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DSC-Differentiated Hepatocytes for Treatment of Liver Diseases

  • Francesco Paduano
  • Massimo Marrelli
  • Akhilesh K. Gaharwar
  • Marco Tatullo
Chapter
Part of the Stem Cell Biology and Regenerative Medicine book series (STEMCELL)

Abstract

Dental stem cells (DSCs) can generate hepatic-like cells and represent a promising therapeutic approach for the treatment of patients suffering from liver disease such as cirrhosis and acute hepatic injury (AHF). A range of studies showed successful differentiation of DSCs into hepatocyte-like cells, demonstrating that the dental stem/progenitor cells of dental tissue. The progenitor cells isolated from dental pulp (DPSCs) and exfoliated deciduous teeth (SHEDs), under specific stimuli, are able to express hepatic specific markers, and most importantly, can engraft functionally into murine and rat models of liver injury. Furthermore, other reports demonstrated that DSCs can be reprogrammed into induced pluripotent stem cells (DP-iPSCs), and then successfully differentiated into hepatocyte-like cells (DP-iPSC-Heps) having characteristics of mature hepatocytes. The engraftment of DP-iPSC-Heps in immunocompromised AHF mouse model can be improved by the additional use of scaffolds that release hepatocyte growth factor (HGF) or liver-specific microRNA122 (miR122). This chapter shows that DSCs are a good candidate to generate hepatocyte-like cells and dental pulp-derived iPSCs-differentiated hepatocytes (DP-iPSCs-Heps) and demonstrates that they could be considered an optimal cell source for liver cell therapy.

