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Cited by 16Tissue Engineering and Regenerative MedicinePluripotent Stem Cells Research3D Printing in Biomedical Research

Human-Origin iPSC-Based Recellularization of Decellularized Whole Rat Livers

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Acun, Aylin, Oganesyan, Ruben, Jaramillo, Maria, Yarmush, Martin L., Uygun, Basak E.·2022·Bioengineering
DOI 10.3390/bioengineering9050219PMC PMC9137624
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Abstract

End-stage liver diseases lead to mortality of millions of patients, as the only treatment available is liver transplantation and donor scarcity means that patients have to wait long periods before receiving a new liver. In order to minimize donor organ scarcity, a promising bioengineering approach is to decellularize livers that do not qualify for transplantation. Through decellularization, these organs can be used as scaffolds for developing new functional organs. In this process, the original cells of the organ are removed and ideally should be replaced by patient-specific cells to eliminate the risk of immune rejection. Induced pluripotent stem cells (iPSCs) are ideal candidates for developing patient-specific organs, yet the maturity and functionality of iPSC-derived cells do not match those of primary cells. In this study, we introduced iPSCs into decellularized rat liver scaffolds prior to the start of differentiation into hepatic lineages to maximize the exposure of iPSCs to native liver matrices. Through exposure to the unique composition and native 3D organization of the liver microenvironment, as well as the more efficient perfusion culture throughout the differentiation process, iPSC differentiation into hepatocyte-like cells was enhanced. The resulting cells showed significantly higher expression of mature hepatocyte markers, including important CYP450 enzymes, along with lower expression of fetal markers, such as AFP. Importantly, the gene expression profile throughout the different stages of differentiation was more similar to native development. Our study shows that the native 3D liver microenvironment has a pivotal role to play in the development of human-origin hepatocyte-like cells with more mature characteristics.

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  • Acun et al. found that after 7 days of media perfusion, iPSCs differentiated into hepatocyte-like cells, showing higher expression of mature markers, including CYP450 enzymes, albumin, and HNF4a, compared to hepatocyte-like cells produced in a 3D geltrex matrix.

    “After 7 days of media perfusion, the iPSCs differentiated into hepatocyte-like cells, showing higher expression of mature markers, including CYP450 enzymes, albumin, and HNF4a, compared to hepatocyte-like cells produced in a 3D geltrex matrix.”

    From Liver tissue engineering using decellularized scaffolds: Current progress, challenges, and opportunities (2024) · cites this paper as [215]

