Skip to main content

Advertisement

SpringerLink
Log in

Effects of mesenchymal stem cells and VEGF on liver regeneration following major resection

  • ORIGINAL ARTICLE
  • Published:
Langenbeck's Archives of Surgery Aims and scope Submit manuscript

Abstract

Purpose

The study aims to determine the effects of mesenchymal stem cell (MSC) therapy and a combination therapy of MSCs transfected with vascular endothelial growth factor (VEGF) for liver regeneration after major resection.

Methods

Thirty-eight rats were divided into four groups: group 1: control (sham operation); group 2: control (70 % hepatic resection); group 3: 70 % hepatic resection + systemically transplanted MSCs; and group 4: 70 % hepatic resection + systemically transplanted MSCs transfected with the VEGF gene. MSCs were injected via the portal vein route in study groups 3 and 4. Expression levels of VEGF, fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), epidermal growth factor (EGF), transforming growth factor (TGF), hepatocyte growth factor (HGF), and augmenter of liver regeneration (ALR) were analyzed in the remnant liver tissue. We investigated the levels of angiogenic factors, VEGF-receptor, angiopoietin-1 (Angpt1) and Angpt2. Biochemical parameters of liver function in blood samples were measured and a histologic assessment of the livers was performed. The postoperative liver weight and volume of each rat were measured 14 days after surgery.

Results

The expression levels of all measured growth factors were significantly increased in groups 3 and 4 compared to the control groups. The levels of Angpt1 and Angpt2 correlated with levels of VEGF and thus were also significantly higher in the study groups. There were significant differences between the estimated liver weights and volumes of group 4 and the resected controls in group 2. With the exception of portal inflammation, levels of all histological parameters were observed to be higher in MSC-treated groups when compared with the resected controls in group 2.

Conclusions

Transplanted stem cells and MSCs transfected with VEGF significantly accelerated many parameters of the healing process following major hepatic resection. After the injection of MSCs and VEGF-transfected MSCs into the portal vein following liver resection, they were engrafted in the liver. They increased bile duct and liver hepatocyte proliferation, and secreted many growth factors including HGF, TGFβ, VEGF, PDGF, EGF, and FGF via paracrine effects. These effects support liver function, regeneration, and liver volume/weight.

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

Access this article

Log in via an institution

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
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Makino H, Shimizu H, Ito H, Kimura F, Ambiru S, Togawa A, Ohtsuka M, Yoshidome H, Kato A, Yoshitomi H, Sawada S, Miyazaki M (2006) Changes in growth factor and cytokine expression in biliary obstructed rat liver and their relationship with delayed liver regeneration after partial hepatectomy. World J Gastroenterol 13:2053–2059

    Article  Google Scholar 

  2. Blumgart LH (2007) Surgery of the liver, biliary tract, and pancreas. In: Blumgart LH, Belghiti J (eds) Liver resection for benign disease and for liver and biliary tumors. Fourth Edition, Vol:2, Philadelphia. 1341–1405

  3. Puglisi MA, Tesori V, Lattanzi W, Piscaglia AC, Gasbarrini GB, D’Ugo DM, Gasbarrini A (2011) Therapeutic implications of mesenchymal stem cells in liver injury. J Biomed Biotechnol 2011:860578

  4. Ghaedi M, Tuleuova N, Zern AM, Wu J, Revzin A (2011) Bottom-up signaling from HGF-containing surfaces promoteshepatic differentiation of mesenchymal stem cells. Biochem Biophys Res Commun 2:295–300

    Article  Google Scholar 

  5. Wu BX, Tao R (2012) Hepatocyte differentiation of mesenchymal stem cells. Hepatobiliary Pancreat Dis Int 11:360–371

    Article  CAS  PubMed  Google Scholar 

  6. Shimizu H, Mitsuhashi N, Ohtsuka M, Ito H, Kimura F, Ambiru S, Togawa A, Yoshidome H, Kato A, Miyazaki M (2005) Vascular endothelial growth factor and angiopoietins regulate sinusoidal regeneration and remodeling after partial hepatectomy in rats. World J Gastroenterol 46:7254–7260

    Article  Google Scholar 

  7. Riehle KJ, Dan YY, Campbell JS, Fausto N (2011) New concepts in liver regeneration. J Gastroenterol Hepatol 26:203–212

    Article  PubMed  PubMed Central  Google Scholar 

  8. Duncan WA, Dorrell C, Grompe M (2009) Stem cells and liver regeneration. Gastroenterology 2:466–481

    Article  Google Scholar 

  9. Burra P, Debora B, Ciccocippo R, Marra F, Piscaglia CA, Porretti L, Gasbarrini A, Russo PF (2011) Therapeutic application of stem cells in gastroenterology: an up-date. World J Gastroenterol 34:3870–3880

    Article  Google Scholar 

  10. Hayashi Y, Tsujii S, Tsujii M, Nishida T, Ishii S, Lijima H, Nakamura T, Eguchi H, Miyoshi E, Hayashi N, Kawano S (2008) Topical implantation of mesenchymal stem cells has beneficial effects on healing of experimental colitis in rats. J Pharmacol Exp Ther 326:523–531

