CoChat
Sign Up
Cited by 14Pluripotent Stem Cells ResearchLiver physiology and pathologyTissue Engineering and Regenerative Medicine

The road to regenerative liver therapies: the triumphs, trials and tribulations

Open access
Raju, Ravali, Chau, David, Verfaillie, Catherine M., Hu, Wei-Shou·2013·Biotechnology Advances
DOI 10.1016/j.biotechadv.2013.08.022PMC PMC4079080
Open this paper in CoChat — free account

Abstract

The liver is one of the few organs that possess a high capacity to regenerate after liver failure or liver damage. The parenchymal cells of the liver, hepatocytes, contribute to the majority of the regeneration process. Thus, hepatocyte transplantation presents an alternative method to treating liver damage. However, shortage of hepatocytes and difficulties in maintaining primary hepatocytes still remain key obstacles that researchers must overcome before hepatocyte transplantation can be used in clinical practice. The unique properties of pluripotent stem cells (PSCs) and induced pluripotent stem cells (iPSCs) have provided an alternative approach to generating enough functional hepatocytes for cellular therapy. In this review, we will present a brief overview on the current state of hepatocyte differentiation from PSCs and iPSCs. Studies of liver regenerative processes using different cell sources (adult liver stem cells, hepatoblasts, hepatic progenitor cells, etc.) will be described in detail as well as how this knowledge can be applied towards optimizing culture conditions for the maintenance and differentiation of these cells towards hepatocytes. As the outlook of stem cell-derived therapy begins to look more plausible, researchers will need to address the challenges we must overcome in order to translate stem cell research to clinical applications.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.biotechadv.2013.08.022

Cites

5 of 5 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • It is difficult to propagate or even maintain hepatocytes in a functional differentiated state in vitro.

    “It is notoriously difficult to propagate or even maintain hepatocytes in a functional differentiated state in vitro.”

    From Hippo Signaling Influences HNF4A and FOXA2 Enhancer Switching during Hepatocyte Differentiation (2014) · cites this paper as Raju et al., 2013

  • Investigators have achieved partial success in propagating/maintaining hepatocytes in vitro by developing 3D tissue culture models and using a multitude of extracellular matrix components in the form of Matrigel.

    “Investigators have achieved partial success by developing 3D tissue culture models and using a multitude of extracellular matrix (ECM) components in the form of Matrigel (Raju et al., 2013).”

    From Hippo Signaling Influences HNF4A and FOXA2 Enhancer Switching during Hepatocyte Differentiation (2014) · cites this paper as Raju et al., 2013

    The Introduction describes difficulty maintaining primary hepatocytes in culture, and its Adult liver stem cells section describes a decellularized liver biomatrix used for differentiation. Searches for Matrigel and 3D tissue culture models found no passage saying those approaches achieved the claimed partial success. (LLM, conf=0.72)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 84

