyte device for the treatment of acute liver failure. Tissue Eng Part A 15：3377-3388, 2009

33）Yagi H, Tafaleng E, Nagaya M, et al：Embryonic and induced pluripotent stem cells as a model for liver disease. Crit Rev Biomed Eng 37：377-398, 2009

34）Takayama K, Mizuguchi H：Generation of human pluripotent stem cell-derived hepatocyte-like cells for drug toxicity screening. Drug Metab Pharmacokinet 32：12-20, 2017

35）Nagamoto Y, Takayama K, Tashiro K, et al：Efficient engraftment of human induced pluripotent stem cell-derived hepatocyte-like cells in uPA/SCID mice by overexpression of FNK, a Bcl-xL mutant gene. Cell Transplant 24：1127-1138, 2015

36）Takayama K, Kawabata K, Nagamoto Y, et al：3D spheroid culture of hESC/hiPSC-derived hepatocyte-like cells for drug toxicity testing. Biomaterials 34：1781-1789, 2013

37）Snykers S, De Kock J, Rogiers V, et al：In vitro differentiation of embryonic and adult stem cells into hepatocytes：state of the art. Stem Cells 27：577-605, 2009

38）Peerani R, Zandstra PW：Enabling stem cell therapies through synthetic stem cell-niche engineering. J Clin Invest 120：60-70, 2010

39）Soto-Gutierrez A, Navarro-Alvarez N, Yagi H, et al：Stem cells for liver repopulation. Cur Opin Organ Transplant 14：667-673, 2009

40）Soto-Gutierrez A, Zhang L, Medberry C, et al：A whole-organ regenerative medicine approach for liver replacement. Tissue Eng Part C Methods 17：677-686, 2011