Fig. 6

Proposed mechanism of hypoxic-conditioned secretome effects on liver regeneration. Liver regeneration is essentially achieved by the combination of two distinct factors: cell proliferation (increase in the number of hepatocytes) and hypertrophy (increase in the size of hepatocytes). Cell proliferation is mediated by the IL-6/STAT3 pathway, and hypertrophy is mediated by the PI3K/PDK/Akt pathway. We provide two independent mechanisms by which hypoxic-conditioned secretome improves liver regeneration. First, hypoxic-preconditioned secretome promotes liver cell proliferation by persistent and uninhibited expression of STAT3 in the liver which is caused by decreased expression of SOCS3. Second, hypoxic-preconditioned secretome promotes liver cell hypertrophy by upregulating Akt expression which is activated by higher expression of SIRT1. IL interleukin, PDK1 3-phosphoinositide-dependent protein kinase 1, PI3K phosphoinositide 3-kinase, STAT3 signal transducers and activators of transcription 3, SIRT1 sirtuin 1, SOCS3 suppressor of cytokine signaling 3