EVIDENCE FOR A NEGATIVE FEEDBACK SYSTEM 

 CONTROLLING LIVER REGENERATION 



Andre D. Glinos 



Growth Physiology Laboratory, 

 Walter Reed Army Institute of Research, Washington, D.C. 



Abstract — Cell division was induced in the resting liver of the rat by lowering the concentration 

 of serum constituents through plasmapheresis, and was inhibited in the regenerating liver by 

 increasing the concentration of the serum by fluid intake restriction. 



Electrophoretic analysis of serum proteins and histochemical investigation of the organiza- 

 tion of cytoplasmic ribonucleoprotein of the liver cells during regeneration suggest that 

 plasma proteins may participate as information-carrying agents in a negative feedback system 

 controlling the growth of liver cells. 



Liver is an excellent tissue for investigating mechanisms of growth control 

 because it regenerates very rapidly. In the rat, removal of up to two-thirds of 

 the total mass of the liver is followed by active cell division leading to complete 

 restoration of the organ within two weeks. 



As early as 1923 Akamatsu (1) reported that tissue cultures of rabbit hver 

 grew better in plasma from partially hepatectomized animals than in normal 

 control plasma, and more recently it was shown that cell division can be induced 

 in the resting liver of a parabiotic rat by a partial hepatectomy performed on 

 its partner (2, 3, 4). These findings were considered to indicate the presence 

 or the increase of growth-stimulating factors in the plasma of partially hepatec- 

 tomized animals. 



In our own studies on the possible participation of the humoral system of 

 communication in the control of this growth, blood serum from animals 

 undergoing liver regeneration was assayed in tissue culture (5). These cultures 

 showed a comparable outgrowth in a high concentration of serum of partially 

 hepatectomized rats and in a low concentration of normal serum. A high 

 concentration of normal serum showed inhibitory effects. Based on these 

 findings a hypothesis was formulated with regard to the induction of the 

 regenerative process in the liver which follows partial hepatectomy. 



According to this hypothesis, certain constituents of normal blood serum 

 exert a growth-inhibitory action at their normal concentration. Partial hepatec- 

 tomy would be expected to result in a decrease of the serum concentration of 

 these constituents. Thus in turn regenerative growth is initiated. During 

 regeneration, as the number of liver cells increases, the concentration of these 

 constituents will also increase. When the original equilibrium between a given 

 number of liver cells and a given concentration of the serum constituents is 

 restored, further growth is expected to cease. The evidence for a negative 

 feedback system of this type should satisfy the following two conditions: 



1. Induction of growth in the resting tissue by plasma dilution. 



2. Inhibition of growth in the regenerating tissue by plasma concentration. 



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