Keywords

Dental stem cells (DSCs) Hepatocyte-like cells Hepatic differentiation 

Abbreviations

ADSCs

Adipose stem cells

AHF

Acute hepatic failure

ALB

Albumin

ALF

Acute liver failure

ALT

Alanine aminotransferase

AST

Aminotransferase

BM-MSCs

Bone marrow stem cells

CHC

Carboxymethyl-hexanol chitosan

CHC/PU-miR122

miR122 complexed with PU-PEI in nanostructured CHC

CK-18

Cytokeratin 18

CPS-1

Carbamoyl phosphate synthetase

Dex

Dexamethasone

DP-iPSC-Heps

Hepatocytes-like cells from dental pulp derived-iPSCs

DP-iPSCs

Dental pulp-derived iPSC

DPSCs

Dental pulp stem cells

DSCs

Dental stem cells

DTCPs

Deciduous tooth pulp cells

EGF

Epidermal growth factor

ESC-Heps

Embryonyc stem cell-derived hepatocytes

ESCs

Embryonic stem cells

ETF

Embryotrophic factor

FBS

Fetal bovine serum

FGF-1

Fibroblast growth factor 1

HCC

Hepatocellular carcinoma

HCV

Hepatitis C virus

hdSHED

Human hepatically differentiated SHED

HGF

Hepatocyte growth factor

HTCP

Tooth-pulp stem cells

IL-6

Interleukin 6

iPSC-Heps

iPSCs-derived hepatocyte-like cells

iPSCs

Induced pluripotent stem cells

ITS

Insulin-transferrin selenium

MAPS

Multipotent adult progenitor cells

miR122

MicroRNA122

OSM

Oncostatin M

PU-PEI

Polyurethane-graft-short-branch polyethylenimine copolymer

SHED

Exfoliated deciduous teeth stem cells

STAT3

Signal transducer and activator of transcription 3

TAA

Thioacetamide

TGPCs

Tooth germ progenitor cells

WJ-MSCs

Wharton’s jelly-derived MSCs

WTPCs

Wisdom tooth pulp cells

α-FP

Alpha-fetoprotein

References

  1. 1.
    Liu W, Song F, Ren L et al (2015) The multiple functional roles of mesenchymal stem cells in participating in treating liver diseases. J Cell Mol Med 19:511–520. doi: 10.1111/jcmm.12482 CrossRefPubMedGoogle Scholar
  2. 2.
    Karidis NP, Delladetsima I, Theocharis S (2015) Hepatocyte turnover in chronic HCV-induced liver injury and cirrhosis. Gastroenterol Res Pract 2015:654105. doi: 10.1155/2015/654105 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Lam BP, Jeffers T, Younoszai Z et al (2015) The changing landscape of hepatitis C virus therapy: focus on interferon-free treatment. Ther Adv Gastroenterol 8:298–312. doi: 10.1177/1756283X15587481 CrossRefGoogle Scholar
  4. 4.
    Ikeda E, Yagi K, Kojima M et al (2008) Multipotent cells from the human third molar: feasibility of cell-based therapy for liver disease. Differentiation 76:495–505. doi: 10.1111/j.1432-0436.2007.00245.x CrossRefPubMedGoogle Scholar
  5. 5.
    Nussler A, Konig S, Ott M et al (2006) Present status and perspectives of cell-based therapies for liver diseases. J Hepatol 45:144–159. doi: 10.1016/j.jhep.2006.04.002 CrossRefPubMedGoogle Scholar
  6. 6.
    Baharvand H, Hashemi SM, Kazemi Ashtiani S, Farrokhi A (2006) Differentiation of human embryonic stem cells into hepatocytes in 2D and 3D culture systems in vitro. Int J Dev Biol 50:645–652. doi: 10.1387/ijdb.052072hb CrossRefPubMedGoogle Scholar
  7. 7.
    Ye J-S, Su X-S, Stoltz J-F et al (2015) Signalling pathways involved in the process of mesenchymal stem cells differentiating into hepatocytes. Cell Prolif 48:157–165. doi: 10.1111/cpr.12165 CrossRefPubMedGoogle Scholar
  8. 8.
    Pournasr B, Mohamadnejad M, Bagheri M et al (2011) In vitro differentiation of human bone marrow mesenchymal stem cells into hepatocyte-like cells. Arch Iran Med 14:244–249. doi:0011144/AIM.004Google Scholar
  9. 9.
    Lee JH, Lee KH, Kim MH et al (2012) Possibility of undifferentiated human thigh adipose stem cells differentiating into functional hepatocytes. Arch Plast Surg 39:593–599. doi: 10.5999/aps.2012.39.6.593 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Prasajak P, Leeanansaksiri W (2013) Developing a new two-step protocol to generate functional hepatocytes from Wharton’s jelly-derived mesenchymal stem cells under hypoxic condition. Stem Cells Int 2013:762196. doi: 10.1155/2013/762196 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Miki T, Lehmann T, Cai H et al (2005) Stem cell characteristics of amniotic epithelial cells. Stem Cells 23:1549–1559. doi: 10.1634/stemcells.2004-0357
  12. 12.
