MKK4 Liver Regeneration

The liver harbors a distinct capacity for endogenous regeneration; however, liver regeneration is often impaired in disease and therefore insufficient to compensate for the loss of hepatocytes and organ function. Here we describe a functional genetic approach for the identification of gene targets that can be exploited to increase the regenerative capacity of hepatocytes. Pools of small hairpin RNAs (shRNAs) were directly and stably delivered into mouse livers to screen for genes modulating liver regeneration. Our studies identify the dual-specific kinase MKK4 as a master regulator of liver regeneration. MKK4 silencing robustly increased the regenerative capacity of hepatocytes in mouse models of liver regeneration and acute and chronic liver failure. Mechanistically, induction of MKK7 and a JNK1-dependent activation of the AP1 transcription factor ATF2 and the Ets factor ELK1 are crucial for increased regeneration of hepatocytes with MKK4 silencing.

Based on this target identification and validation, a spin-off was founded and has successfully completed a first round of investment.

http://heparegenix.com/index.html

http://heparegenix.com/pdf/HepaRegeniX_Feb-2017_non-confidential.pdf

Torsten Wuestefeld, Marina Pesic, Ramona Rudalska, Daniel Dauch, Thomas Longerich, Tae-Won Kang, Tetyana Yevsa, Florian Heinzmann, Lisa Hoenicke, Anja Hohmeyer, Anna Potapova, Ina Rittelmeier, Michael Jarek, Robert Geffers, Maren Scharfe, Frank Klawonn, Peter Schirmacher, Nisar P. Malek, Michael Ott, Alfred Nordheim, Arndt Vogel, Michael P. Manns, Lars Zender: A Direct In Vivo RNAi Screen Identifies MKK4 as a Key Regulator of Liver Regeneration. The Journal Cell (2013), Elsevier Inc.