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HUMORAL REGULATION OF LIVER REGENERATION AND TISSUE GROWTH COUN G. D. MORLEY* At present one of the greatest challenges to biologists is to understand the regulation of cell growth, a phenomenon encompassing the growth and development of tissues, their ability to respond to injury, and the loss of control of these processes with the emergence of neoplasias. Humoral factors circulating in the blood, lymph, or other extracellular fluids may play an important role in the control of cell growth. Indeed, a family of peptides and polypeptides has been described that are concerned solely with regulating the growth or differentiation of specific tissues, and that appear to be distinct from hormones such as somatotrophin. In this article I shall review the problem of humoral growth regulation , with emphasis on regenerating rat liver, which is one of the most rapidly proliferating tissues and one that has been studied most completely . The Historical Background ofLiver Regeneration Studies The hows and whys of liver regeneration have been fascinating to scientists and laymen alike for a very long time. The first reference to liver regeneration is in Greek mythology: the story of Prometheus who was chained to the rock "on Mount Caucasus, where a vulture preyed on his liver, which was renewed as fast as devoured" [1, p. 19]. The scientific study of liver regeneration can be traced to the eighteenth and early nineteenth centuries. However, the modern era was initiated by Higgins and Anderson [2], in 1931, in their classic study of partial hepatectomies and liver regeneration in rodents, in which they were able to show that surgical removal of65±5 percent ofthe liver ofrats could be performed ?The Liver Study Unit, Department of Medicine, University of Chicago and Franklin McLean Memorial Research Institute (operated by the University of Chicago for the United States Atomic Energy Commission; formerly the Argonne Cancer Research Hospital), Chicago, Illinois 60637. 1 thank Drs. Eugene Goldwasser andJames Boyer for their careful reviews of the manuscript. Perspectives in Biology and Medicine · Spring 1974 I 411 with low mortality rates. Remarkably, within 3 weeks the liver would regain its normal size. Later work by Ingle [3] demonstrated that multiple sequential partial hepatectomies could be performed on the same rat, the liver apparently being able to regenerate indefinitely, although, because of tissue scarring, hepatic function steadily deteriorated. Biochemical rather than physiological studies of this growth phenomenon began in the early 1950s and have been increasing in number continually since then. At first, changes in cell composition were studied; later, when radioisotopes became available, studies concentrated on DNA, RNA, and protein synthesis. It was found that the stimulation of DNA synthesis following partial hepatectomy varied in timing and magnitude with (a) the age of the animal (the older the animal, the less extensive and the slower the rise in DNA synthesis in the liver) [4]; (b) the nutritional state of the animal (starved animals had a depressed response to partial hepatectomy) [5]; (c) the hormonal status of the animal (the loss of pituitary hormones, adrenal hormones, etc., slowed but did not abolish the regenerative response) [6, 7]; and finally, (d) the amount of liver removed (the greater the amount removed, the greater the initial rise in DNA synthesis) [8]. Other workers tried to study the control system for this remarkable phenomenon of growth induction. Many stimuli were proposed, including overloading ofthe liver remnant with metabolic products, changes in the levels of various hormones such as the corticosteroids, or, more recently, a form of humoral control via blood-borne stimulators [9] (or conceivably loss of blood-borne inhibitors [10]). Evidence for humoral regulation of liver regeneration began to accumulate more than 10 years ago from transfusion experiments between partially hepatectomized and normal animals, even though these were often badly controlled and the results consequently difficult to interpret. As techniques improved, Bücher, Grisham, and others [9, 1 1] were able to show, by studying parabiotic rats, that circulating blood from a partially hepatectomized rat could stimulate DNA synthesis and mitoses in the normal liver of an unoperated animal. Other lines of evidence appeared which indicated that serum or liver breis from partially hepatectomized rats stimulated hepatic DNA synthesis in the liver of the normal...