  1. [1]Lemaigre F Zaret KS Liver development update: new embryo models, cell lineage control, and morphogenesis Current opinion in genetics & development 2004 14 582 590 15380251
  2. [2]Carpentier B Gautier A Legallais C Artificial and bioartificial liver devices: present and future Gut 2009 58 1690 1702 19923348
  3. [3]Nyberg SL Bridging the gap: Advances in artificial liver support Liver transplantation: official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society 2012 22767444
  4. [4]Soltys KA Soto-Gutierrez A Nagaya M Baskin KM Deutsch M Ito R Barriers to the successful treatment of liver disease by hepatocyte transplantation Journal of hepatology 2010 53 769 774 20667616 PMC2930077
  5. [5]Hughes RD Mitry RR Dhawan A Current status of hepatocyte transplantation Transplantation 2012 93 342 347 22082820
  6. [6]Fukumitsu K Yagi H Soto-Gutierrez A Bioengineering in organ transplantation: targeting the liver Transplantation proceedings 2011 43 2137 2138 21839215 PMC3156419
  7. [7]Johnson MH Chisholm JC Fleming TP Houliston E A role for cytoplasmic determinants in the development of the mouse early embryo? Journal of embryology and experimental morphology 1986 97 Suppl 97 121 2442282
  8. [8]Yamanaka Y Lanner F Rossant J FGF signal-dependent segregation of primitive endoderm and epiblast in the mouse blastocyst Development 2010 137 715 724 20147376
  9. [9]Gardner RL Rossant J Investigation of the fate of 4–5 day post-coitum mouse inner cell mass cells by blastocyst injection Journal of embryology and experimental morphology 1979 52 141 152 521746
  10. [10]De Miguel MP Arnalich Montiel F Lopez Iglesias P Blazquez Martinez A Nistal M Epiblast-derived stem cells in embryonic and adult tissues The International journal of developmental biology 2009 53 1529 1540 19757397
  11. [11]Liu P Wakamiya M Shea MJ Albrecht U Behringer RR Bradley A Requirement for Wnt3 in vertebrate axis formation Nature genetics 1999 22 361 365 10431240
  12. [12]Conlon FL Lyons KM Takaesu N Barth KS Kispert A Herrmann B A primary requirement for nodal in the formation and maintenance of the primitive streak in the mouse Development 1994 120 1919 1928 7924997
  13. [13]Feldman B Dougan ST Schier AF Talbot WS Nodal-related signals establish mesendodermal fate and trunk neural identity in zebrafish Current biology: CB 2000 10 531 534 10801442
  14. [14]Gritsman K Zhang J Cheng S Heckscher E Talbot WS Schier AF The EGF-CFC protein one-eyed pinhead is essential for nodal signaling Cell 1999 97 121 132 10199408
  15. [15]Kim SW Yoon SJ Chuong E Oyolu C Wills AE Gupta R Chromatin and transcriptional signatures for Nodal signaling during endoderm formation in hESCs Developmental biology 2011 357 492 504 21741376
  16. [16]David NB Rosa FM Cell autonomous commitment to an endodermal fate and behavior by activation of Nodal signalling Development 2001 128 3937 3947 11641218
  17. [17]Schier AF Nodal signaling in vertebrate development Annual review of cell and developmental biology 2003 19 589 621 14570583
  18. [18]Ciruna B Rossant J FGF signaling regulates mesoderm cell fate specification and morphogenetic movement at the primitive streak Developmental cell 2001 1 37 49 11703922
  19. [19]Rossant J Ciruna B Partanen J FGF signaling in mouse gastrulation and anteroposterior patterning Cold Spring Harbor symposia on quantitative biology 1997 62 127 133 9598344
  20. [20]Jung J Initiation of Mammalian Liver Development from Endoderm by Fibroblast Growth Factors Science 1999 284 1998 2003 10373120
  21. [21]Douarin N An experimental analysis of liver development Medical biology 1975 53 427 765644
  22. [22]Fukuda-Taira S Hepatic induction of in the avian embryo: Specificity of reactive endoderm and inductive mesoderm Journal of embryology 1981 63 7310284
  23. [23]Rossi JM Dunn NR Hogan BL Zaret KS Distinct mesodermal signals, including BMPs from the septum transversum mesenchyme, are required in combination for hepatogenesis from the endoderm Genes Dev 2001 15 1998 2009 11485993 PMC312750
  24. [24]Zhang W Yatskievych TA Baker RK Antin PB Regulation of Hex gene expression and initial stages of avian hepatogenesis by Bmp and Fgf signaling Developmental biology 2004 268 312 326 15063170
  25. [25]Matsumoto K Yoshitomi H Rossant J Zaret KS Liver organogenesis promoted by endothelial cells prior to vascular function Science 2001 294 559 563 11577199
  26. [26]Ishikawa KS Masui T Ishikawa K Shiojiri N Immunolocalization of hepatocyte growth factor and its receptor (c-Met) during mouse liver development Histochemistry and cell biology 2001 116 453 462 11735009
  27. [27]Hussain SZ Sneddon T Tan X Micsenyi A Michalopoulos GK Monga SP Wnt impacts growth and differentiation in ex vivo liver development Experimental cell research 2004 292 157 169 14720515
  28. [28]Kamiya AK Ito T Matsui Y Morikawa T Senba Y Nakashima E Taga K Yoshida T Kanji Kishimoto T Miyajima A Fetal liver development requires a paracrine action of oncostatin M through the gp130 signal transducer The EMBO Journal 1999 18 PMC1171297 10205167
  29. [30]Zaret KS Regulatory phases of early liver development: paradigms of organogenesis Nature reviews Genetics 2002 3 499 512 12094228
  30. [31]Li T Huang J Jiang Y Zeng Y He F Zhang MQ Multi-stage analysis of gene expression and transcription regulation in C57/B6 mouse liver development Genomics 2009 93 235 242 19015022 PMC2995988
  31. [32]Kung JW Forbes SJ Stem cells and liver repair Current opinion in biotechnology 2009 20 568 574 19837579