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  1. [1]Byass P. The global burden of liver disease: A challenge for methods and for public health BMC Med. 2014 12 159 10.1186/s12916-014-0159-5 25286285 PMC4168048 · DOI
  2. [2]Starzl T.E. Marchioro T.L. Kaulla K.N.V. Hermann G. Brittain R.S. Waddell W.R. Homotransplantation of the liver in humans Surg. Gynecol. Obstet. 1963 117 659 676 14100514 PMC2634660
  3. [4]Badylak S.F. Taylor D. Uygun K. Whole-organ tissue engineering: Decellularization and recellularization of three-dimensional matrix scaffolds Annu. Rev. Biomed. Eng. 2011 13 27 53 10.1146/annurev-bioeng-071910-124743 21417722 PMC10887492 · DOI · Paper page
  4. [5]Sabetkish S. Kajbafzadeh A.-M. Sabetkish N. Khorramirouz R. Akbarzadeh A. Seyedian S.L. Pasalar P. Orangian S. Beigi R.S.H. Aryan Z. Whole-organ tissue engineering: Decellularization and recellularization of three-dimensional matrix liver scaffolds J. Biomed. Mater. Res. A 2015 103 1498 1508 10.1002/jbm.a.35291 25045886 · DOI · Paper page
  5. [6]Takahashi K. Tanabe K. Ohnuki M. Narita M. Ichisaka T. Tomoda K. Yamanaka S. Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors Cell 2007 131 861 872 10.1016/j.cell.2007.11.019 18035408 · DOI · Paper page
  6. [7]Si-Tayeb K. Noto F.K. Nagaoka M. Li J. Battle M.A. Duris C. North P.E. Dalton S. Duncan S.A. Highly efficient generation of human hepatocyte–like cells from induced pluripotent stem cells Hepatology 2010 51 297 305 10.1002/hep.23354 19998274 PMC2946078 · DOI · Paper page
  7. [9]Liu H. Ye Z. Kim Y. Sharkis S. Jang Y.-Y. Generation of endoderm-derived human induced pluripotent stem cells from primary hepatocytes Hepatology 2010 51 1810 1819 10.1002/hep.23626 20432258 PMC2925460 · DOI
  8. [10]Song Z. Cai J. Liu Y. Zhao D. Yong J. Duo S. Song X. Guo Y. Zhao Y. Qin H. Efficient generation of hepatocyte-like cells from human induced pluripotent stem cells Cell Res. 2009 19 1233 1242 10.1038/cr.2009.107 19736565 · DOI · Paper page
  9. [11]Espejel S. Roll G.R. McLaughlin K.J. Lee A.Y. Zhang J.Y. Laird D.J. Okita K. Yamanaka S. Willenbring H. Induced pluripotent stem cell-derived hepatocytes have the functional and proliferative capabilities needed for liver regeneration in mice J. Clin. Investig. 2010 120 3120 3126 10.1172/JCI43267 20739754 PMC2929736 · DOI
  10. [12]Toba Y. Kiso A. Nakamae S. Sakurai F. Takayama K. Mizuguchi H. FGF signal is not required for hepatoblast differentiation of human iPS cells Sci. Rep. 2019 9 3713 10.1038/s41598-019-40305-2 30842525 PMC6403225 · DOI
  11. [13]Gao X. Li R. Cahan P. Zhao Y. Yourick J.J. Sprando R.L. Hepatocyte-like cells derived from human induced pluripotent stem cells using small molecules: Implications of a transcriptomic study Stem Cell Res. Ther. 2020 11 393 10.1186/s13287-020-01914-1 32917265 PMC7488531 · DOI · Paper page
  12. [14]Jaramillo M. Yeh H. Yarmush M.L. Uygun B.E. Decellularized human liver extracellular matrix (hDLM)-mediated hepatic differentiation of human induced pluripotent stem cells (hIPSCs) J. Tissue Eng. Regen. Med. 2018 12 e1962 e1973 10.1002/term.2627 29222839 PMC5906168 · DOI
  13. [15]Kanagavel V. Ren S. Irudayam J.I. Xiong W. Talavera D. Klein A. French S. Arumugaswami V. Organ engineering using decellularized liver scaffold recellularized with iPSC-derived hepatocytes (398.10) FASEB J. 2014 28 398.10 10.1096/fasebj.28.1_supplement.398.10 · DOI
