Editors' ChoiceAging

Regeneration Switch

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Science Signaling  23 Mar 2010:
Vol. 3, Issue 114, pp. ec88
DOI: 10.1126/scisignal.3114ec88

The capacity to heal and to regenerate tissues after damage decreases as animals age, and regeneration and healing in aged animals proceeds more slowly than in young ones. Because pregnancy affects many physiological processes, including some involved in healing, Gielchinsky et al. tested whether pregnancy also affected liver regeneration in aged (10- to 12-month-old) mice. Two days after partial hepatectomy, the total liver volume of aged pregnant mice had returned to about 96% of the preoperative volume, whereas aged nonpregnant mice had recovered only 46% of their original liver volume and young nonpregnant mice had recovered 82%. Pregnancy also improved survival after hepatectomy and increased the regenerating livers’ synthetic capacity. BrdU (5-bromo-2-deoxyuridine) labeling experiments indicated that liver regeneration in nonpregnant mice proceeded through a hyperplastic mechanism in which the increase in liver volume depended mainly on cell proliferation. In contrast, regeneration in pregnant or pseudopregnant mice was associated with an increase in the size (hypertrophy) of hepatocytes. In pregnant mice subjected to partial hepatectomy before delivery, regeneration returned to the hyperplastic mode after delivery, indicating that the switch to the hypertrophic mode was reversible. Because the mammalian target of rapamycin (mTOR) pathway is a key regulator of cell growth, the authors investigated the role of mTOR signaling in this switch. The abundance of phosphorylated forms of the mTOR targets Akt, S6 kinase, and 4E-BP1 increased in pregnant but not in nonpregnant mice assayed 1 to 4 days after hepatectomy. Treatment with the mTORC1 (mTOR complex 1) inhibitor rapamycin increased hepatocyte proliferation and prevented hepatocyte hypertrophy in pregnant mice after partial hepatectomy. Liver regeneration in young nonpregnant animals treated with bisperoxovanadium, an inhibitor of the mTOR signaling repressor PTEN (phosphatase and tensin homolog deleted on chromosome 10), involved the hypertrophic mechanism, and this switch from hyperplastic to hypertrophic modes was also prevented by treating the animals with rapamycin. mTOR signaling therefore modulates a reversible switch between hyperplastic and hypertrophic modes of liver regeneration. Because hypertrophic regeneration is not compromised by age as severely as hyperplastic regeneration is, this suggests a possible mechanism for improving liver regeneration in aged humans suffering from liver disease.

Y. Gielchinsky, N. Laufer, E. Weitman, R. Abramovitch, Z. Granot, Y. Bergman, E. Pikarsky, Pregnancy restores the regenerative capacity of the aged liver via activation of an mTORC1-controlled hyperplasia/hypertrophy switch. Genes Dev. 24, 543–548 (2010). [Abstract] [Full Text]

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