Somatic Reprogramming—Above and Beyond Pluripotency

Abstract

Pluripotent stem cells, having long been considered the fountain of youth, have caught the attention of many researchers from diverse backgrounds due to their capacity for unlimited self-renewal and potential to differentiate into all cell types. Over the past 15 years, the advanced development of induced pluripotent stem cells (iPSCs) has displayed an unparalleled potential for regenerative medicine, cell-based therapies, modeling human diseases in culture, and drug discovery. The transcription factor quartet (Oct4, Sox2, Klf4, and c-Myc) reprograms highly differentiated somatic cells back to a pluripotent state recapitulated embryonic stem cells (ESCs) in different aspects, including gene expression profile, epigenetic signature, and functional pluripotency. With the prior fruitful studies in SCNT and cell fusion experiments, iPSC finds its place and implicates that the differentiated somatic epigenome retains plasticity for re-gaining the pluripotency and further stretchability to reach a totipotency-like state. These achievements have revolutionized the concept and created a new avenue in biomedical sciences for clinical applications. With the advent of 15 years’ progress-making after iPSC discovery, this review is focused on how the current concept is established by revisiting those essential landmark studies and summarizing its current biomedical applications status to facilitate the new era entry of regenerative therapy.

Metabolic control of induced pluripotency

“…One makes use of reprogramming TFs ( Takahashi and Yamanaka, 2006 ), while the other, which was developed more recently, uses a cocktail of several low-molecular-weight inhibitors and activators ( Hou et al, 2013 ). These approaches appear to be quite different in terms of the molecular mechanisms, staging, timing, and epigenetics of reprogramming, and a chemical-based approach has been practically uninvestigated in terms of its metabolic regulation [reviewed in ( Meir and Li, 2021 ; Lange et al, 2022 ; Wang et al, 2023 )]. Here, we discuss mainly the current view of the metabolic characteristics described for reprogramming from terminally differentiated somatic cells to pluripotent stem cells using the transgene-based strategy.…”

“…Four TFs, Oct4, Sox2, Klf4, and cMyc, convert the epigenome of somatic cells into an ESC-like pluripotent state. This approach has been extensively investigated in terms of the molecular mechanisms of its regulation by transcription factor network, metabolic, and epigenetic factors ( Buganim et al, 2013 ; Takahashi and Yamanaka, 2016 ; Deng et al, 2021 ; Teslaa and Teitell, 2015 ; Wu et al, 2016 ; Nishimura et al, 2019 ; Tsogtbaatar et al, 2020 ; Meir and Li, 2021 ). Stage-dependent landmarks of cell reprogramming have been identified in several studies through genome-wide analyses of the transcriptome, proteome, epigenome, and metabolome ( Maherali et al, 2007 ; Mikkelsen et al, 2008 ; Zhao et al, 2009 ; Stadtfeld et al, 2010 ; Gundry et al, 2012 ; Hansson et al, 2012 ).…”

“…These data, along with the results of single-cell expression analyses ( Buganim et al, 2012 ), suggest that iPSC formation is a stepwise process tightly controlled by a set of functionally linked genes. Based on the revealed stage-specific regulatory networks, three phases of the reprogramming process were identified: initiation, maturation, and stabilization ( Figure 1 ) ( Mikkelsen et al, 2008 ; Samavarchi-Tehrani et al, 2010 ; Buganim et al, 2012 ; David and Polo, 2014 ; Meir and Li, 2021 ). During the initiation stage, cells undergo mesenchymal-to-epithelial (MET) transition, characterized by the repression of transforming factor beta (TGFbeta), activation of bone morphogenic protein (BMP), stress activated of mitogen-activated protein kinase (MAPK) and p38 MAPK signaling, and extensive remodeling of chromatin ( Maherali and Hochedlinger, 2009 ; Li et al, 2010 ; Chen et al, 2011 ; Hu et al, 2014 ; Neganova et al, 2016 ; Neganova et al, 2017 ; Francesconi et al, 2019 ; Meir and Li, 2021 ).…”

Induced Pluripotent Stem Cells: Advances and Applications in Regenerative Medicine

“…Regardless of their combination, reprogramming factors remodel the epigenetic configuration of somatic cells in a way that allows for the conversion of these mature somatic cells into immature pluripotent SCs. Mechanisms of reprogramming into iPSCs are reviewed in detail by Meir and Li [29].…”

Advances in Cellular Reprogramming-Based Approaches for Heart Regenerative Repair

“…Therefore, translating these reprogramming approaches into a clinical setting requires a greater understanding of the epigenetic mechanism underlying various processes of cell lineage conversion. The related mechanisms of iPSC or iCM reprogramming have been systemically discussed elsewhere [ 110 , 111 , 112 , 113 ]. Here, the potential mechanisms of iCPC reprogramming ( Figure 3 B) are summarized.…”