Skip to main content
Log in

Development of hepatic tissue engineering

  • Review Article
  • Published:
Pediatric Surgery International Aims and scope Submit manuscript

Abstract

Liver transplantation is still the only treatment for end-staged liver diseases in children. However, donor organ shortage and immunosuppression are major limitations. Thus, approaches of hepatocyte transplantation are under investigation. Using cells might permit mass expansion, cryopreservation, and the ex vivo genetic modification of cells. For the development of cell-transplantation techniques, the use of three-dimensional scaffolds as carrier was shown to be advantageous. Polymeric matrices permit the formation of a neo-tissue and stimulation by the modification of the matrix surface. Another important issue is to define the right cell type for transplantation. Adult hepatocytes have a limited growth and differentiation potential. In contrast, fetal liver cells (FLC) possess an enormous growth and a bipotential differentiation potential. Thus, these cells may be very attractive as a cell resource for developing cell-based liver replacement. A third major issue in this approach is the neo-vascularization. Therefore, the transplantation in a recently developed model using a microsurgically created arterioveno-venous (AV) loop as a central vessel for the neo-tissue was used for transplantation of FLC in a fibrin-matrix. Initial results indicated that the transplantation of FLC using the AV-loop transplantation model may be promising for the development of highly vascularized in vivo tissue-engineered liver support systems.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Schiff L, Schiff E (eds) (1993) Diseases of the liver, 1st edn. J.B. Lippincott, Philadelphia

    Google Scholar 

  2. Harper AM, Rosendale JD (1996) The UNOS OPTN waiting list and donor registry: 1988–1996. Clin Transplant 10:69–90

    Google Scholar 

  3. Argawal A, Pescovitz MD (2006) Immunosuppression in pediatric solid organ transplantation. Semin Pediatr Surg 15:142–152. doi:10.1053/j.sempedsurg.2006.03.002

    Article  Google Scholar 

  4. Otte JB, de Goyet J, Sokal E et al (1990) Size reduction of donor liver is a safe way to alleviate the shortage of size-matched organs in pediatric liver transplantation. Ann Surg 211:146–157. doi:10.1097/00000658-199002000-00006

    Article  PubMed  CAS  Google Scholar 

  5. UNOS-Database http://www.unos.org/data, 03/2008

  6. Raper SE (1995) Hepatocyte transplantation and gene therapy. Clin Transplant 9:249–254

    PubMed  CAS  Google Scholar 

  7. Smets F, Najimi M, Sokal EM (2008) Cell transplantation in the treatment of liver diseases. Pediatr Transplant 12:6–13

    PubMed  CAS  Google Scholar 

  8. Tiao GM, Alonso MH, Ryckman FC (2006) Pediatric liver transplantation. Semin Pediatr Surg 15:218–227. doi:10.1053/j.sempedsurg.2006.03.008

    Article  PubMed  Google Scholar 

  9. Asonuma K, Gilbert JC, Stein JE, Takeda T, Vacanti JP (1992) Quantitation of transplanted hepatic mass necessary to cure the gunn rat model of hyperbilirubinemia. J Pediatr Surg 27:298–301. doi:10.1016/0022-3468(92)90850-7

    Article  PubMed  CAS  Google Scholar 

  10. Bianco P, Robey PG (2001) Stem cells in tissue engineering. Nature 414:118–121. doi:10.1038/35102181

    Article  PubMed  CAS  Google Scholar 

  11. Malhi H, Gupta S (2001) Hepatocyte transplantation: new horizons and challenges. J Hepatobiliary Pancreat Surg 8:40–50. doi:10.1007/s005340170049

    Article  PubMed  CAS  Google Scholar 

  12. Kaufmann PM, Sano K, Uyama S, Schloo B, Vacanti JP (1994) Heterotopic hepatocyte transplantation using three dimensional polymers: evaluation of the stimulatory effects by portocaval shunt or islet cell cotransplantation. Transplant Proc 26:3343–3345