    Mohamadnejad M, Alimoghaddam K, Mohyeddin-Bonab M et al (2007) Phase 1 trial of autologous bone marrow mesenchymal stem cell transplantation in patients with decompensated liver cirrhosis. Arch Iran Med 10:459–466. doi:07104/AIM.008Google Scholar
  13. 13.
    Kharaziha P, Hellström PM, Noorinayer B et al (2009) Improvement of liver function in liver cirrhosis patients after autologous mesenchymal stem cell injection: a phase I-II clinical trial. Eur J Gastroenterol Hepatol 21:1199–1205. doi: 10.1097/MEG.0b013e32832a1f6c CrossRefPubMedGoogle Scholar
  14. 14.
    El-Ansary M, Abdel-Aziz I, Mogawer S et al (2012) Phase II trial: undifferentiated versus differentiated autologous mesenchymal stem cells transplantation in Egyptian patients with HCV induced liver cirrhosis. Stem Cell Rev 8:972–981. doi: 10.1007/s12015-011-9322-y CrossRefPubMedGoogle Scholar
  15. 15.
    Yamaza T, Kentaro A, Chen C et al (2010) Immunomodulatory properties of stem cells from human exfoliated deciduous teeth. Stem Cell Res Ther 1:5. doi: 10.1186/scrt5 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Ma L, Makino Y, Yamaza H et al (2012) Cryopreserved dental pulp tissues of exfoliated deciduous teeth is a feasible stem cell resource for regenerative medicine. PLoS One 7, e51777. doi: 10.1371/journal.pone.0051777 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Ishkitiev N, Yaegaki K, Imai T et al (2012) High-purity hepatic lineage differentiated from dental pulp stem cells in serum-free medium. J Endod 38:475–480. doi: 10.1016/j.joen.2011.12.011 CrossRefPubMedGoogle Scholar
  18. 18.
    Ferro F, Spelat R, D’Aurizio F et al (2012) Dental pulp stem cells differentiation reveals new insights in Oct4A dynamics. PLoS One 7, e41774. doi: 10.1371/journal.pone.0041774 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Ishkitiev N, Calenic B, Aoyama I et al (2012) Hydrogen sulfide increases hepatic differentiation in tooth-pulp stem cells. J Breath Res 6:017103. doi: 10.1088/1752-7155/6/1/017103 CrossRefPubMedGoogle Scholar
  20. 20.
    Yamaza T, Alatas FS, Yuniartha R et al (2015) In vivo hepatogenic capacity and therapeutic potential of stem cells from human exfoliated deciduous teeth in liver fibrosis in mice. Stem Cell Res Ther 6:171. doi: 10.1186/s13287-015-0154-6 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Ishkitiev N, Yaegaki K, Imai T et al (2015) Novel management of acute or secondary biliary liver conditions using hepatically differentiated human dental pulp cells. Tissue Eng Part A 21:586–593. doi: 10.1089/ten.TEA.2014.0162 CrossRefPubMedGoogle Scholar
  22. 22.
    Ishkitiev N, Yaegaki K, Calenic B et al (2010) Deciduous and permanent dental pulp mesenchymal cells acquire hepatic morphologic and functional features in vitro. J Endod 36:469–474. doi: 10.1016/j.joen.2009.12.022 CrossRefPubMedGoogle Scholar
  23. 23.
    Chen YK, Huang AHC, Chan AWS, Lin LM (2013) Human dental pulp stem cells derived from cryopreserved dental pulp tissues of vital extracted teeth with disease demonstrate hepatic-like differentiation. J Tissue Eng Regen Med. doi: 10.1002/term.1763 PubMedCentralGoogle Scholar
  24. 24.
    Okada M, Ishkitiev N, Yaegaki K et al (2014) Hydrogen sulphide increases hepatic differentiation of human tooth pulp stem cells compared with human bone marrow stem cells. Int Endod J 47:1142–1150. doi: 10.1111/iej.12262 CrossRefPubMedGoogle Scholar
  25. 25.
    Cho Y-A, Noh K, Jue S-S et al (2015) Melatonin promotes hepatic differentiation of human dental pulp stem cells: clinical implications for the prevention of liver fibrosis. J Pineal Res 58:127–135. doi: 10.1111/jpi.12198 CrossRefPubMedGoogle Scholar
  26. 26.
    Sun G-Y, Dong L-Y, An W (2014) Involvement of hepatic stimulator substance in the regulation of hepatoblast maturation into hepatocytes in vitro. Stem Cells Dev 23:1675–1687. doi: 10.1089/scd.2013.0468 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Schwartz RE, Reyes M, Koodie L et al (2002) Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells. J Clin Invest 109:1291–1302. doi: 10.1172/JCI15182 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Kang X-Q, Zang W-J, Bao L-J et al (2005) Fibroblast growth factor-4 and hepatocyte growth factor induce differentiation of human umbilical cord blood-derived mesenchymal stem cells into hepatocytes. World J Gastroenterol 11:7461–7465CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Neuss S, Becher E, Wöltje M et al (2004) Functional expression of HGF and HGF receptor/c-met in adult human mesenchymal stem cells suggests a role in cell mobilization, tissue repair, and wound healing. Stem Cells 22:405–414. doi: 10.1634/stemcells.22-3-405 CrossRefPubMedGoogle Scholar
