肝脏组织工程研究进展

杨扬; 王励

doi:10.3969/j.issn.1674-7445.2017.05.001

肝脏组织工程研究进展

doi: 10.3969/j.issn.1674-7445.2017.05.001

杨扬^,,
王励

510630 广州，中山大学附属第三医院肝脏外科暨肝移植中心中山大学器官移植研究所

基金项目:

国家自然科学基金 81370575

国家自然科学基金 81570593

广东省自然科学基金研究团队项目 2015A030312013

广州市科技计划项目-健康医疗协同创新重大专项 158100076

广州市科技计划项目-健康医疗协同创新重大专项 201400000001-3

中山大学临床医学研究5010项目 2014006

详细信息

作者简介:
杨扬，教授、主任医师，博士研究生导师。现任中山大学附属第三医院肝脏外科主任，器官移植中心副主任。兼任中国医师协会器官移植医师分会常委、中华医学会器官移植学分会青年委员会副主任委员、中华医学会外科学分会青年委员会副主任委员、中华医学会外科学分会移植学组委员、广东省医学会外科学分会首届青年委员会主任委员、广东省医学会医事法学分会副主任委员。兼任《器官移植》杂志常务编委，《Liver Research》杂志编辑部主任，《中华肝脏外科手术学电子杂志》副总编辑及编辑部主任，《中华医学杂志》、《中华肝胆外科杂志》等杂志编委。2001年8月获得外科学(器官移植学)博士学位。2005年在美国Mount Sinai医学院移植中心进修。擅长肝脏、胆道、门静脉高压与胰腺外科疾病的诊断与处理，主持或参与1 300余例临床肝移植。对肝脏外科、肝移植、移植免疫、干细胞在肝脏疾病的应用等方面有深入的研究，在肝移植术后并发症的预防和治疗方面有较为丰富的经验。在国内外期刊上发表论文数十篇，副主编专著2部。作为课题负责人获国家自然科学基金5项，863项目分课题1项，十二五国家科技重大专项分题1项，广东省自然科学基金面上项目、重点项目及重点攻关课题7项，广州市科技重点专项2项。获教育部科技进步一等奖2项、国家科技部科技进步二等奖1项、广东省科技进步一等奖3项、广州市科技进步一等奖1项。

通讯作者:
杨扬，Email: yysysu@163.com

中图分类号: R617, R318.1
计量
- 文章访问数: 283
- HTML全文浏览量: 60
- PDF下载量: 20
- 被引次数: 0
出版历程
- 收稿日期: 2017-08-01
- 网络出版日期: 2021-01-19
- 刊出日期: 2017-09-15

摘要

摘要: 随着科学技术的迅速发展，通过干细胞与组织工程的新技术来再造人类肝脏，为解决供肝短缺提供了新的思路，是未来科学研究的重点。本文从去细胞化基质支架构建肝脏类器官、生物材料微型模具构建肝脏类器官、细胞诱导的无支架培养构建肝脏类器官、构建嵌合体制备人工肝脏等方面介绍肝脏组织工程研究的最新进展。
- 肝移植 /
- 组织工程 /
- 去细胞化基质支架 /
- 生物材料微型模具 /
- 细胞诱导的无支架培养 /
- 干细胞 /
- 人工肝脏 /
- 类器官 /
- 嵌合体

HTML全文

图 1 基于肝脏基质支架的培养方法^[4]

Figure 1. Culture method based on liver matrix scaffold

下载: 全尺寸图片幻灯片

图 2 基于微型模具制作新型肝脏“组织种子”^[20]

Figure 2. Fabrication of new liver tissue seed based on micro mold

下载: 全尺寸图片幻灯片

图 3 人猪嵌合胚胎的培育^[43]

Figure 3. Cultivation of human and porcine chimeric embryos

下载: 全尺寸图片幻灯片

参考文献(45)

