Data_Sheet_11_Exploration of the Transcriptional Landscape of ALPPS Reveals the Pathways of Accelerated Liver Regeneration.DOCX
Background and Aims: ALPPS (associating liver partition and portal vein ligation for staged hepatectomy), a novel 2-staged hepatectomy, dramatically accelerates liver regeneration and thus enables extensive liver tumor resection. The signaling networks underlying the ALPPS-induced accelerated regeneration process are largely unknown.
Methods: We performed transcriptome profiling (TP) of liver tissue obtained from a mouse model of ALPPS, standard hepatectomy (68% model), and additional control surgeries (sham, PVL and Tx). We also performed TP using human liver biopsies (n = 5) taken from the occluded lobe and the future liver remnant (FLR) during the first step of ALPPS surgery (4–5 h apart). We used Oncofinder computational tools, which covers 378 ISPs, for unsupervised, unbiased quantification of ISP activity.
Results: Gene expression cluster analysis revealed an ALPPS specific signature: the IGF1R Signaling Pathway (Cell survival), the ILK Pathway (Induced cell proliferation), and the IL-10 Pathway (Stability determination) were significantly enriched, whereas the activity of the Interferon Pathway (Transcription) was reduced (p < 0.05). Further, the PAK- and ILK-associated ISPs were activated at an earlier time point, reflecting significant acceleration of liver regeneration (p < 0.001). These pathways, which were also recovered in human liver biopsies, control cell growth and proliferation, inflammatory response, and hypoxia-related processes.
Conclusions: ALPPS is not a straightforward addition of portal vein ligation (PVL) plus transection—it is more. The early stages of normal and accelerated liver regeneration are clearly discernible by a significantly increased and earlier activation of a small number of signaling pathways. Compounds mimicking these responses may help to improve the ALPPS method and further reduce the hospitalization time of the patient.
History
References
- https://doi.org//10.1016/S0002-9610(02)01373-9
- https://doi.org//10.1056/NEJMra065156
- https://doi.org//10.1097/SLA.0b013e31824856f5
- https://doi.org//10.1007/s00268-014-2513-3
- https://doi.org//10.1097/SLA.0b013e318266fa1f
- https://doi.org//10.1097/SLA.0b013e318248577d
- https://doi.org//10.1097/SLA.0000000000001087
- https://doi.org//10.1016/0016-5085(79)90418-9
- https://doi.org//10.1053/gast.2003.50098
- https://doi.org//10.1016/S0006-291X(88)81134-3
- https://doi.org//10.1002/jcp.1041350212
- https://doi.org//10.1586/egh.10.87
- https://doi.org//10.1073/pnas.72.3.1157
- https://doi.org//10.1126/science.1121435
- https://doi.org//10.1126/science.1123842
- https://doi.org//10.1038/sj.onc.1200891
- https://doi.org//10.1101/gad.390506
- https://doi.org//10.1084/jem.20070820
- https://doi.org//10.1084/jem.20092434
- https://doi.org//10.1016/j.jhep.2016.10.014
- https://doi.org//10.3389/fgene.2014.00055
- https://doi.org//10.1080/15384101.2017.1361068
- https://doi.org//10.18632/oncotarget.7209
- https://doi.org//10.3389/fmolb.2014.00008
- https://doi.org//10.1097/SLA.0000000000000949
- https://doi.org//10.1053/j.gastro.2012.08.043
- https://doi.org//10.1186/gb-2013-14-4-r36
- https://doi.org//10.1093/bioinformatics/bti394
- https://doi.org//10.1371/journal.pone.0107497
- https://doi.org//10.1080/15384101.2016.1147633
- https://doi.org//10.1002/hep.23525
- https://doi.org//10.1096/fj.05-4704fje
- https://doi.org//10.1002/hep.23059
- https://doi.org//10.1053/j.gastro.2004.08.055
- https://doi.org//10.1016/j.cytogfr.2011.01.001
- https://doi.org//10.1038/onc.2011.177
- https://doi.org//10.1038/onc.2009.119
- https://doi.org//10.3748/wjg.v19.i9.1380
- https://doi.org//10.1016/j.surg.2016.05.018
- https://doi.org//10.2353/ajpath.2006.060360
- https://doi.org//10.1002/hep.28809
- https://doi.org//10.1097/SLA.0000000000001696
- https://doi.org//10.2174/138161212802430521
- https://doi.org//10.1016/S1499-3872(15)60036-4
- https://doi.org//10.3727/096504015X14496932933575
- https://doi.org//10.1002/hep.29226