In a paper published this week in the prestigious medical magazine "Genes and Development", a group from the departments of Obstetrics and Gynecology at the Hadassah University Hospital and Developmental Biology and Pathology at the Hebrew University Medical School demonstrates that pregnancy restores liver regeneration in aged mice.
Tissue regenerative capacity declines with age, and healing in response to injury is delayed. This effect is observed in liver, skin, bone, hematopoietic system, blood vessels, nerve, and muscle. It is attributed to altered function of many biologic processes such as changes in growth factors or extra-cellular matrix functions, accumulation of DNA damage, increase in intracellular oxygen reactive species and a decline in progenitor cell responsiveness. It was recently shown that connecting the circulation of a young and old mouse could restore the regenerative capacity of muscle in the old mouse.
Pregnancy is a unique natural state in which animals partly share blood systems – an adult animal (the pregnant mother) is exposed to an extremely young animal (the fetus). In the work published now the group from Jerusalem (Dr. Yuval Gielchinsky, Prof. Neri Laufer, Mr. Efi Weitman, Dr. Rinat Abramovich, Dr. Zvi Grannot, Prof. Yehudit Bergman and Dr. Eli Pikarsky) demonstrates a remarkable ability of pregnancy to rejuvenate the regenerative capacity of livers of old mice.
Partial hepatectomy was used as a model for acute organ loss of function due to surgical stress as found following trauma or cancer liver surgery. Two days following hepatectomy, young non pregnant and pregnant mice demonstrated normal volume regeneration and none died due to the procedure. Old non pregnant mice were able to restore less than half of the liver volume and suffered a 47% mortality rate. In contrast, pregnancy markedly enhanced liver regeneration in old mice and reduced mortalily to 9%.
Liver regeneration following partial hepatectomy, usually occurs through proliferation of liver tissue cells (hepatocytes) and is greatly impaired during aging. This work shows that pregnancy causes a switch from proliferation (hyperplasia)-based liver regeneration to a cell growth (hypertrophy)-mediated regeneration process.
By inhibiting signals of the intracellular pathway that serves as the key mediator of the switch from proliferation to hypertrophy in pregnant mice, the researchers were able to block hypertrophy, while increasing hepatocyte proliferation in hepatectomized pregnant mice. Moreover, pharmacological activation of this pathway in aged non-pregnant mice was sufficient to induce the hypertrophy module of liver regeneration, mimicking the pregnant state. This treatment dramatically improved hepatic regenerative capacity and survival of aged mice.
These findings demonstrate that regeneration via proliferation - the default module in non-pregnant mice, is severely compromised by age. However, regeneration via cell-growth, employed in pregnant mice, is relatively resistant to the detrimental effects of aging. Activation of such alternative regenerative modules, rather than rejuvenation of default pathways, could be a useful therapeutic strategy for ameliorating age-related functional deterioration.
The article summarizes 4 years of research. The research team has already registered a provisional patent for the development of a medication based on their findings. The patent was registered through Hadasit and Yissum, the technology transfer arms of Hadassah and the Hebrew university.
"This discovery is of specific value with regard to aged organisms, as this means of regeneration is unaffected by age", the researchers say. "It is possible that similar means could be employed to enhance the ability of the liver to regenerate in aged individuals. Such advances could have considerable impact on such individuals who are eligible for and/or in need of liver surgery, yet are at significant risk of surgical complications".