Skip to main content
SpringerLink
Log in

Hepatocyte growth factor gene-modified bone marrow-derived mesenchymal stem cells transplantation promotes angiogenesis in a rat model of hindlimb ischemia

  • Published:
Journal of Huazhong University of Science and Technology [Medical Sciences] Aims and scope Submit manuscript

Summary

Angiogenic gene therapy and cell-based therapy for peripheral arterial disease(PAD) have been studied intensively currently. This study aimed to investigate whether combining mesenchymal stem cells(MSCs) transplantation with ex vivo human hepatocyte growth factor(HGF) gene transfer was more therapeutically efficient than the MSCs therapy alone in a rat model of hindlimb ischemia. One week after establishing hindlimb ischemia models, Sprague-Dawley(SD) rats were randomized to receive HGF gene-modified MSCs transplantation(HGF-MSC group), untreated MSCs transplantation (MSC group), or PBS injection(PBS group), respectively. Three weeks after injection, angiogenesis was significantly induced by both MSCs and HGF-MSCs transplantation, and capillary density was the highest in the HGF-MSC group. The number of transplanted cell-derived endothelial cells was greater in HGF-MSC group than in MSC group after one week treatment. The expression of angiogenic cytokines such as HGF and VEGF in local ischemic muscles was more abundant in HGF-MSC group than in the other two groups. In vitro, the conditioned media obtained from HGF-MSCs cultures exerted proproliferative and promigratory effects on endothelial cells. It is concluded that HGF gene-modified MSCs transplantation therapy may induce more potent angiogenesis than the MSCs therapy alone. Engraftment of MSCs combined with angiogenic gene delivery may be a promising therapeutic strategy for the treatment of severe PAD.

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

Similar content being viewed by others

References

  1. Belch JJ, Topol EJ, Agnelli G, et al. Critical issues in peripheral arterial disease detection and management: a call to action. Arch Intern Med, 2003,163(8):884–892

    Article  PubMed  Google Scholar 

  2. Weitz JI, Byrne J, Clagett GP, et al. Diagnosis and treatment of chronic arterial insufficiency of the lower extremities: a critical review. Circulation, 1996,94(11): 3026–3049

    Article  PubMed  CAS  Google Scholar 

  3. Bobek V, Taltynov O, Pinterova D, et al. Gene therapy of the ischemic lower limb-Therapeutic angiogenesis. Vascul Pharmacol, 2006,44(6):395–405

    Article  PubMed  CAS  Google Scholar 

  4. Dormandy JA, Rutherford RB. Management of peripheral arterial disease(PAD). TASC Working Group. TransAtlantic Inter-Society Consensus(TASC). J Vasc Surg, 2000,31(1 Pt 2):S1–S296

    PubMed  CAS  Google Scholar 

  5. Hamou C, Callaghan MJ, Thangarajah H, et al. Mesenchymal stem cells can participate in ischemic neovascularization. Plast Reconstr Surg, 2009,123(2 Suppl):45S–55S

    PubMed  CAS  Google Scholar 

  6. Al-Khaldi A, Al-Sabti H, Galipeau J, et al. Therapeutic angiogenesis using autologous bone marrow stromal cells: improved blood flow in a chronic limb ischemia model. Ann Thorac Surg, 2003,75(1):204–209

    Article  PubMed  Google Scholar 

  7. Kinnaird T, Stabile E, Burnett MS, et al. Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms. Circulation, 2004,109(12):1543–1549

    Article  PubMed  CAS  Google Scholar 

  8. Iwase T, Nagaya N, Fujii T, et al. Comparison of angiogenic potency between mesenchymal stem cells and mononuclear cells in a rat model of hindlimb ischemia. Cardiovasc Res, 2005,66(3):543–551

    Article  PubMed  CAS  Google Scholar 

  9. Picinich SC, Mishra PJ, Glod J, et al. The therapeutic potential of mesenchymal stem cells. Cell- & tissue-based therapy. Expert Opin Biol Ther, 2007,7(7):965–973

    Article  PubMed  CAS  Google Scholar 

  10. Ozawa K, Sato K, Oh I, et al. Cell and gene therapy using mesenchymal stem cells(MSCs). J Autoimmun, 2008,30(3):121–127

    Article  PubMed  CAS  Google Scholar 

  11. Kim SW, Lee DW, Yu LH, et al. Mesenchymal stem cells overexpressing GCP-2 improve heart function through enhanced angiogenic properties in a myocardial infarction model. Cardiovasc Res, 2012,95(4):495–506

