Animals, including mammals, share the intrinsic ability to regenerate specific tissues and organs. Patterns of tissue regeneration are generally divided into two distinct systems (Fig.1). One is the “stem cell system.EIn tissues, such as nerve or muscle, stem cells usually remain in a quiescent and undifferentiated state (but committed to differentiate into specific cell types), but are able to proliferate to produce daughter cells that will differentiate into the required tissues, in response to injuries. The other is the “simple duplication system.EIn parenchymal organs, such as kidney, liver or lung, differentiated cells proliferate without dedifferentiation to replace excised or injured tissues.
Although regenerative medicine is occasionally misunderstood as the biology of stem cells, many organs of the human body regenerate by the simple duplication system. Thus, an understanding of the molecular mechanisms involved in the simple duplication system will directly lead to new clinical strategies to combat many organ
HGF as a Regeneration/Repair Factor
Liver regeneration is generally regarded as one the most dramatic phenomena in higher animals. In fact, a transplanted liver weighing about 400 g regenerates up to 1 kg within a month. Although the humoral substance triggering liver regeneration was unknown for some time, Nakamura’s group (Osaka University) was the first to purify and clone HGF (hepatocyte growth factor) and identity it as a potent mitogen for fully differentiated hepatocytes. HGF, a heterodimeric molecule composed of a 69 kDa a-chain and a 34 kDa ß-chain, possesses multiple biological activities by binding to the cell-surface receptor cMet, a cMet proto-oncogene product (Fig.2).
HGF has been shown to exhibit a wide variety of physiological activities, not only as a mitogenic factor for liver cells, but also as mitogenic, anti-apoptotic (cell death), morphogenic, and angiogenic factors for various other types of cells. In the case of the regeneration of the liver, following acute injuries such as partial hepatectomy, hepatitis, and liver ischemia, the HGF concentration in blood increases. HGF is induced in an autocrine and paracrine fashion in the injured liver. In addition, HGF can also be supplied to the injured local site from distant undamaged organs (lung, kidney etc.) through the endocrine system.
In this manner, HGF induced by injuries has an important role in the regeneration and protection of the liver. In fact, when rats or mice with liver injury are treated with anti-HGF IgG, which neutralizes the HGF activity, a remarkable expansion of the injured area and subsequent liver failure are observed. Similar results are observed in other organ injuries. Therefore, HGF is an intrinsic repair factor with an organotrophic role in the regeneration and protection of various organs, including the liver, kidney, lung, heart and the blood vessel as well as nervous systems (Fig.3).
Regeneration and Recovery of Intractable Diseases
HGF is a molecule that supports the autogenesis of the human body. However, if the injury of organs and the bacterial and viral infection exceed the capacity for autogenic regeneration, it will result in the development of acute diseases. Moreover, in chronic fibrosis diseases, such as liver cirrhosis and chronic renal failure, a decrease in HGF expression is always observed. In other words, an insufficient regenerative system (or reduction in autogenic) causes the development and progress of chronic fibrosis diseases. The activation of the intrinsic regenerative ability by administration of exogenous HGF is expected to prevent development of these symptoms and serve as a medical treatment for various diseases both in acute and chronic stages. Until now, HGF medication in many animal disease models has shown remarkable effects in the prevention and recovery of disease. Based on these experimental results, the potential target diseases of HGF are summarized in the table below. It has been shown that apoptosis of differentiated cells with a specific function (hepatocyte, cardiomyocyte, neuron, etc.) is closely related to the development of acute organ failures, such as in fulminant hepatitis, cardiac infarction, acute renal failure, and stroke. Consequently, it is important to prevent rapid cell death for the initial treatment of these incurable diseases. Exogenous administration of recombinant HGF protein is effective for the prevention of disease progression and the promotion of organ regeneration in animal models of fulminant hepatitis, cardiac infarction, acute renal failure, renal transplantation, acute pneumonia, and stroke. Many patients are currently suffering from chronic fibrosis, which has been labeled an incurable disease. In animal experiments, HGF has shown powerful therapeutic effects on chronic fibrosis diseases (liver cirrhosis, chronic renal failure, pulmonary fibrosis, cardiomyopathy, etc). The therapeutic effects of HGF on acute organ failure and chronic fibrosis diseases depend on the various physiological functions of HGF, which lead to repair and protection of higher tissues. Therefore, the mechanism of therapeutic actions by HGF is fundamentally applicable to different tissue types and organs.
Potential diseases and conditions to which HGF can be applied therapeutically