  32. [33]Minguet S Cortegano I Gonzalo P Martinez-Marin JA de Andres B Salas C A population of c-Kit(low)(CD45/TER119)-hepatic cell progenitors of 11-day postcoitus mouse embryo liver reconstitutes cell-depleted liver organoids The Journal of clinical investigation 2003 112 1152 1163 14561700 PMC213486
  33. [34]Suzuki A Zheng Y Kondo R Kusakabe M Takada Y Fukao K Flow-cytometric separation and enrichment of hepatic progenitor cells in the developing mouse liver Hepatology 2000 32 1230 1239 11093729
  34. [35]Oertel M Menthena A Chen YQ Teisner B Jensen CH Shafritz DA Purification of fetal liver stem/progenitor cells containing all the repopulation potential for normal adult rat liver Gastroenterology 2008 134 823 832 18262526
  35. [36]Tanimizu N Saito H Mostov K Miyajima A Long-term culture of hepatic progenitors derived from mouse Dlk+ hepatoblasts Journal of cell science 2004 117 6425 6434 15572411
  36. [37]Okada K Kamiya A Ito K Yanagida A Ito H Kondou H Prospective isolation and characterization of bipotent progenitor cells in early mouse liver development Stem Cells Dev 2012 21 1124 1133 21861758
  37. [38]Miki R Tatsumi N Matsumoto K Yokouchi Y New primary culture systems to study the differentiation and proliferation of mouse fetal hepatoblasts Am J Physiol Gastrointest Liver Physiol 2008 294 G529 539 18096607
  38. [40]Dan YY Riehle KJ Lazaro C Teoh N Haque J Campbell JS Isolation of multipotent progenitor cells from human fetal liver capable of differentiating into liver and mesenchymal lineages Proceedings of the National Academy of Sciences of the United States of America 2006 103 9912 9917 16782807 PMC1502553
  39. [41]Schmelzer E Zhang L Bruce A Wauthier E Ludlow J Yao HL Human hepatic stem cells from fetal and postnatal donors The Journal of experimental medicine 2007 204 1973 1987 17664288 PMC2118675
  40. [42]Turner R Lozoya O Wang Y Cardinale V Gaudio E Alpini G Human hepatic stem cell and maturational liver lineage biology Hepatology 2011 53 1035 1045 21374667 PMC3066046
  41. [43]Overturf K al-Dhalimy M Ou CN Finegold M Grompe M Serial transplantation reveals the stem-cell-like regenerative potential of adult mouse hepatocytes The American journal of pathology 1997 151 1273 1280 9358753 PMC1858091
  42. [44]Tanaka M Itoh T Tanimizu N Miyajima A Liver stem/progenitor cells: their characteristics and regulatory mechanisms Journal of biochemistry 2011 149 231 239 21217146
  43. [45]Kuwahara R Kofman AV Landis CS Swenson ES Barendswaard E Theise ND The hepatic stem cell niche: identification by label-retaining cell assay Hepatology 2008 47 1994 2002 18454509 PMC2847183
  44. [46]Tanaka M Miyajima A Identification and isolation of adult liver stem/progenitor cells Methods Mol Biol 2012 826 25 32 22167637
  45. [47]Dolle L Best J Empsen C Mei J Van Rossen E Roelandt P Successful isolation of liver progenitor cells by aldehyde dehydrogenase activity in naive mice Hepatology 2012 55 540 552 21953779
  46. [48]Zhang L Theise N Chua M Reid LM The stem cell niche of human livers: symmetry between development and regeneration Hepatology 2008 48 1598 1607 18972441
  47. [49]Wang Y Cui CB Yamauchi M Miguez P Roach M Malavarca R Lineage restriction of human hepatic stem cells to mature fates is made efficient by tissue-specific biomatrix scaffolds Hepatology 2011 53 293 305 21254177
  48. [50]D’Amour KA Agulnick AD Eliazer S Kelly OG Kroon E Baetge EE Efficient differentiation of human embryonic stem cells to definitive endoderm Nature biotechnology 2005 23 1534 1541 16258519
  49. [51]Agius E Oelgeschlager M Wessely O Kemp C De Robertis EM Endodermal Nodal-related signals and mesoderm induction in Xenopus Development 2000 127 1173 1183 10683171 PMC2292107
  50. [52]Duboc V Lapraz F Saudemont A Bessodes N Mekpoh F Haillot E Nodal and BMP2/4 pattern the mesoderm and endoderm during development of the sea urchin embryo Development 2010 137 223 235 20040489
  51. [53]Gadue P Huber TL Paddison PJ Keller GM Wnt and TGF-beta signaling are required for the induction of an in vitro model of primitive streak formation using embryonic stem cells Proc Natl Acad Sci U S A 2006 103 16806 16811 17077151 PMC1636536
  52. [54]Lowe LA Yamada S Kuehn MR Genetic dissection of nodal function in patterning the mouse embryo Development 2001 128 1831 1843 11311163
  53. [55]Bakre MM Hoi A Mong JC Koh YY Wong KY Stanton LW Generation of multipotential mesendodermal progenitors from mouse embryonic stem cells via sustained Wnt pathway activation The Journal of biological chemistry 2007 282 31703 31712 17711862
  54. [57]Robertson EJ Norris DP Brennan J Bikoff EK Control of early anterior-posterior patterning in the mouse embryo by TGF-beta signalling Philosophical transactions of the Royal Society of London Series B, Biological sciences 2003 358 1351 1357 discussion 1357 PMC1693235 14511481
  55. [58]Cheng X Ying L Lu L Galvao AM Mills JA Lin HC Self-renewing endodermal progenitor lines generated from human pluripotent stem cells Cell stem cell 2012 10 371 384 22482503 PMC3580854
  56. [59]Zaret KS Grompe M Generation and regeneration of cells of the liver and pancreas Science 2008 322 1490 1494 19056973 PMC2641009
  57. [60]Sekhon SS Tan X Micsenyi A Bowen WC Monga SP Fibroblast growth factor enriches the embryonic liver cultures for hepatic progenitors The American journal of pathology 2004 164 2229 2240 15161655 PMC1615755
  58. [61]Kamiya AK Miyajima TA Oncostatin M and hepatocyte growth factor induce hepatic maturation via distinct signaling pathways FEBS J 2001 492 11248243