  30. 30.
    Oyagi S, Hirose M, Kojima M et al (2006) Therapeutic effect of transplanting HGF-treated bone marrow mesenchymal cells into CCl4-injured rats. J Hepatol 44:742–748. doi: 10.1016/j.jhep.2005.10.026 CrossRefPubMedGoogle Scholar
  31. 31.
    Kosai K, Matsumoto K, Nagata S et al (1998) Abrogation of Fas-induced fulminant hepatic failure in mice by hepatocyte growth factor. Biochem Biophys Res Commun 244:683–690CrossRefPubMedGoogle Scholar
  32. 32.
    Burr AW, Toole K, Chapman C et al (1998) Anti-hepatocyte growth factor antibody inhibits hepatocyte proliferation during liver regeneration. J Pathol 185:298–302. doi: 10.1002/(SICI)1096-9896(199807)185:3<298::AID-PATH88>3.0.CO;2-B CrossRefPubMedGoogle Scholar
  33. 33.
    Salehinejad P, Alitheen NB, Mandegary A et al (2013) Effect of EGF and FGF on the expansion properties of human umbilical cord mesenchymal cells. In Vitro Cell Dev Biol Anim 49:515–523. doi: 10.1007/s11626-013-9631-3 CrossRefPubMedGoogle Scholar
  34. 34.
    Doetzlhofer A, White PM, Johnson JE et al (2004) In vitro growth and differentiation of mammalian sensory hair cell progenitors: a requirement for EGF and periotic mesenchyme. Dev Biol 272:432–447. doi: 10.1016/j.ydbio.2004.05.013 CrossRefPubMedGoogle Scholar
  35. 35.
    Lin N, Lin J, Bo L et al (2010) Differentiation of bone marrow-derived mesenchymal stem cells into hepatocyte-like cells in an alginate scaffold. Cell Prolif 43:427–434. doi: 10.1111/j.1365-2184.2010.00692.x CrossRefPubMedGoogle Scholar
  36. 36.
    Teramoto T, Matsunaga T, Toba M et al (2009) Role of dexamethasone and oncostatin M on the formation of vacuoles in human fetal liver cells. Biol Pharm Bull 32:209–212CrossRefPubMedGoogle Scholar
  37. 37.
    Das ZC, Gupta MK, Uhm SJ, Lee HT (2014) Supplementation of insulin-transferrin-selenium to embryo culture medium improves the in vitro development of pig embryos. Zygote 22:411–418. doi: 10.1017/S0967199412000731 CrossRefPubMedGoogle Scholar
  38. 38.
    Al-Adsani A, Burke ZD, Eberhard D et al (2010) Dexamethasone treatment induces the reprogramming of pancreatic acinar cells to hepatocytes and ductal cells. PLoS One 5, e13650. doi: 10.1371/journal.pone.0013650 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Ishiwata I, Tokieda Y, Kiguchi K et al (2000) Effects of embryotrophic factors on the embryogenesis and organogenesis of mouse embryos in vitro. Hum Cell 13:185–195PubMedGoogle Scholar
  40. 40.
    Liang H, Block TM, Wang M et al (2012) Interleukin-6 and oncostatin M are elevated in liver disease in conjunction with candidate hepatocellular carcinoma biomarker GP73. Cancer Biomark 11:161–171. doi: 10.3233/CBM-2012-00276 PubMedPubMedCentralGoogle Scholar
  41. 41.
    Kamiya A, Kinoshita T, Miyajima A (2001) Oncostatin M and hepatocyte growth factor induce hepatic maturation via distinct signaling pathways. FEBS Lett 492:90–94CrossRefPubMedGoogle Scholar
  42. 42.
    Sidhu JS, Liu F, Omiecinski CJ (2004) Phenobarbital responsiveness as a uniquely sensitive indicator of hepatocyte differentiation status: requirement of dexamethasone and extracellular matrix in establishing the functional integrity of cultured primary rat hepatocytes. Exp Cell Res 292:252–264CrossRefPubMedGoogle Scholar
  43. 43.
    Hong SH, Gang EJ, Jeong JA et al (2005) In vitro differentiation of human umbilical cord blood-derived mesenchymal stem cells into hepatocyte-like cells. Biochem Biophys Res Commun 330:1153–1161. doi: 10.1016/j.bbrc.2005.03.086 CrossRefPubMedGoogle Scholar
  44. 44.
