The ability of the liver to repair itself is well known, as the myth of Prometheus so evocatively demonstrates. However, the mechanisms required for liver repair are not yet well understood. Ding et al. from the laboratory of Shahin Rafii at Weill Cornell Medical College have shown that endothelial cells play a critical role in liver regeneration. Not only do they line the blood vessels and expand when needed for vascularization, but liver sinusoidal endothelial cells (LSECs) also promote hepatocyte growth in tissue repair by secreting critical factors.
Surgical resection of 70 percent of mouse liver (3 lobes) rapidly induces compensatory hypertrophy and proliferation in the remnant lobes. Nearly all of the remnant hepatocytes undergo one or two cell cycles within the first three to four days, followed by replication of remnant bile duct cells and vessels, including the sinusoidal endothelium. In contrast to diffuse toxic liver injuries, the remnant liver after partial hepatectomy is relatively free of inflammation or cellular damage.
In an earlier publication, the Rafii lab showed that sinusoidal endothelium of the bone marrow provides essential support for proliferation of hematopoietic stem cells, in part through vascular endothelial growth factor (VEGF) and its receptors.1 Here, the authors hypothesized that VEGF receptor-expressing SECs play a critical role in the regenerative response to partial hepatectomy. Evidence is presented supporting a model in which LSECs elaborate “angiocrine trophogens,” inducing hepatocyte proliferation within the first four days after partial hepatectomy. Over subsequent days, the LSECs themselves proliferate, providing needed vessels within the new liver mass.
The investigators found that LSECs from mouse livers express VEGF receptor 3 (VEGF-R3) and -receptor 2 (-R2) but lack expression of CD34, which is expressed on many, but not all ECs. Within the adult mouse liver, VEGF-R2 and VEGF-R3 were restricted to LSECs. In the first four days after partial hepatectomy, hepatocytes proliferated rapidly, while LSECs did not. However, following the initial burst of hepatocyte replication, LSECs underwent “proliferative angiogenesis” in the regenerating remnant liver.
Using generalized and endothelial-specific gene deletion strategies, VEGF-R2 and VEGF-R3 were shown to be key players in this process. Differences in LSEC gene expression between normal and regenerating liver were investigated and Id1, a transcriptional regulator, was found to be upregulated after partial hepatectomy. Mice in which the Id1 gene is knocked out had defective regeneration after partial hepatectomy. The failure of Id1-null livers to regenerate normally could be rescued by transplantation into the portal circulation of wild-type LSECs. The investigators determined that Id1-null LSECs express much less hepatocyte growth factor (HGF) and Wnt2 than controls, while other factors such as thrombomodulin were unaffected. Restoration of HGF, Wnt2, or both into Id1-null LSECs partially restored hepatectomy-induced regeneration, with the combination of HGF and Wnt2 being more effective than either alone.
Thus, LSEC-derived HGF and Wnt2 are critical for liver regeneration after partial hepatectomy. This raises the intriguing possibility that LSECs or the angiocrine factors they produce might be exploited for therapeutic purposes in patients undergoing liver resection for tumor or organ donation or in patients receiving an inappropriately small liver allograft. Whether LSECs or their angiocrine factors play a similar role in repair after different types of liver injury is unknown. One of the most remarkable findings of the two studies from the Rafii laboratory is that ECs from the bone marrow and liver produce different growth factors in response to local damage. How endothelial cells in the different organs sense tissue damage and how they become specialized to provide unique factors remains a mystery.
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Kobayashi H, Butler JM, O’Donnell R, et al. Angiocrine factors from Akt-activated endothelial cells balance self-renewal and differentiation of haematopoietic stem cells. Nat Cell Biol. 2010. 12:1046-1056.