    Article  CAS  PubMed  Google Scholar 

  11. Chan PB, Hui YT, Yeung WC, Li J, Mo I, Chan GF (2007) Self-assembled collagen-human mesenchymal stem cell microspheres for regenerative medicine. Biomaterials 28:4652–4666

    Article  CAS  PubMed  Google Scholar 

  12. Markel AT, Crisostomo RP, Lahm T, Novotny MN, Rescoria JF, Tector JA, Meldrum RD (2008) Stem cells as a potential future treatment of pediatric intestinal disorders. J Pediatr Surg 11:1953–1963

    Article  Google Scholar 

  13. Enestvedt KC, Hosack L, Winn RS, Diggs SB, Uchida B, O’Rourke WR, Jobe AB (2008) VEGF gene therapy augments localized angiogenesis and promotes anastomic wound healing: a pilot study in a clinically relevant animal model. J Gastrointest Surg 12:1762–1772

    Article  PubMed  Google Scholar 

  14. Cross JK, Mustoe AT (2003) Growth factors in wound healing. Surg Clin N Am 83:531–545

    Article  PubMed  Google Scholar 

  15. Werner S, Grose R (2003) Regulation of wound healing by growth factors and cytokines. Physiol Rev 83:835–860

    CAS  PubMed  Google Scholar 

  16. Shimuzu H, Miyazaki M, Wakabayashi Y, Mitsuhashi N, Kato A, Ito H, Nakagawa K, Yoshidome H, Kataoka M, Nakajima N (2001) Vascular endothelial growth factor secreted by replicating hepatocytes induces sinusoidal endothelial cell proliferation during regeneration after partial hepatectomy in rats. J Hepatol 34:683–689

    Article  Google Scholar 

  17. Martins PN, Theruvath PT, Neuhaus P (2007) Rodent models of partial hepatectomies. Liver Int 3–11

  18. Greene AK, Puder M (2003) Partial hepatectomy in the mouse: technique and perioperative management. J Investig Surg 16:99–102

    Article  Google Scholar 

  19. Best J, Dolle L, Manka P, Coombes J, Grunsven AL, Syn W (2013) Role of liver progenitors in acute liver injury. Front Physiol 4:1–8

    Article  Google Scholar 

  20. Cantz T, Manns PM, Ott M (2008) Stem cells in liver regeneration and therapy. Cell Tissue Res 331:271–282

    Article  PubMed  Google Scholar 

  21. Chen WX, Zhu JD, Ju LY, Zhou FS (2012) Therapeutic effect of transplanting magnetically labeled bone marrow stromal stem cells in a liver injury rat model with 70%-hepatectomy. Med Sci Monit 10:375–382

    Google Scholar 

  22. Hang LH, Xia Q (2014) Role of BMSCs in liver regeneration and metastasis after hepatectomy. World J Gastroenterol 20(1):126–132

    Article  PubMed  PubMed Central  Google Scholar 

  23. Zhou LW, Medine NC, Zhu L, Hay CD (2012) Stem cell differentiation and human liver disease. World J Gastroenterol 18(17):2018–2025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Tanimuzu N, Miyajima A (2007) A molecular mechanism of liver development and regeneration. Int Rev Cytol 259:1–48

    Article  Google Scholar 

  25. Ding SB, Nolan JD, Butler MJ et al (2010) Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration. Nature 468(7321):310–315

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Fausto N (2004) Liver regeneration and repair: hepatocytes, progenitor cells, and stem cells. Hepatology 39:1477–1487

    Article  PubMed  Google Scholar 

  27. Kallis YN, Alison MR, Forbes SJ (2007) Bone marrow stem cells and liver disease. Gut England 716–724

  28. Ren G, Chen X, Dong F, Li W, Ren X, Zhang Y, Shi Y (2012) Concise review: mesenchymal stem cells and translational medicine: emerging issues. Stem Cells Transl Med 1:51–58

    Article  CAS  PubMed  Google Scholar 

  29. Crisostomo PR, Wang Y, Merkel TA et al (2008) Human mesenchymal stem cells stimulated by TNF-α, LPS, or hypoxia produce growth factors by NF-kB but not JNK-dependent mechanism. Am J Physiol Cell Physiol 294:675–682

    Article  Google Scholar 

  30. Caplan AI, Dennis JE (2006) Mesenchymal stem cells as trophic mediators. J Cell Biochem 98:1076–1084

    Article  CAS  PubMed  Google Scholar 

  31. Shibuya M (2013) VEGF-VEGFR signals in health and disease. Biomol Ther 22(1):1–9

    Article  Google Scholar 

  32. Shibuya M (2013) Vascular endothelial growth factor and its receptor system: physiological functions in angiogenesis and pathological roles in various diseases. J Biochem 153(1):13–19