    PubMed  CAS  Google Scholar 

  13. Fox IJ, Chowdhury JR, Kaufmann SS, Goetzen TC, Chowdhury NR, Warkentin PI, Dorko K, Sauter BV, Strom SC (1998) Treatment of the Crigler–Najjar syndrome type I with hepatocyte transplantation. N Engl J Med 338:1422–1426. doi:10.1056/NEJM199805143382004

    Article  PubMed  CAS  Google Scholar 

  14. Muraca M, Gerunda G, Neri D, Vilei MT, Granato A, Feltracco P, Meroni M, Giron G, Burlino AB (2002) Hepatocyte transplantation as a treatment for glycogen storage disease type Ia. Lancet 359:317–318. doi:10.1016/S0140-6736(02)07529-3

    Article  PubMed  Google Scholar 

  15. Nieto JA, Escandon J, Betancor C, Ramos J, Canton C, Cuervas-Mons V (1989) Evidence that temporary complete occlusion of splenic vessels prevents massive embolization and sudden death associated with intrasplenic hepatocellular transplantation. Transplantation 47:449–450. doi:10.1097/00007890-198903000-00009

    Article  PubMed  CAS  Google Scholar 

  16. Schneider A, Attaran M, Gratz KF, Bleck JS, Winkler M, Manns MP, Ott M (2003) Intraportal infusion of 99m technetium macro aggregated albumin particles and hepatocytes in rabbits: assessment of shunting and portal hemodynamic changes. Transplantation 75:296–302. doi:10.1097/01.TP.0000044454.43076.7B

    Article  PubMed  CAS  Google Scholar 

  17. Xiandong W, Ar’Rajab A, Ahren B, Andersson R, Bengmark S (1992) The effect of pancreatic islets on transplanted hepatocytes in the treatment of acute liver failure in rats. Res Exp Med (Berl) 191:429–435. doi:10.1007/BF02576698

    Article  Google Scholar 

  18. Demetriou AA, Whiting JF, Feldman D, Levenson SM, Chowdhury NR, Moscioni AD, Kram M, Chowdhury JR (1986) Replacement of liver function in rats by transplantation of microcarrier attached hepatocytes. Science 233:1190–1192. doi:10.1126/science.2426782

    Article  PubMed  CAS  Google Scholar 

  19. Mooney D, Hansen L, Vacanti J, Langer R, Farmer S, Ingber D (1992) Switching from differentiation to growth in hepatocytes: control by extracellular matrix. J Cell Physiol 151:497–505. doi:10.1002/jcp.1041510308

    Article  PubMed  CAS  Google Scholar 

  20. Mooney DJ, Park S, Kaufmann PM, Sano K, McNamara K, Vacanti JP, Langer R (1995) Biodegradable sponges for hepatocyte transplantation. J Biomed Mater Res 29:959–965. doi:10.1002/jbm.820290807

    Article  PubMed  CAS  Google Scholar 

  21. Kaufmann PM, Heimrath S, Kim BD, Mooney DJ (1997) Highly porous polymer matrices as three dimensional culture system for hepatocytes. Cell Transplant 6:463–468. doi:10.1016/S0963-6897(97)00052-3

    Article  PubMed  CAS  Google Scholar 

  22. Lee H, Cusick RA, Browne F, Kim TH, Ma PX, Utsunomiya H, Langer R, Vacanti JP (2002) Local delivery of basic fibroblast growth factor increases both angiogenesis and engraftment of hepatocytes in tissue-engineered polymer devices. Transplantation 73:1589–1593. doi:10.1097/00007890-200205270-00011

    Article  PubMed  CAS  Google Scholar 

  23. Fiegel HC, Havers J, Kneser U, Smith MK, Moeller T, Kluth D, Mooney DJ, Rogiers X, Kaufmann PM (2004) Influence of flow conditions and matrix coatings on growth and differentiation of three-dimensionally cultured rat hepatocytes. Tissue Eng 10:165–174. doi:10.1089/107632704322791817

