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The generation of induced renal epithelial cells (iRECs) from fibroblasts holds great promise for regenerative medicine in renal disease (Kaminski et al. 2016, 2017; Allison 2017; Wyatt and Dubois 2017). Previous study reported that repetitive transduction of separate H1, E, P, and H4 lentiviruses convert mouse and human fibroblasts into iRECs in vitro (Kaminski et al. 2016). However, the inefficient iREC generation has become a major hurdle in the field in deciphering renal reprogramming mechanisms, modeling kidney diseases and directing iREC reprogramming in vivo (Allison 2017; Wyatt and Dubois 2017). The current renal reprogramming approach suffers from heterogeneous, weak and uncontrollable expression of RFs. This requires an advanced vector system for a high and controllable expression in fibroblasts to improve reprogramming efficiency.
Hnf1β, Emx2, Pax8, and Hnf4α are four transcriptional factors residing at the top of transcriptional hierarchy in renal gene regulatory networks (Miyamoto et al. 1997; Heliot et al. 2013; Paces-Fessy et al. 2012; Desgrange et al. 2017; Naylor et al. 2013; Bouchard et al. 2002; Narlis et al. 2007; Marable et al. 2020). During the initiation of nephrogenesis, Hnf1β controls proximal-intermediate nephron segment identity through regulating Notch signaling components (Lfng, Dll1 and Jag1) and Irx1/2 (Heliot et al. 2013). Hnf4α participates in the differentiation of Cdh6-expressing progenitors into proximal tubular epithelial cells (Marable et al. 2020). Pax8 interacts with Pax2 to regulate nephron differentiation and kidney branching morphogenesis (Narlis et al. 2007). Interestingly, Hnf4α is also essential for conversion of fibroblasts to functional hepatocytes (Huang et al. 2014). During organogenesis, faithful execution of developmental programs for tissue patterning and organ formation require a precise dosage and temporal expression of regulatory transcriptional factors (Miyamoto et al. 1997; Heliot et al. 2013; Paces-Fessy et al. 2012; Desgrange et al. 2017; Naylor et al. 2013; Bouchard et al. 2002; Narlis et al. 2007; Marable et al. 2020). Disruption of this delicate balance is likely to compromise tissue specification, patterning and cell reprogramming (Liu et al. 2022; Sun et al. 2019; Grand et al. 2023). For instance, the absence of HNF1β in nephron progenitors of the metanephric mesenchyme disrupts the interaction of Notch signaling and Irx1/2, resulting in defects in nephron differentiation, and proximal and distal tubule development (Heliot...