    Article  CAS  PubMed  Google Scholar 

  33. Karkkainen MJ, Petrova TV (2000) Vascular endothelial growth factor receptors in the regulation of angiogenesis and lymphangiogenesis. Oncogene 19(49):5598–5605

    Article  CAS  PubMed  Google Scholar 

  34. Heidaran MA, Pierce JH, Jensen RA et al (1990) Chimeric alpha- and - beta platelet derived growth factor receptors define three immunoglobulin-like domains of the alpha-PDGF receptor that determine PDGF-AA binding specificity. J Biol Chem 265(31):18741–4

    CAS  PubMed  Google Scholar 

  35. Michalopoulos KG (2010) Liver regeneration after partial hepatectomy: critical analysis of mechanistic dilemmas. AJP 176(1):2–13

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Francavilla A, Hagiya M, Porter KA, Polimeno L, Ihara I, Starzl TE (1994) Augmenter of liver regeneration: its place in the universe of hepatic growth factors. Hepatology 20:747–757

    Article  CAS  PubMed  Google Scholar 

  37. Gandhi CR, Kuddus R, Subbotin VM, Prelich J, Murase N, Rao AS, Nalesnik MA, Watkins SC, Deleo A, Trucco M, Starzl TE (1999) A fresh look at augmenter of liver regeneration in rats. Hepatology 29:1435–1445

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Gandhi CR, Murase N, Starzl TE (2010) Cholera toxin-sensitive GTP-binding protein-coupled activation of augmenter of liver regeneration (ALR) receptor and its function in rat Kupffer cells. J Cell Physiol 222:365–373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Balber AE (2011) Concise review: aldehyde dehydrogenase bright stem and progenitor cell populations from normal tissues: characteristics, activities, and emerging uses in regenerative medicine. Stem Cells 29(4):570–575

    Article  CAS  PubMed  Google Scholar 

  40. Hematti P (2008) Role of mesenchymal stromal cells in solid organ transplantation. Transplant Rev 22(4):262–273

    Article  Google Scholar 

  41. Kuo TK, Hung SP, Chuang CH et al (2008) Stem cell therapy for liver disease: parameters governing the success of using bone marrow mesenchymal stem cells. Gastroenterology 134:2111–2121

    Article  PubMed  PubMed Central  Google Scholar 

  42. Banas A, Teratani T, Yamamoto Y et al (2009) Rapid hepatic fate specification of adipose-derived stem cells and their therapeutic potential for liver failure. J Gastroenterol Hepatol 24:70–77

    Article  CAS  PubMed  Google Scholar 

  43. Carvelho AB, Quintanilha LF, Dias JV et al (2008) Bone marrow multipotent mesenchymal stromal cells do not reduce fibrosis or improve function in a rat model of severe chronic liver injury. Stem Cells 26:1307–1314

    Article  Google Scholar 

Download references

Acknowledgments

We thank Irmak Bircan for discussion and suggestions about the manuscript.

Author information

Authors and Affiliations

  1. Department of Surgery, Bakirkoy Dr.Sadi Konuk Training and Research Hospital, Istanbul, Turkey

    Gokhan Adas, Ozgur Kemik & Mustafa Kalayci

  2. Faculty of Medicine, Istanbul Training Hospital, Department of Surgery, Baskent University, Oymaci Sok. No:7, 34662, Altunizade Uskudar, Istanbul, Turkey

    Bora Koc

  3. Department of Endocrinology, Okmeydani Training and Research Hospital, Istanbul, Turkey

    Mine Adas

  4. Center for Stem Cell and Gene Therapies Research and Practice, Institute of Health Sciences, Stem Cell Department, Kocaeli University, Izmit, Kocaeli, Turkey

    Gokhan Duruksu, Cansu Subasi & Seda Unal

  5. Faculty of Medicine, Department of Biochemistry, Istanbul University, Istanbul, Turkey

    Ahu Kemik

  6. Department of Pathology, Bakirköy Dr.Sadi Konuk Training and Research Hospital, Istanbul, Turkey

    Damlanur Sakiz

  7. Faculty of Medicine, Department of Statistics, Istanbul University, Istanbul, Turkey

    Sevim Purisa

  8. Center for Regenerative Medicine and Stem Cell Research and Manufacturing (LivMedCell), Liv Hospital, Istanbul, Turkey

    Erdal Karaoz

Authors
  1. Gokhan Adas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bora Koc
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mine Adas
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gokhan Duruksu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Cansu Subasi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ozgur Kemik
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ahu Kemik
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Damlanur Sakiz
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Mustafa Kalayci
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Sevim Purisa
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Seda Unal
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Erdal Karaoz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bora Koc.

Ethics declarations

Conflicts of interest

The authors declare that they have no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Adas, G., Koc, B., Adas, M. et al. Effects of mesenchymal stem cells and VEGF on liver regeneration following major resection. Langenbecks Arch Surg 401, 725–740 (2016). https://doi.org/10.1007/s00423-016-1380-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00423-016-1380-9

Keywords

Search

Navigation