Functional genomic screening during somatic cell reprogramming identifies Dkk3 as a roadblock of pancreatic regeneration

The reprogramming process partly eliminates disease- and aging-associated phenotypes, inducing a „partial cure” or „rejuvenation” in pluripotent stem cells as shown in studies using somatic cells from centenarians or chronically sick patients as templates. Interestingly, adult stem cells share common features with their pluripotent counterparts, such as differentiation potential and self-renewal, and at least partially share certain molecular programs. Thus, we propose that studying somatic cell reprogramming could serve as a tool to gain valuable insights into adult stem cell fitness and organ regeneration. As logical consequence we have successfully applied a straightforward functional genomics approach using RNA-interference techniques during iPS formation. This way we have identified a set of factors limiting both cellular reprogramming and stem cell fitness in the hematopoietic system. Since Dkk3 (Dickkopf 3) is a factor limiting these two features, we aimed to investigate the role of Dkk3 during liver and pancreas regeneration upon injury. To do so, we used Dkk3 null mice to examine its role in a cerulein-induced acute pancreatitis context. First, there was no effect acute injury but Dkk3 loss appeared relevant in the regeneration phase of the pancreas. Specifically, we demonstrated that DKK3 inactivation triggers a better pancreatic acinar regeneration four days after pancreatitis induction. Furthermore, DKK3 knockout mice display a significant decrease of acinar-to-ductal metaplasia lesions, correlated with lower edema and inflammation scores, and a diminished fibrotic content. Additional mechanistical insights are given by organoid cultures derived from wild type and Dkk3 null pancreata. In contrast, partial hepatectomy in Dkk3 null mice revealed just a trend toward better regeneration. As suggested by these results, DKK3 appears to act as a brake of acinar regeneration after pancreatic insult in a tissue-spefic manner.