    Article  PubMed  CAS  Google Scholar 

  12. Morishita R, Nakamura S, Hayashi S, et al. Therapeutic angiogenesis induced by human recombinant hepatocyte growth factor in rabbit hind limb ischemia model as cytokine supplement therapy. Hypertension, 1999,33(6):1379–1384

    Article  PubMed  CAS  Google Scholar 

  13. Wang S, Qin X, Sun D, et al. Effects of hepatocyte growth factor overexpressed bone marrow-derived mesenchymal stem cells on prevention from left ventricular remodelling and functional improvement in infarcted rat hearts. Cell Biochem Funct, 2012,30(7): 574–581

    Article  PubMed  CAS  Google Scholar 

  14. Cho KR, Choi JS, Hahn W, et al. Therapeutic angiogenesis using naked DNA expressing two isoforms of the hepatocyte growth factor in a porcine acute myocardial infarction model. Eur J Cardiothorac Surg, 2008,34(4):857–863

    Article  PubMed  Google Scholar 

  15. Yuan B, Zhao Z, Zhang YR, et al. Short-term safety and curative effect of recombinant adenovirus carrying hepatocyte growth factor gene on ischemic cardiac disease. In Vivo, 2008,22(5):629–632

    PubMed  CAS  Google Scholar 

  16. Nakamura Y, Morishita R, Nakamura S, et al. A vascular modulator, hepatocyte growth factor, is associated with systolic pressure. Hypertension, 1996,28(3):409–413

    Article  PubMed  CAS  Google Scholar 

  17. Matsumoto R, Omura T, Yoshiyama M, et al. Vascular endothelial growth factor-expressing mesenchymal stem cell transplantation for the treatment of acute myocardial infarction. Arterioscler Thromb Vasc Biol, 2005,25(6):1168–1173

    Article  PubMed  CAS  Google Scholar 

  18. Kinnaird TD, Stabile E, Burnett MS, et al. HIF-1alpha/VP16 enhances the in-vitro arteriogenic potential of mesenchymal stem cells. Circulation, 2003,108:337A

    Google Scholar 

  19. Li L, Zhang Y, Li Y, et al. Mesenchymal stem cell transplantation attenuates cardiac fibrosis associated with isoproterenol-induced global heart failure. Transpl Int, 2008,21(12):1181–1189

    Article  PubMed  CAS  Google Scholar 

  20. Dull T, Zufferey R, Kelly M, et al. A third-generation lentivirus vector with a conditional packaging system. J Virol, 1998,72(11):8463–8471

    PubMed  CAS  Google Scholar 

  21. Hobo K, Shimizu T, Sekine H, et al. Therapeutic angiogenesis using tissue engineered human smooth muscle cell sheets. Arterioscler Thromb Vasc Biol, 2008,28(4):637–643

    Article  PubMed  CAS  Google Scholar 

  22. Wang JS, Shum-Tim D, Galipeau J, et al. Marrow stromal cells for cellular cardiomyoplasty: feasibility and potential clinical advantages. J Thorac Cardiovasc Surg, 2000,120(5):999–1005

    Article  PubMed  CAS  Google Scholar 

  23. Duan HF, Wu CT, Wu DL, et al. Treatment of myocardial ischemia with bone marrow-derived mesenchymal stem cells overexpressing hepatocyte growth factor. Mol Ther, 2003,8(3):467–474

    Article  PubMed  CAS  Google Scholar 

  24. Yang ZJ, Ma DC, Wang W, et al. Experimental study of bone marrow-derived mesenchymal stem cells combined with hepatocyte growth factor transplantation via noninfarct-relative artery in acute myocardial infarction. Gene Ther, 2006,13(22):1564–1568

    Article  PubMed  CAS  Google Scholar 

  25. Zhao MZ, Nonoguchi N, Ikeda N, et al. Novel therapeutic strategy for stroke in rats by bone marrow stromal cells and ex vivo HGF gene transfer with HSV-1 vector. J Cereb Blood Flow Metab, 2006,26(9):1176–1188

    PubMed  CAS  Google Scholar 

  26. Guo Y, He J, Wu J, et al. Locally overexpressing hepatocyte growth factor prevents post-ischemic heart failure by inhibition of apoptosis via calcineurin-mediated pathway and angiogenesis. Arch Med Res, 2008,39(2):179–188