    Dong J, Mandenius C-F, Lübberstedt M et al (2008) Evaluation and optimization of hepatocyte culture media factors by design of experiments (DoE) methodology. Cytotechnology 57:251–261. doi: 10.1007/s10616-008-9168-6 CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Snykers S, Vanhaecke T, Papeleu P et al (2006) Sequential exposure to cytokines reflecting embryogenesis: the key for in vitro differentiation of adult bone marrow stem cells into functional hepatocyte-like cells. Toxicol Sci 94:330–341. doi: 10.1093/toxsci/kfl058, discussion 235–9CrossRefPubMedGoogle Scholar
  46. 46.
    Kuznetsov SA, Mankani MH, Robey PG (2000) Effect of serum on human bone marrow stromal cells: ex vivo expansion and in vivo bone formation. Transplantation 70:1780–1787CrossRefPubMedGoogle Scholar
  47. 47.
    Takahashi K, Tanabe K, Ohnuki M et al (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872. doi: 10.1016/j.cell.2007.11.019 CrossRefPubMedGoogle Scholar
  48. 48.
    Park I-H, Zhao R, West JA et al (2008) Reprogramming of human somatic cells to pluripotency with defined factors. Nature 451:141–146. doi: 10.1038/nature06534 CrossRefPubMedGoogle Scholar
  49. 49.
    Chien Y, Liao Y-W, Liu D-M et al (2012) Corneal repair by human corneal keratocyte-reprogrammed iPSCs and amphiphatic carboxymethyl-hexanoyl chitosan hydrogel. Biomaterials 33:8003–8016. doi: 10.1016/j.biomaterials.2012.07.029 CrossRefPubMedGoogle Scholar
  50. 50.
    Yamanaka S (2009) A fresh look at iPS cells. Cell 137:13–17. doi: 10.1016/j.cell.2009.03.034 CrossRefPubMedGoogle Scholar
  51. 51.
    Nukaya D, Minami K, Hoshikawa R et al (2015) Preferential gene expression and epigenetic memory of induced pluripotent stem cells derived from mouse pancreas. Genes Cells 20:367–381. doi: 10.1111/gtc.12227 CrossRefPubMedGoogle Scholar
  52. 52.
    Liu H, Ye Z, Kim Y et al (2010) Generation of endoderm-derived human induced pluripotent stem cells from primary hepatocytes. Hepatology 51:1810–1819. doi: 10.1002/hep.23626 CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Rashid ST, Corbineau S, Hannan N et al (2010) Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells. J Clin Invest 120:3127–3136. doi: 10.1172/JCI43122 CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Chen Y-F, Tseng C-Y, Wang H-W et al (2012) Rapid generation of mature hepatocyte-like cells from human induced pluripotent stem cells by an efficient three-step protocol. Hepatology 55:1193–1203. doi: 10.1002/hep.24790 CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Tamaoki N, Takahashi K, Tanaka T et al (2010) Dental pulp cells for induced pluripotent stem cell banking. J Dent Res 89:773–778. doi: 10.1177/0022034510366846 CrossRefPubMedGoogle Scholar
  56. 56.
    Oda Y, Yoshimura Y, Ohnishi H et al (2010) Induction of pluripotent stem cells from human third molar mesenchymal stromal cells. J Biol Chem 285:29270–29278. doi: 10.1074/jbc.M109.055889 CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Chien Y, Chang Y-L, Li H-Y et al (2015) Synergistic effects of carboxymethyl-hexanoyl chitosan, cationic polyurethane-short branch PEI in miR122 gene delivery: accelerated differentiation of iPSCs into mature hepatocyte-like cells and improved stem cell therapy in a hepatic failure model. Acta Biomater 13:228–244. doi: 10.1016/j.actbio.2014.11.018 CrossRefPubMedGoogle Scholar
  58. 58.
    Chiang C-H, Wu W-W, Li H-Y et al (2015) Enhanced antioxidant capacity of dental pulp-derived iPSC-differentiated hepatocytes and liver regeneration by injectable HGF-releasing hydrogel in fulminant hepatic failure. Cell Transplant 24:541–559. doi: 10.3727/096368915X686986 CrossRefPubMedGoogle Scholar
  59. 59.
    Doddapaneni R, Chawla YK, Das A et al (2013) Overexpression of microRNA-122 enhances in vitro hepatic differentiation of fetal liver-derived stem/progenitor cells. J Cell Biochem 114:1575–1583. doi: 10.1002/jcb.24499 CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Francesco Paduano
    • 1
  • Massimo Marrelli
    • 2
  • Akhilesh K. Gaharwar
    • 3
    • 4
  • Marco Tatullo
    • 1
  1. 1.Research and Development in Biomedicine – Stem Cells UnitTECNOLOGICA Research InstituteCrotoneItaly
  2. 2.Department of Maxillofacial SurgeryCalabrodentalCrotoneItaly
  3. 3.Department of Biomedical EngineeringTexas A&M UniversityCollege StationUSA
  4. 4.Department of Materials Science and EngineeringTexas A&M UniversityCollege StationUSA

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