  14. [16]Wang B. Jakus A.E. Baptista P.M. Soker S. Soto-Gutierrez A. Abecassis M.M. Shah R.N. Wertheim J.A. Functional Maturation of Induced Pluripotent Stem Cell Hepatocytes in Extracellular Matrix—A Comparative Analysis of Bioartificial Liver Microenvironments Stem Cells Transl. Med. 2016 5 1257 1267 10.5966/sctm.2015-0235 27421950 PMC4996436 · DOI
  15. [18]Uygun B.E. Soto-Gutierrez A. Yagi H. Izamis M.-L. Guzzardi M.A. Shulman C. Milwid J. Kobayashi N. Tilles A. Berthiaume F. Organ reengineering through development of a transplantable recellularized liver graft using decellularized liver matrix Nat. Med. 2010 16 814 820 10.1038/nm.2170 20543851 PMC2930603 · DOI · Paper page
  16. [19]Bühler N.E.M. Schulze-Osthoff K. Königsrainer A. Schenk M. Controlled processing of a full-sized porcine liver to a decellularized matrix in 24 h J. Biosci. Bioeng. 2015 119 609 613 10.1016/j.jbiosc.2014.10.019 25468420 · DOI · Paper page
  17. [20]Mazza G. Rombouts K. Hall A.R. Urbani L. Luong T.V. Al-Akkad W. Longato L. Brown D. Maghsoudlou P. Dhillon A.P. Decellularized human liver as a natural 3D-scaffold for liver bioengineering and transplantation Sci. Rep. 2015 5 13079 10.1038/srep13079 26248878 PMC4528226 · DOI · Paper page
  18. [21]Acun A. Oganesyan R. Uygun K. Yeh H. Yarmush M.L. Uygun B.E. Liver donor age affects hepatocyte function through age-dependent changes in decellularized liver matrix Biomaterials 2021 270 120689 10.1016/j.biomaterials.2021.120689 33524812 PMC7906943 · DOI · Paper page
  19. [22]Nghiem-Rao T.H. Pfeifer C. Asuncion M. Nord J. Schill D. Pulakanti K. Patel S.B. Cirillo L.A. Rao S. Human induced pluripotent stem cell derived hepatocytes provide insights on parenteral nutrition associated cholestasis in the immature liver Sci. Rep. 2021 11 12386 10.1038/s41598-021-90510-1 34117281 PMC8196029 · DOI
  20. [24]Chen Y. Devalliere J. Bulutoglu B. Yarmush M.L. Uygun B.E. Repopulation of intrahepatic bile ducts in engineered rat liver grafts Technology 2019 7 46 55 10.1142/S2339547819500043 31388515 PMC6684151 · DOI · Paper page
  21. [25]Chen Y. Geerts S. Jaramillo M. Uygun B.E. Preparation of Decellularized Liver Scaffolds and Recellularized Liver Grafts Methods Mol. Biol. 2018 1577 255 270 10.1007/7651_2017_56 28735385 PMC6688852 · DOI
  22. [26]Uygun B.E. Price G. Saeidi N. Izamis M.-L. Berendsen T. Yarmush M. Uygun K. Decellularization and Recellularization of Whole Livers JoVE 2011 48 e2394 10.3791/2394 PMC3197392 21339718 · DOI
  23. [27]Agmon G. Christman K.L. Controlling stem cell behavior with decellularized extracellular matrix scaffolds Curr. Opin. Solid State Mater. Sci. 2016 20 193 201 10.1016/j.cossms.2016.02.001 27524932 PMC4979580 · DOI
  24. [28]Hynes R.O. The extracellular matrix: Not just pretty fibrils Science 2009 326 1216 1219 10.1126/science.1176009 19965464 PMC3536535 · DOI · Paper page
  25. [29]Sassi L. Ajayi O. Campinoti S. Natarajan D. McQuitty C. Siena R. Mantero S. De Coppi P. Pellegata A. Chokshi S. A Perfusion Bioreactor for Longitudinal Monitoring of Bioengineered Liver Constructs Nanomaterials 2021 11 275 10.3390/nano11020275 33494337 PMC7912543 · DOI
  26. [30]Xia N. Zhang P. Fang F. Wang Z. Rothstein M. Angulo B. Chiang R. Taylor J. Pera R.A.R. Transcriptional comparison of human induced and primary midbrain dopaminergic neurons Sci. Rep. 2016 6 20270 10.1038/srep20270 26842779 PMC4740755 · DOI
  27. [31]Doss M.X. Sachinidis A. Current Challenges of iPSC-Based Disease Modeling and Therapeutic Implications Cells 2019 8 403 10.3390/cells8050403 PMC6562607 31052294 · DOI