    Article  PubMed  CAS  Google Scholar 

  27. Bian L, Guo ZK, Wang HX, et al. In vitro and in vivo immunosuppressive characteristics of hepatocyte growth factor-modified murine mesenchymal stem cells. In Vivo, 2009,23(1):21–27

    PubMed  CAS  Google Scholar 

  28. Neuss S, Becher E, Woltje M, et al. 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, 2004,22(3):405–414

    Article  PubMed  CAS  Google Scholar 

  29. Cai L, Johnstone BH, Cook TG, et al. Suppression of hepatocyte growth factor production impairs the ability of adipose-derived stem cells to promote ischemic tissue revascularization. Stem Cells, 2007,25(12):3234–3243

    Article  PubMed  CAS  Google Scholar 

  30. Sakon M, Kita Y, Yoshida T, et al. Plasma hepatocyte growth factor levels are increased in systemic inflammatory response syndrome. Surg Today, 1996,26(4):236–241

    Article  PubMed  CAS  Google Scholar 

  31. Rosu-Myles M, Stewart E, Trowbridge J, et al. A unique population of bone marrow cells migrates to skeletal muscle via hepatocyte growth factor/c-met axis. J Cell Sci, 2005,118(Pt 19):4343–4352

    Article  Google Scholar 

  32. Forte G, Minieri M, Cossa P, et al. Hepatocyte growth factor effects on mesenchymal stem cells: proliferation, migration, and differentiation. Stem Cells, 2006,24(1): 23–33

    Article  PubMed  CAS  Google Scholar 

  33. Aoki M, Morishita R, Taniyama Y, et al. Angiogenesis induced by hepatocyte growth factor in non-infarcted myocardium and infarcted myocardium: up-regulation of essential transcription factor for angiogenesis, ets. Gene Ther, 2000,7(5):417–427

    Article  PubMed  CAS  Google Scholar 

  34. Van Belle E, Witzenbichler B, Chen D, et al. Potentiated angiogenic effect of scatter factor/hepatocyte growth factor via induction of vascular endothelial growth factor: the case for paracrine amplification of angiogenesis. Circulation, 1998,97(4):381–390

    Article  PubMed  Google Scholar 

  35. Xin X, Yang S, Ingle G, et al. Hepatocyte growth factor enhances vascular endothelial growth factor-induced angiogenesis in vitro and in vivo. Am J Pathol, 2001,158(3):1111–1120

    Article  PubMed  CAS  Google Scholar 

  36. Zhu XY, Zhang XZ, Xu L, et al. Transplantation of adipose-derived stem cells overexpressing hHGF into cardiac tissue. Biochem Biophys Res Commun, 2009,379(4):1084–1090

    Article  PubMed  CAS  Google Scholar 

  37. Morishita R. Recent progress in gene therapy for cardiovascular disease. Circ J, 2002,66(12):1077–1086

    Article  PubMed  CAS  Google Scholar 

  38. Kinnaird T, Stabile E, Burnett MS, et al. Bone-marrow-derived cells for enhancing collateral development: mechanisms, animal data, and initial clinical experiences. Circ Res, 2004,95(4):354–363

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Guan-hua Su  (苏冠华), Yong-xin Lu  (卢永昕), Xin-xin Shuai  (帅欣欣), Yu-hua Liao  (廖玉华), Qi-yun Liu  (刘启云) & Ping Luo  (罗 平)

  2. Department of Cardiology, Wuhan Pu’ai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430033, China

    Yu-fei Sun  (孙雨霏) & Jun Han  (韩 俊)

Authors
  1. Guan-hua Su  (苏冠华)
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yu-fei Sun  (孙雨霏)
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yong-xin Lu  (卢永昕)
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xin-xin Shuai  (帅欣欣)
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yu-hua Liao  (廖玉华)
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Qi-yun Liu  (刘启云)
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jun Han  (韩 俊)
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ping Luo  (罗 平)
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yong-xin Lu  (卢永昕).

Additional information

Both authors contributed equally to this work.

This project was supported by a grant from the National Natural Science Foundation of China (No. 30470457).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Su, Gh., Sun, Yf., Lu, Yx. et al. Hepatocyte growth factor gene-modified bone marrow-derived mesenchymal stem cells transplantation promotes angiogenesis in a rat model of hindlimb ischemia. J. Huazhong Univ. Sci. Technol. [Med. Sci.] 33, 511–519 (2013). https://doi.org/10.1007/s11596-013-1151-6

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11596-013-1151-6

Key words

Search

Navigation