    Article  PubMed  CAS  Google Scholar 

  24. Kneser U, Kaufmann PM, Fiegel HC et al (1999) Heterotopic hepatocyte transplantation utilizing pancreatic islet cotransplantation for hepatotrophic stimulation: morphologic and morphometric evaluation. Pediatr Surg Int 15:168–174. doi:10.1007/s003830050547

    Article  PubMed  CAS  Google Scholar 

  25. Uyama S, Kaufmann PM, Takeda T, Vacanti JP (1993) Delivery of whole liver-equivalent hepatocyte mass using polymer devices and hepatotrophic stimulation. Transplantation 55:932–935

    PubMed  CAS  Google Scholar 

  26. Kneser U, Kaufmann PM, Fiegel HC et al (1999) Long-term differentiated function of heterotopically transplanted hepatocytes on three dimensional polymer matrices. J Biomed Mater Res 47:494–503. doi:10.1002/(SICI)1097-4636(19991215)47:4<494::AID-JBM5>3.0.CO;2-L

    Article  PubMed  CAS  Google Scholar 

  27. Uyama S, Kaufmann PM, Kneser U, Fiegel HC et al (2001) Hepatocyte transplantation using biodegradable matrices in ascorbic acid-deficient rats: comparison with heterotopically transplanted liver grafts. Transplant 71:1226–1231. doi:10.1097/00007890-200105150-00008

    Article  CAS  Google Scholar 

  28. Berthiaume F, Moghe PV, Toner M, Yarmush ML (1996) Effect of extracellular matrix topology on cell structure, function, and physiological responsiveness: hepatocytes cultured in a sandwich configuration. FASEB J 10:1471–1484

    PubMed  CAS  Google Scholar 

  29. Block GD, Locker J, Bowen WC, Petersen BE, Katyal S, Strom SC, Riley T, Howard TA, Michalopoulos GK (1996) Population expansion, clonal growth, and specific differentiation patterns in primary cultures of hepatocytes induced by hgf/sf, egf and tgf alpha in a chemically defined (HGM) medium. J Cell Biol 132:1133–1149. doi:10.1083/jcb.132.6.1133

    Article  PubMed  CAS  Google Scholar 

  30. Reid LM (1990) Stem cell biology, hormone/matrix synergies and liver differentiation. Curr Opin Cell Biol 2:121–130. doi:10.1016/S0955-0674(05)80042-0

    Article  PubMed  CAS  Google Scholar 

  31. Guguen-Guillouzo C, Clément B, Baffet G, Beaumont C, Morel-Chany E, Glaise D, Guillouzo A (1983) Maintenance and reversibility of active albumin secretion by adult rat hepatocytes co-cultured with another liver epithelial cell type. Exp Cell Res 143:47–54. doi:10.1016/0014-4827(83)90107-6

    Article  PubMed  CAS  Google Scholar 

  32. Shimaoka S, Nakamura T, Ichihara A (1987) Stimulation of growth of primary cultured adult rat hepatocytes without growth factors by coculture with nonparenchymal liver cells. Exp Cell Res 172:228–242. doi:10.1016/0014-4827(87)90109-1

    Article  PubMed  CAS  Google Scholar 

  33. Bhatia SN, Balis UJ, Yarmush ML, Toner M (1999) Effect of cell–cell interactions in preservation of cellular phenotype: cocultivation of hepatocytes and nonparenchymal cells. FASEB J 13:1883–1900

    PubMed  CAS  Google Scholar 

  34. Mizuguchi T, Hui T, Palm K, Sugiyama N, Mitaka T, Demetriou AA, Rozga J (2001) Enhanced proliferation and differentiation of rat hepatocytes cultured with bone marrow stromal cells. J Cell Physiol 189:106–119. doi:10.1002/jcp.1136

    Article  PubMed  CAS  Google Scholar 

  35. Rozga J, Williams F, Ro MS, Neuzil DF, Giorgio TD, Backfisch G, Moscioni AD, Hakim R, Demetriou AA (1993) Development of a bioartificial liver: properties and function of a hollow-fiber module inoculated with liver cells. Hepatology 17:258–265

