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Human hepatocyte growth factor (HGF) is an 80kD [1] pleiotropic protein that is endogenously produced by a variety cell types from the mesenchymal cell lineage (such as cardiomyocytes and neurons)[2]. It is produced and proteolytically cleaved to its active state in response to cellular injury, or during apoptosis. HGF binds to c-met receptors found on mesenchymal cell types, to produce its many different effects such as increased cellular motility, morphogenesis, proliferation and differentiation [3]. Research has shown that HGF has potent angiogenic, anti-fibrotic, and anti-apoptotic properties [1] [2] [3] [4] [5] [6] [7]. It has also been shown to act as a chemo-attractant for adult mesenchymal stem cells via c-met receptor binding [3] [2].

Medicinal Use

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Human HGF plasmid DNA transfection of cardiomyocytes is currently being examined as a potential treatment for coronary artery disease (a major cause of Myocardial infarction (MI)), as well treatment for the damage that occurs to the heart after MI [1] [8]. After MI, the myocardium suffers from Reperfusion injury which leads to death of cardiomyocyte and detrimental remodelling of the heart, consequently reducing proper cardiac function [8]. Transfection of cardiac myocytes with human HGF reduces ischemic reperfusion injury after MI. The benefits of HGF therapy include preventing improper remodelling of the heart and ameliorating heart dysfunction post-MI [1] [5].

Research & Clinical Trials

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Animal research has demonstrated that administration of HGF cDNA plasmids into ischemic cardiac tissue can increase cardiac function (improved left ventricular ejection fraction and fractional shortening compared to control subjects) after induced MI or ischemia[4] [5]. Transfection with HGF plasmids in damaged cardiac tissue also promotes angiogenesis (increased capillary density compared to control subjects), as well as decreasing detrimental remodelling of the tissue at the site of injury (decreased fibrotic deposition) [6] [2] [4]. The increased production of HGF by transfected cardiomyocytes during injury has also shown to be a powerful chemo-attractant of adult mesenchymal stem cells via HGF/c-Met binding [3] [2]. The mitogenic and morphogenic properties of HGF induce recruited stem cells to take on cardiomyocyte phenotypes, potentially helping in the healing of ischemic tissue [3]. The benefits of HGF in experimental models have led to its investigation in clinical trials. A phase I clinical trial entailed injecting an adenovirus vector with the human HGF (Ad-hHGF) gene into the coronary vessels localized to ischemic tissue. Results demonstrate that it is in fact safe to administer the Ad-hHGF vector into patients with coronary artery disease in hopes of re-vascularizing damaged tissue in patients for which CABG or PCI are not available or possible. Despite the trial’s limitations (ie. no assessment of left ventricular function and sample size was quite small), upon follow up assessments at 12 months, none of the patients receiving the treatment had been readmitted to hospital for MI, angina or aggravated heart failure [1].

References

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  1. ^ a b c d e Z. Yang et al. Phase I clinical trial on intracoronary administration of Ad-hHGF. Mol Biol Rep. 2009; 36:1323–1329.
  2. ^ a b c d e S. Vogel et al. Hepatocyte growth factor-mediated attraction of mesenchymal stem cells for apoptotic neuronal and cardiomyocytic cells. Cell. Mol. Life Sci. 2010; 67:295–303.
  3. ^ a b c d e G. Forte et al. Hepatocyte Growth Factor Effects on Mesenchymal Stem Cells Proliferation, Migration, and Differentiation. Stem Cells. 2006; 24: 23–33.
  4. ^ a b c W. Hahn et al. Enhanced cardioprotective effects by coexpression of two isoforms of hepatocyte growth factor from naked plasmid DNA in a rat ischemic heart disease model. J Gene Med. 2011; 13: 549–555.
  5. ^ a b c Y. Shirakawa et al. Gene transfection with human hepatocyte growth factor complementary DNA plasmids attenuates cardiac remodeling after acute myocardial infarction in goat hearts implanted with ventricular assist devices. J Thorac Cardiovasc Surg. 2005; 130:624-632.
  6. ^ a b J. Azuma et al. Angiogenic and antifibrotic actions of hepatocyte growth factor improve cardiac dysfunction in porcine ischemic cardiomyopathy. Gene Therapy. 2006; 13:1206–1213.
  7. ^ V. Sala, T. Crepaldi. Novel therapy for myocardial infarction: can HGF/Met be beneficial? Cell. Mol. Life Sci. 2011; 68:1703–1717.
  8. ^ a b D.M. Yellon, D.J. Hausenloy. Myocardial Referfusion Injury.The New England J. of Med. 2007; 357 (11):1121-1135.

[1] [2] [3] [4] [5] [6] [7] [8]

  1. ^ G. Forte et al. Hepatocyte Growth Factor Effects on Mesenchymal Stem Cells: Proliferation, Migration, and Differentiation. Stem Cells. 2006; 24: 23–33.
  2. ^ J. Azuma et al. Angiogenic and antifibrotic actions of hepatocyte growth factor improve cardiac dysfunction in porcine ischemic cardiomyopathy. Gene Therapy. 2006; 13:1206–1213.
  3. ^ S. Vogel et al. Hepatocyte growth factor-mediated attraction of mesenchymal stem cells for apoptotic neuronal and cardiomyocytic cells. Cell. Mol. Life Sci. 2010; 67:295–303.
  4. ^ W. Hahn et al. Enhanced cardioprotective effects by coexpression of two isoforms of hepatocyte growth factor from naked plasmid DNA in a rat ischemic heart disease model. J Gene Med. 2011; 13: 549–555.
  5. ^ Y. Shirakawa et al. Gene transfection with human hepatocyte growth factor complementary DNA plasmids attenuates cardiac remodeling after acute myocardial infarction in goat hearts implanted with ventricular assist devices. J Thorac Cardiovasc Surg. 2005; 130:624-632.
  6. ^ Z. Yang et al. Phase I clinical trial on intracoronary administration of Ad-hHGF. Mol Biol Rep. 2009; 36:1323–1329.
  7. ^ D.M. Yellon, D.J. Hausenloy. Myocardial Referfusion Injury.The New England J. of Med. 2007; 357 (11):1121-1135.
  8. ^ V. Sala, T. Crepaldi. Novel therapy for myocardial infarction: can HGF/Met be beneficial? Cell. Mol. Life Sci. 2011; 68:1703–1717.
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