[1]	Kim WR, Lake JR, Smith JM, et al. OPTN/SRTR 2015 annual data report: liver[J]. Am J Transplant, 2017, 17 (Suppl 1): 174-251. DOI: 10.1111/ajt.14126.
[2]	Wang Y, Nicolas CT, Chen HS, et al. Recent advances in decellularization and recellularization for tissue-engineered liver grafts[J]. Cells Tissues Organs, 2017, 203(4): 203-214. DOI: 10.1159/000452761.
[3]	Caralt M. Present and future of regenerative medicine: liver transplantation[J]. Transplant Proc, 2015, 47(8): 2377-2379. DOI: 10.1016/j.transproceed.2015.08.029.
[4]	Mazza G, Rombouts K, Rennie Hall A, et al. Decellularized human liver as a natural 3D-scaffold for liver bioengineering and transplantation[J]. Sci Rep, 2015, 5: 13079. DOI: 10.1038/srep13079.
[5]	Baptista PM, Siddiqui MM, Lozier G, et al. The use of whole organ decellularization for the generation of a vascularized liver organoid[J]. Hepatology, 2011, 53(2): 604-617. DOI: 10.1002/hep.24067.
[6]	Hassanein W, Uluer MC, Langford J, et al. Recellularization via the bile duct supports functional allogenic and xenogenic cell growth on a decellularized rat liver scaffold[J]. Organogenesis, 2017, 13(1): 16-27. DOI: 10.1080/15476278.2016.1276146.
[7]	Ko IK, Peng L, Peloso A, et al. Bioengineered transplantable porcine livers with re-endothelialized vasculature[J]. Biomaterials, 2015, 40: 72-79. DOI: 10.1016/j.biomaterials.2014.11.027.
[8]	Soto-Gutierrez A, Zhang L, Medberry C, et al. A whole-organ regenerative medicine approach for liver replacement[J]. Tissue Eng Part C Methods, 2011, 17(6): 677-686. DOI: 10.1089/ten.tec.2010.0698.
[9]	Uygun BE, Soto-Gutierrez A, Yagi H, et al. Organ reengineering through development of a transplantable recellularized liver graft using decellularized liver matrix[J]. Nat Med, 2010, 16(7): 814-820. DOI: 10.1038/nm.2170.
[10]	Yagi H, Fukumitsu K, Fukuda K, et al. Human-scale whole-organ bioengineering for liver transplantation: a regenerative medicine approach[J]. Cell Transplant, 2013, 22(2): 231-242. DOI: 10.3727/096368912X654939.
[11]	Lin P, Chan WC, Badylak SF, et al. Assessing porcine liver-derived biomatrix for hepatic tissue engineering[J]. Tissue Eng, 2004, 10(7/8): 1046-1053. DOI: 10.1089/ten.2004.10.1046
[12]	Crapo PM, Gilbert TW, Badylak SF. An overview of tissue and whole organ decellularization processes[J]. Biomaterials, 2011, 32(12): 3233-3243. DOI: 10.1016/j.biomaterials.2011.01.057.
[13]	Conklin BS, Wu H, Lin PH, et al. Basic fibroblast growth factor coating and endothelial cell seeding of a decellularized heparin-coated vascular graft[J]. Artif Organs, 2004, 28(7): 668-675. DOI: 10.1111/j.1525-1594.2004.00062.x.
[14]	Nakamura S, Ijima H. Solubilized matrix derived from decellularized liver as a growth factor-immobilizable scaffold for hepatocyte culture[J]. J Biosci Bioeng, 2013, 116(6): 746-753. DOI: 10.1016/j.jbiosc.2013.05.031.
[15]	Uygun BE, Yarmush ML, Uygun K. Application of whole-organ tissue engineering in hepatology[J]. Nat Rev Gastroenterol Hepatol, 2012, 9(12): 738-744. DOI: 10.1038/nrgastro.2012.140.
[16]	Verhulsel M, Vignes M, Descroix S, et al. A review of microfabrication and hydrogel engineering for micro-organs on chips[J]. Biomaterials, 2014, 35(6): 1816-1832. DOI: 10.1016/j.biomaterials.2013.11.021.
[17]	Yamada M, Utoh R, Ohashi K, et al. Controlled formation of heterotypic hepatic micro-organoids in anisotropic hydrogel microfibers for long-term preservation of liver-specific functions[J]. Biomaterials, 2012, 33(33):8304-8315. DOI: 10.1016/j.biomaterials.2012.07.068.
[18]	Rennert K, Steinborn S, Gröger M, et al. A microfluidically perfused three dimensional human liver model[J]. Biomaterials, 2015, 71:119-131. DOI: 10.1016/j.biomaterials.2015.08.043.
[19]	Chen AA, Thomas DK, Ong LL, et al. Humanized mice with ectopic artificial liver tissues[J]. Proc Natl Acad Sci USA, 2011, 108(29): 11842-11847. DOI: 10.1073/pnas.1101791108.
[20]	Stevens KR, Scull MA, Ramanan V, et al. In situ expansion of engineered human liver tissue in a mouse model of chronic liver disease[J]. Sci Transl Med, 2017, 9(399): eaah5505. DOI: 10.1126/scitranslmed.aah5505.
[21]	Coghlan A. 3D printer makes tiniest human liver ever[EB/OL]. (2013-04-23). https://www.newscientist.com/article/dn23419-3d-printer-makes-tiniest-human-liver-ever.html.
[22]	Sasai Y. Next-generation regenerative medicine: organogenesis from stem cells in 3D culture[J]. Cell Stem Cell, 2013, 12(5): 520-530. DOI: 10.1016/j.stem.2013.04.009.