    Article  PubMed  CAS  Google Scholar 

  36. Suzuki A, Zheng YW, Kondo R, Kusakabe M, Takada Y, Fukao K, Nakauchi H, Taniguchi H (2000) Flow-cytometric separation and enrichment of hepatic progenitor cells in the developing mouse liver. Hepatology 32:1230–1239. doi:10.1053/jhep.2000.20349

    Article  PubMed  CAS  Google Scholar 

  37. Taniguchi H, Suzuki A, Zheng Y, Kondo R, Takada Y, Fukunaga K, Seino K, Yuzawa K, Otsuka M, Fukao K, Nakauchi H (2000) Usefulness of flow-cytometric cell sorting for the enrichment of hepatic stem and progenitor cells in the liver. Transplant Proc 32:249–251. doi:10.1016/S0041-1345(99)00947-1

    Article  PubMed  CAS  Google Scholar 

  38. Suzuki A, Zheng YW, Kaneko S, Onodera M, Kukao K, Nakauchi H, Taniguchi H (2002) Clonal identification and characterization of self-renewing pluripotent stem cells in the developing liver. J Cell Biol 156:173–184. doi:10.1083/jcb.200108066

    Article  PubMed  CAS  Google Scholar 

  39. Dabeva MD, Petkov PM, Sandhu J, Oren R, Laconi E, Hurston E, Shafritz DA (2000) Proliferation and differentiation of fetal liver epithelial progenitor cells after transplantation in the rat liver. Am J Pathol 156:2017–2031

    PubMed  CAS  Google Scholar 

  40. Sandhu JS, Petkov PM, Dabeva MD, Shafritz DA (2001) Stem cell properties and repopulation of the rat liver by fetal liver epithelial progenitor cells. Am J Pathol 159:1323–1334

    PubMed  CAS  Google Scholar 

  41. Nierhoff D, Ogawa A, Oertel M, Chen YQ, Shafritz DA (2005) Purification and characterization of mouse fetal liver epithelial cells with high in vivo repopulation capacity. Hepatology 42:130–139. doi:10.1002/hep.20735

    Article  PubMed  Google Scholar 

  42. Fiegel HC, Park JH, Lioznov MV, Martin A, Jaeschke-Melli S, Kaufmann PM, Fehse B, Zander AR, Kluth D (2003) Characterization of cell types during rat liver development. Hepatology 37:148–154. doi:10.1053/jhep.2003.50007

    Article  PubMed  Google Scholar 

  43. Thorgeirsson SS (1996) Liver regeneration 9: hepatic stem cells in liver regeneration. FASEB J 10:1249–1256

    PubMed  CAS  Google Scholar 

  44. Michalopoulos GK, DeFrances MC (1997) Liver regeneration. Science 276:60–66. doi:10.1126/science.276.5309.60

    Article  PubMed  CAS  Google Scholar 

  45. Strain AJ, Crosby HA (2000) Hepatic stem cells. Gut 46:743–745. doi:10.1136/gut.46.6.743

    Article  PubMed  CAS  Google Scholar 

  46. Vessey CJ, de la Hall PM (2001) Hepatic stem cells. Pathology 33:130–141. doi:10.1080/00313020120038719

    Article  PubMed  CAS  Google Scholar 

  47. Haruna Y, Saito K, Spaulding S, Nalesnik MA, Gerber MA (1996) Identification of bipotential progenitor cells in human liver development. Hepatology 23:476–481. doi:10.1002/hep.510230312

    Article  PubMed  CAS  Google Scholar 

  48. Lazaro CA, Rhim JA, Yamada Y, Fausto N (1998) Generation of hepatocytes from oval cell precursors in culture. Cancer Res 58:5514–5522

    PubMed  CAS  Google Scholar 

  49. Evarts RP, Nagy P, Marsden E, Thorgeirsson SS (1993) A precursor-product relationship exists between oval cells and hepatocytes in rat liver. Carcinogenesis 8:1737–1740. doi:10.1093/carcin/8.11.1737

