Embryonic stem cells (ESCs) and induced pluripotent stem cell (iPSCs), i.e. somatic body cells reprogrammed into ESCs, are the most powerful sources of regenerative medicine. Pluripotency of iPSCs and ESCs bears the capacity to enable all possible cell and organ replacement strategies for regenerative and rejuvenating medicine. This cellular ability is unique and maintained under self-renewal culture propagation conditions that enable intracellular signaling mediators to stabilize the molecular circuits and functions of pluripotency via transcriptional and epigenetic mechanisms inter alia. Understanding these sustained networks that auto-equilibrate in steady states of reciprocatively regulated pluripotency factors that globally organize the stemness genome, transcriptome, and proteome, is crucial for future strategies of regenerative medicine. All stem cells are regulated by such stemness and differentiation circuits and ESC pluripotency is still their best model system. A self-sustaining network of transcriptional activators and repressors specifies the undifferentiated identity and gatekeeps differentiation via hierarchical master regulators like Oct-3/4, Nanog, Sox-2, and Klf-4 at its core (my project from 2004 to 2009). These factors are of the highest functional-regulatory order and can even globally reprogram specialized body cells into iPSCs. The mechanisms of stemness and differentiation are key to decode the postgenomic program of life and its overall complexity represents a new organizational challenge for system biology and open science, which will help to generate cell-based replacement materials and to heal genetic diseases like cancer. As a proof-of-principle, this work further analyzes the role of the signaling mediator β-catenin in stemness and pluripotency and reveals new transcriptional modalities, which further exemplifies the requirement to dissect all multi-functionalities in an open systems biology approach of open science and innovation, and proposes a stem cell hub termed iStemCore.
Keywords ESCs; IPSCs; Oct3/4; Nanog; KLF-4; Sox; Stemness; Beta-Catenin; CTNNB1; Cadherin; Stem Cells; Maintenance; Lif; Pluripotency; Wnt; Signaling; Systems Biology; Biomarker; Open Science; Cdh1; E-Cadherin; Cell Adhesion; Rex-1; TERT; Transcription; Factor; Network; Reprogramming; Biomedicine; Regenerative Medicine; Tissue, Cell; Engineering; Organ Replacement; Cell Fate; Cell Identity; Circuits
Abbreviations ESCs: Embryonic Stem Cells; IPSCs: Induced Pluripotent Stem Cell; HTS: HighThroughput Screening; HSCs : Hematopoietic Stem Cell; LOF: Loss-Of-Function; GOF: Gain-Of-Function; TERT: Telomerase reverse transcriptase; CTNNB1: gene encoding the βcatenin protein; Rex-1: Reduced expression 1 protein of the ZFP42 gene; Cdh-1: gene encoding the E-cadherin protein; iPSCs: induced pluripotent stem cells; SOPs: standard operating procedures; GSK3: glycogen synthase kinase