[23]	Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors[J]. Cell, 2007, 131(5): 861-872. DOI: 10.1016/j.cell.2007.11.019.
[24]	Matsumoto K, Yoshitomi H, Rossant J, et al. Liver organogenesis promoted by endothelial cells prior to vascular function[J]. Science, 2001, 294(5542): 559-563. DOI: 10.1126/science.1063889.
[25]	Korzh S, Pan X, Garcia-Lecea M, et al. Requirement of vasculogenesis and blood circulation in late stages of liver growth in zebrafish[J]. BMC Dev Biol, 2008, 8:84. DOI: 10.1186/1471-213X-8-84.
[26]	Takebe T, Sekine K, Enomura M, et al. Vascularized and functional human liver from an iPSC-derived organ bud transplant[J]. Nature, 2013, 499(7459): 481-484. DOI: 10.1038/nature12271.
[27]	Takebe T, Enomura M, Yoshizawa E, et al. Vascularized and complex organ buds from diverse tissues via mesenchymal cell-driven condensation[J]. Cell Stem Cell, 2015, 16(5): 556-565. DOI: 10.1016/j.stem.2015.03.004.
[28]	Guye P, Ebrahimkhani MR, Kipniss N, et al. Genetically engineering self-organization of human pluripotent stem cells into a liver bud-like tissue using GATA6[J]. Nat Commun, 2016, 7:10243. DOI: 10.1038/ncomms10243.
[29]	Ozair MZ, Noggle S, Warmflash A, et al. SMAD7 directly converts human embryonic stem cells to telencephalic fate by a default mechanism[J]. Stem Cells, 2013, 31(1): 35-47. DOI: 10.1002/stem.1246.
[30]	Peterkin T, Gibson A, Patient R. GATA-6 maintains BMP-4 and Nkx2 expression during cardiomyocyte precursor maturation[J]. EMBO J, 2003, 22(16): 4260-4273. DOI: 10.1093/emboj/cdg400.
[31]	Rhim JA, Sandgren EP, Palmiter RD, et al. Complete reconstitution of mouse liver with xenogeneic hepatocytes[J]. Proc Natl Acad Sci USA, 1995, 92(11): 4942-4946. doi: 10.1073/pnas.92.11.4942
[32]	Dandri M, Burda MR, Török E, et al. Repopulation of mouse liver with human hepatocytes and in vivo infection with hepatitis B virus[J]. Hepatology, 2001, 33(4): 981-988. DOI: 10.1053/jhep.2001.23314.
[33]	Tateno C, Yoshizane Y, Saito N, et al. Near completely humanized liver in mice shows human-type metabolic responses to drugs[J]. Am J Pathol, 2004, 165(3): 901-912. DOI: 10.1016/S0002-9440(10)63352-4.
[34]	Meuleman P, Libbrecht L, De Vos R, et al. Morphological and biochemical characterization of a human liver in a uPA-SCID mouse chimera[J]. Hepatology, 2005, 41(4): 847-856. DOI: 10.1002/hep.20657.
[35]	Azuma H, Paulk N, Ranade A, et al. Robust expansion of human hepatocytes in Fah^-/-/Rag2^-/-/Il2rg^-/-mice[J]. Nat Biotechnol, 2007, 25(8): 903-910. DOI: 10.1038/nbt1326.
[36]	Bissig KD, Le TT, Woods NB, et al. Repopulation of adult and neonatal mice with human hepatocytes: a chimeric animal model[J]. Proc Natl Acad Sci USA, 2007, 104(51): 20507-20511. DOI: 10.1073/pnas.0710528105.
[37]	Rashid T, Kobayashi T, Nakauchi H. Revisiting the flight of icarus: making human organs from PSCs with large animal chimeras[J]. Cell Stem Cell, 2014, 15(4): 406-409. DOI: 10.1016/j.stem.2014.09.013.
[38]	Kim H, Kim JS. A guide to genome engineering with programmable nucleases[J]. Nat Rev Genet, 2014, 15(5): 321-334. DOI: 10.1038/nrg3686.
[39]	Hsu PD, Lander ES, Zhang F. Development and applications of CRISPR-Cas9 for genome engineering[J]. Cell, 2014, 157(6): 1262-1278. DOI: 10.1016/j.cell.2014.05.010.
[40]	Yang L, Güell M, Niu D, et al. Genome-wide inactivation of porcine endogenous retroviruses (PERVs)[J]. Science, 2015, 350(6264): 1101-1104. DOI: 10.1126/science.aad1191.
[41]	Cooper DK, Ekser B, Ramsoondar J, et al. The role of genetically engineered pigs in xenotransplantation research[J]. J Pathol, 2016, 238(2): 288-299. DOI: 10.1002/path.4635.
[42]	Shaw D, Dondorp W, Geijsen N, et al. Creating human organs in chimaera pigs: an ethical source of immunocompatible organs?[J]. J Med Ethics, 2015, 41(12): 970-974. DOI: 10.1136/medethics-2014-102224.
[43]	Wu J, Platero-Luengo A, Sakurai M, et al. Interspecies chimerism with mammalian pluripotent stem cells[J]. Cell, 2017, 168(3): 473-486. DOI: 10.1016/j.cell.2016.12.036.
[44]	Xiang AP, Mao FF, Li WQ, et al. Extensive contribution of embryonic stem cells to the development of an evolutionarily divergent host[J]. Hum Mol Genet, 2008, 17(1): 27-37. DOI: 10.1093/hmg/ddm282.
[45]	Li W, Huang L, Lin W, et al. Engraftable neural crest stem cells derived from cynomolgus monkey embryonic stem cells[J]. Biomaterials, 2015, 39: 75-84. DOI: 10.1016/j.biomaterials.2014.10.056.