    Article  Google Scholar 

  50. Thorgeirsson SS, Evarts RP, Bisgaard HC, Fujio K, Hu Z (1993) Hepatic stem cell compartment: activation and lineage commitment. Proc Soc Exp Biol Med 204:253–260

    PubMed  CAS  Google Scholar 

  51. Petersen BE, Zajak VF, Michalopoulos GK (1998) Hepatic oval cell activation in response to injury following chemically induced periportal or pericentral damage in rats. Hepatology 27:1030–1038. doi:10.1002/hep.510270419

    Article  PubMed  CAS  Google Scholar 

  52. Fiegel HC, Kluth J, Lioznov MV et al (2003) Hepatic lineages isolated from developing rat liver show different ways of maturation. Biochem Biophys Res Commun 305:46–53. doi:10.1016/S0006-291X(03)00662-4

    Article  PubMed  CAS  Google Scholar 

  53. Fiegel HC, Bruns H, Höper C et al (2006) Cell growth and differentiation of different hepatic cells isolated from fetal rat livers in vitro. Tissue Eng 12:123–130. doi:10.1089/ten.2006.12.123

    Article  PubMed  CAS  Google Scholar 

  54. Oertel M, Menthena A, Chen YQ, Shafritz DA (2007) Comparison of hepatic properties and transplantation of Thy1+ and Thy1− cells isolated from embryonic day 14 rat fetal liver. Hepatology 46:1236–1245. doi:10.1002/hep.21775

    Article  PubMed  CAS  Google Scholar 

  55. McLaren A (2001) Ethical and social considerations of stem cell research. Nature 414:129–131. doi:10.1038/35102194

    Article  PubMed  CAS  Google Scholar 

  56. Kaufmann PM, Kneser U, Fiegel HC, Kluth D, Herbst H, Rogiers X (1999) Long-term hepatocyte transplantation using three-dimensional matrices. Transplant Proc 31:1928–1929. doi:10.1016/S0041-1345(99)00208-0

    Article  PubMed  CAS  Google Scholar 

  57. Johnson LB, Aiken J, Mooney D, Schloo BL, Griffith-Cima L, Langer R, Vacanti JP (1994) The mesentery as a laminated vascular bed for hepatocyte transplantation. Cell Transplant 3:273–281

    PubMed  Google Scholar 

  58. Mooney DJ, Sano K, Kaufmann PM, Majahod K, Schloo B, Vacanti JP, Langer R (1997) Long-term engraftment of hepatocytes transplanted on biodegradable polymer sponges. J Biomed Mater Res 37:413–420. doi:10.1002/(SICI)1097-4636(19971205)37:3<413::AID-JBM12>3.0.CO;2-C

    Article  PubMed  CAS  Google Scholar 

  59. Harley HA, Morgan T, Redeker AG, Reynolds TB, Villamil F, Weiner JF, Yellin A (1986) Results of a randomized trial of end-to-side portacaval shunt and distal splenorenal shunt in alcoholic liver disease and variceal bleeding. Gastroenterology 91:802–809

    PubMed  CAS  Google Scholar 

  60. Fiegel HC, Pryymachuk G, Rath S, Bleiziffer O, Beier JP, Bruns H, Kluth D, Metzger R, Horch RE, Till H, Kneser U (2008) Fetal hepatocyte transplantation in a vascularised AV-loop transplantation model in the rat. JCMM (in press). doi:10.1111/j.1582-4934.2008.00369.x

  61. Gilbert JC, Takada T, Stein JE, Langer R, Vacanti JP (1993) Cell transplantation of genetically altered cells on biodegradable polymer scaffolds in syngeneic rats. Transplantation 56:423–427

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Mrs. G. Pryymachuk, Mrs. G. Scholz, and the medical student Mrs. K. Straßburger for technical assistance.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Henning Cornelius Fiegel.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fiegel, H.C., Kneser, U., Kluth, D. et al. Development of hepatic tissue engineering. Pediatr Surg Int 25, 667–673 (2009). https://doi.org/10.1007/s00383-009-2389-8

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00383-009-2389-8

Keywords

Navigation