  59. [62]Clotman F Jacquemin P Plumb-Rudewiez N Pierreux CE Van der Smissen P Dietz HC Control of liver cell fate decision by a gradient of TGF beta signaling modulated by Onecut transcription factors Genes Dev 2005 19 1849 1854 16103213 PMC1186184
  60. [63]Schoneveld OJ Gaemers IC Lamers WH Mechanisms of glucocorticoid signalling Biochimica et biophysica acta 2004 1680 114 128 15488991
  61. [64]Aurich I Mueller LP Aurich H Luetzkendorf J Tisljar K Dollinger MM Functional integration of hepatocytes derived from human mesenchymal stem cells into mouse livers Gut 2007 56 405 415 16928726 PMC1856821
  62. [65]Stock P Bruckner S Ebensing S Hempel M Dollinger MM Christ B The generation of hepatocytes from mesenchymal stem cells and engraftment into murine liver Nature protocols 2010 5 617 627 20224562
  63. [66]Aurich H Sgodda M Kaltwasser P Vetter M Weise A Liehr T Hepatocyte differentiation of mesenchymal stem cells from human adipose tissue in vitro promotes hepatic integration in vivo Gut 2009 58 570 581 19022918
  64. [67]Banas A Purification of adipose tissue mesenchymal stem cells and differentiation toward hepatic-like cells Methods Mol Biol 2012 826 61 72 22167640
  65. [68]Agarwal S Holton KL Lanza R Efficient differentiation of functional hepatocytes from human embryonic stem cells Stem Cells 2008 26 1117 1127 18292207
  66. [69]Basma H Soto-Gutierrez A Yannam GR Liu L Ito R Yamamoto T Differentiation and transplantation of human embryonic stem cell-derived hepatocytes Gastroenterology 2009 136 990 999 19026649 PMC2732349
  67. [70]Si-Tayeb K Noto FK Nagaoka M Li J Battle MA Duris C Highly efficient generation of human hepatocyte-like cells from induced pluripotent stem cells Hepatology 2010 51 297 305 19998274 PMC2946078
  68. [72]Huang P He Z Ji S Sun H Xiang D Liu C Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors Nature 2011 475 386 389 21562492
  69. [73]Roelandt P Pauwelyn KA Sancho-Bru P Subramanian K Ordovas L Vanuytsel K Human embryonic and rat adult stem cells with primitive endoderm-like phenotype can be fated to definitive endoderm, and finally hepatocyte-like cells PloS one 5 e12101 20711405 PMC2920330
  70. [74]Zhao D Chen S Cai J Guo Y Song Z Che J Derivation and characterization of hepatic progenitor cells from human embryonic stem cells PloS one 2009 4 e6468 19649295 PMC2714184
  71. [75]Asgari S Moslem M Bagheri-Lankarani K Pournasr B Miryounesi M Baharvand H Differentiation and Transplantation of Human Induced Pluripotent Stem Cell-derived Hepatocyte-like Cells Stem cell reviews 2011 22076752
  72. [76]Iacob R Rudrich U Rothe M Kirsch S Maasoumy B Narain N Induction of a mature hepatocyte phenotype in adult liver derived progenitor cells by ectopic expression of transcription factors Stem cell research 2011 6 251 261 21474405
  73. [77]Takayama K Inamura M Kawabata K Sugawara M Kikuchi K Higuchi M Generation of metabolically functioning hepatocytes from human pluripotent stem cells by FOXA2 and HNF1alpha transduction Journal of hepatology 2012 22659344
  74. [79]Yusa K Rashid ST Strick-Marchand H Varela I Liu PQ Paschon DE Targeted gene correction of alpha1-antitrypsin deficiency in induced pluripotent stem cells Nature 2011 478 391 394 21993621 PMC3198846
  75. [80]Roelandt P Obeid S Paeshuyse J Vanhove J Van Lommel A Nahmias Y Human pluripotent stem cell-derived hepatocytes support complete replication of hepatitis C virus Journal of hepatology 2012 57 246 251 22521345
  76. [81]Schwartz RE Trehan K Andrus L Sheahan TP Ploss A Duncan SA Modeling hepatitis C virus infection using human induced pluripotent stem cells Proceedings of the National Academy of Sciences of the United States of America 2012 109 2544 2548 22308485 PMC3289320
  77. [82]Wu X Robotham JM Lee E Dalton S Kneteman NM Gilbert DM Productive hepatitis C virus infection of stem cell-derived hepatocytes reveals a critical transition to viral permissiveness during differentiation PLoS pathogens 2012 8 e1002617 22496645 PMC3320597
  78. [83]Yoshida T Takayama K Kondoh M Sakurai F Tani H Sakamoto N Use of human hepatocyte-like cells derived from induced pluripotent stem cells as a model for hepatocytes in hepatitis C virus infection Biochemical and biophysical research communications 2011 416 119 124 22093821
  79. [84]Cayo MA Cai J Delaforest A Noto FK Nagaoka M Clark BS JD induced pluripotent stem cell-derived hepatocytes faithfully recapitulate the pathophysiology of familial hypercholesterolemia Hepatology 2012 PMC3900031 22653811
  80. [85]Cameron CM Hu WS Kaufman DS Improved development of human embryonic stem cell-derived embryoid bodies by stirred vessel cultivation Biotechnol Bioeng 2006 94 938 948 16547998
  81. [86]Park Y Subramanian K Verfaillie CM Hu WS Expansion and hepatic differentiation of rat multipotent adult progenitor cells in microcarrier suspension culture Journal of biotechnology 2010 150 131 139 20696191
  82. [88]Sharma S Raju R Sui S Hu WS Stem cell culture engineering - process scale up and beyond Biotechnology journal 2011 6 1317 1329 21721127
  83. [89]Serra M Brito C Correia C Alves PM Process engineering of human pluripotent stem cells for clinical application Trends in biotechnology 2012 30 350 359 22541338
  84. [90]Ratcliffe E Thomas RJ Williams DJ Current understanding and challenges in bioprocessing of stem cell-based therapies for regenerative medicine British medical bulletin 2011 100 137 155 21852279