  28. [32]Iii R.L.G. Hannan N. Bort R. Hanley N. Drake R.A.L. Cameron G.W.W. Wynn T. Vallier L. Maturation of Induced Pluripotent Stem Cell Derived Hepatocytes by 3D-Culture PLoS ONE 2014 9 e86372 10.1371/journal.pone.0086372 24466060 PMC3899231 · DOI
  29. [33]Asai A. Aihara E. Watson C. Mourya R. Mizuochi T. Shivakumar P. Phelan K. Mayhew C. Helmrath M. Takebe T. Paracrine signals regulate human liver organoid maturation from induced pluripotent stem cells Development 2017 144 1056 1064 10.1242/dev.142794 28275009 PMC5358109 · DOI
  30. [34]Piccini I. Rao J. Seebohm G. Greber B. Human pluripotent stem cell-derived cardiomyocytes: Genome-wide expression profiling of long-term in vitro maturation in comparison to human heart tissue Genom. Data 2015 4 69 72 10.1016/j.gdata.2015.03.008 26484180 PMC4535944 · DOI · Paper page
  31. [35]Feyen D.A. McKeithan W.L. Bruyneel A.A. Spiering S. Hörmann L. Ulmer B. Zhang H. Briganti F. Schweizer M. Hegyi B. Metabolic Maturation Media Improve Physiological Function of Human iPSC-Derived Cardiomyocytes Cell Rep. 2020 32 107925 10.1016/j.celrep.2020.107925 32697997 PMC7437654 · DOI · Paper page
  32. [36]Zabulica M. Srinivasan R.C. Vosough M. Hammarstedt C. Wu T. Gramignoli R. Ellis E. Kannisto K. De L’Hortet A.C. Takeishi K. Guide to the Assessment of Mature Liver Gene Expression in Stem Cell-Derived Hepatocytes Stem Cells Dev. 2019 28 907 919 10.1089/scd.2019.0064 31122128 PMC6648222 · DOI
  33. [37]Feldhoff R.C. Taylor J.M. Jefferson L.S. Synthesis and secretion of rat albumin in vivo, in perfused liver, and in isolated hepatocytes. Effects of hypophysectomy and growth hormone treatment J. Biol. Chem. 1977 252 3611 3616 10.1016/S0021-9258(17)40296-1 863898 · DOI
  34. [38]Fabris G. Dumortier O. Pisani D.F. Gautier N. van Obberghen E. Amino acid-induced regulation of hepatocyte growth: Possible role of Drosha Cell Death Dis. 2019 10 566 10.1038/s41419-019-1779-7 31332188 PMC6646398 · DOI
  35. [39]Mangnall D. Bird N.C. Majeed A.W. The molecular physiology of liver regeneration following partial hepatectomy Liver Int. 2003 23 124 138 10.1034/j.1600-0676.2003.00812.x 12654135 · DOI

Cited by

Sorted by citations

Authors
Acun, A., Oganesyan, R., Jaramillo, M., Yarmush, M. L., & Uygun, B. E.
Affiliations
  • Harvard University (US)
  • Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Shriners Hospitals for Children, Boston, MA 02114, USA
  • Rutgers, The State University of New Jersey (US)
Corresponding author
Uygun, Basak E.
ORCID
Venue
Bioengineering
Publisher
MDPI AG
Published
2022-05-19
Volume
9
Issue
5
Pages
219
ISSN
2306-5354 (ISSN-L)
DOI
10.3390/bioengineering9050219
PMC
PMC9137624
OpenAlex
W4280561560
Cited by
16
References
3
Citations by year
2026: 1 · 2025: 1 · 2024: 5 · 2023: 7 · 2022: 2
FWCI
3.58
Type
journal article
Language
en
Open access
Licence
Locations
  • Bioengineering (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (R01DK084053, 84702)
  • Shriners Hospitals for Children (R01DK084053, 84702)
Topics
  • Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
  • Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
Keywords
induced pluripotent stem cells, decellularized liver scaffold, recellularization, hepatocyte-like cells, iPSC differentiation, perfusion culture, cytochrome P450, end-stage liver disease, liver transplantation, rat liver

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