Although there are clinical advances in mechanical circulatory support devices and heart transplantation, the ultimate therapy for a failing heart may be cardiac regeneration from reprogrammed somatic cells or induced pluripotent stem cells, which avoids the pitfalls in ethics of embryonic cells, device anticoagulants, or immunosuppressants (Heilmann 2008, Mauritz et al. 2008, Narazaki et al. 2008, Passier et al. 2008, Sauer 2008, Schenke-Layland et al. 2008, Siepe et al. 2008, Tulloch et al. 2008). Prior studies found nucleostemin (GNL3) may play a pivotal role in cardiac repair (Tjwa and Dimmeler 2008, Siddiqi et al. 2008). On the other hand, SOX2-OCT4-NANOG complex, the ectopically induced transcription factors for induced pluripotent stem (iPS) cells, is the key to stem cell pluripotency (Cyranoski 2008, Mauritz et al. 2008, Narazaki et al. 2008, Tulloch et al. 2008). We would like to explore their interactions by bioinformatic approach for future molecular biologists (Yosef et al. 2008, Garg et al. 2008).

Literature review was done with NCBI online Entrez Gene and PubMed to identify the candidate molecules that may interact with nucleostemin (GNL3), SOX2, OCT4 (POU5F1), and NANOG (Mauritz et al. 2008, Schenke-Layland et al. 2008, Siddiqi et al. 2008, Tjwa and Dimmeler 2008, Tulloch et al. 2008, Yosef et al. 2008). Ingenuity Pathway Analysis (IPA) 7.5 ® was then used to build the pathway networks exploiting the interplays of interactions with GNL3 and SOX2-OCT4-NANOG. Functional analyses of pathophysiological processes as well as canonical pathways were conducted and integrated.

Functional pathway networks were built for nucleostemin (GNL3), with the interactions with the iPS (SOX2-OCT4-NANOG) network in the subcellular level (Fig. 1​). In the GNL3 network, molecules related to cardiovascular system development and function were identified: CDKN2A, TP53 (tumor protein p53), ID3, NPM1, and IL2 (p=8.4e-4 ~ 9.9e-4 by right-tailed Fisher Exact Test). In canonical pathways, PPP2R5A involved in cardiac beta-adrenergic signaling and Fgf (fibroblast growth factor) involved in human embryonic stem cell pluripotency. Nucleostemin was found having interactions in common with NANOG of the iPS networks via two molecules: Fgf and TP53.

In the exploratory analysis, the functional pathway networks of nucleostemin and iPS interact via TP53 (tumor protein P53) and Fgf (fibroblast growth factor), which could be further investigated to provide clues for the future research of postnatal cardiac regeneration (Huang et al. 2008).