Information has been obtained concerning the extracellular control of liver regeneration by transplanting, with blood vessel anastomoses, auxiliary livers into isologous rats. Partial or whole livers, vascularized one of three ways, were inserted into hosts with whole or partially hepatectomized livers in which there was either a normal blood supply or an absence of portal flow. Bile ducts of transplants were either cannulated or ligated. Hepatic parenchymal cell activity was determined by number of mitoses and incorporation of 32P into DNA.

Findings obtained from a variety of host and transplant combinations indicate the following. (a) They failed to confirm a factor, as more conventionally described by others, in hepatic regeneration. A partial (30%)-liver transplant failed to initiate a parenchymal cell response in whole host livers and, similarly, partial hepatectomy of the latter resulted in no stimulation of such cells in whole-liver transplants. An explanation for the difference in results is presented which suggests that there is a portal blood factor (PBF) which is capable of stimulating hepatic cells and that its effectiveness is inversely related to the number of liver cells present. (b) This PBF was neither destroyed nor inhibited in systemic blood, since livers in portacaval-shunted, partially hepatectomized, nontransplanted animals responded similarly to such livers in nonshunted animals. (c) The diversion of portal blood through a whole-liver transplant prior to its entry into the systemic circulation prevented such a response in the liver remnant of the host as well as in the transplant. (d) Diversion of portal blood through a partial liver transplant resulted in a response in the transplant similar to that which occurred in the remnant of a partially hepatectomized, nontransplanted animal, despite the presence of an additional whole liver (host), which failed to demonstrate stimulation. (e) When a partial liver was transplanted into a hepatectomized host and the transplant received portal blood, it responded as would a similar nontransplanted liver remnant, whereas the host liver remnant response was considerably diminished, indicating utilization of the factor by the transplant so that little was available for stimulation of the host liver. Such findings are difficult to relate to reduction of inhibitor by partial hepatectomy as a factor in regeneration. They more readily suggest that a disturbance of the “normal” relationship between the quantity of PBF available and the number of hepatic cells present results in the regenerative response. With proliferation of liver cells and restoration of the “equilibrium,” regeneration ceases. Studies relative to the nature, site of origin, mechanism of action, and regulation of concentration of PBF are in progress.

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Supported by USPHS Grants AM-13228 and AI-08206.

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