Cited by

Sorted by citations

Authors
Raju, R., Chau, D., Verfaillie, C. M., & Hu, W.-S.
Affiliations
University of Minnesota (US)
Corresponding author
Hu, Wei-Shou
ORCID
Venue
Biotechnology Advances
Publisher
Elsevier BV
Published
2013-11
Volume
31
Issue
7
Pages
1085-1093
ISSN
0734-9750 (ISSN-L)
DOI
10.1016/j.biotechadv.2013.08.022
PMC
PMC4079080
OpenAlex
W1964661419
Cited by
14
References
5
Citations by year
2026: 1 · 2024: 1 · 2023: 1 · 2019: 1 · 2017: 1 · 2016: 2 · 2015: 1 · 2014: 5 · 2013: 1
FWCI
0.28
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Biotechnology Advances (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Lirias (submittedVersion)
Funders
  • NIH (GM08347)
  • FP7-IP-HeMiBio
  • IWT-SBO
  • HEPSTEM
  • FWO
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
Keywords
liver regeneration, hepatocyte transplantation, pluripotent stem cells, induced pluripotent stem cells, hepatocyte differentiation, hepatic progenitor cells, hepatoblasts, stem cell-derived hepatocytes, cell therapy, clinical translation
MeSH terms
Animals, Biotechnology, Cell Differentiation, Humans, Liver, Liver Regeneration, Stem Cells, Hepatocytes, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review