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Frontiers in Biology

Front. Biol.    2016, Vol. 11 Issue (2) : 75-84     DOI: 10.1007/s11515-016-1396-0
Chemical-only reprogramming to pluripotency
Behnam Ebrahimi()
Yazd Cardiovascular Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
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Direct reprogramming technology has emerged as an outstanding technique for the generation of induced pluripotent stem cells (iPSCs) and various specialized cells directly from somatic cells of different species. Reprogramming techniques conventionally use viral vectors encoding transcription factors to induce fate conversion. However, the introduction of transgenes limits the therapeutic applications of the reprogrammed cells. To overcome safety-related concerns, small molecules offer some advantages over the existing methods for the control of gene expression and induction of cell fate conversion. Technical advances in optimizing concentrations, durations, structures, and combinations of small molecules make chemical reprogramming a safe and feasible method. This review provides a concise overview of cutting-edge findings regarding chemical-only reprogramming as one of the integration-free approaches to iPSC generation.

Keywords cellular reprogramming      small molecule      chemical reprogramming      induced pluripotency      regenerative medicine     
Corresponding Authors: Behnam Ebrahimi   
Just Accepted Date: 12 April 2016   Issue Date: 17 May 2016
 Cite this article:   
Behnam Ebrahimi. Chemical-only reprogramming to pluripotency[J]. Front. Biol., 2016, 11(2): 75-84.
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Starting cells Induction Stage (chemical agents) Maturation Product cells References
1 Mouse fibroblasts Stage 1: a cocktail of five small molecules, “VC6PF” (VPA, CHIR99021, 616452 (RepSox), Parnate (or tranylcypromine), and forskolin), was used for 16–20 days.Stage 2: small-molecule, DZNep (Z), was added to the VC6PF for the next 20–24 days.TTNPB (T) was used as an enhancer.[C6FZ essential compounds;VT optional compounds] Reprogramming medium was replaced with 2i-medium with dual inhibition (2i) of glycogen synthase kinase-3 (GSK3) and mitogen-activated protein kinase (ERK) with CHIR99021 and PD0325901, respectively for the last 12–16 days. Chemically-induced pluripotent stem cells (CiPSCs) Hou et al., 2013
2 Mouse fibroblasts Chemical cocktail consists of VC6PFT plus BrdU were added from day 0 to day 32, and Z (DZNep) was added from day 16 to day 32. The minimal influential set was BrdU, CHIR99021, RepSox (6) and forskolin. After day 32, medium containing chemicals was replaced with the 2i-medium. Chemically induced pluripotent stem cells (CiPSCs) Long et al., 2015
3 Mouse fibroblasts Stage 1: VC6PF+ EPZ004777+ AM580 (A) for 16 daysStage 2: VC6PFZ+ A+ SGC0946+ 5-aza-dc for 12 days N2B27/ 2i+ LIF for 12 days Chemically induced pluripotent stem cells (CiPSCs) Zhao et al., 2015
4 Mouse neural stem cells (NSCs) and Stage 1: 0.5 mM VPA, 15 mM CHIR, 2 mM 616452, 10 mM Parnate, 20 mM forskolin, 1 mM Ch 55, 5 mM EPZ.Stage 2: From day 20, 0.05 mM DZNep was added into the stage 1 chemical reprogramming medium. 2i-medium (with DMEM/F-12 containing N2 and B27 supplements) from day 40-44.(2i-medium: Knockout DMEM containing 10% KSR, 10% FBS+ 2 mM GlutaMAX, 1% NEAA, 55 mM b-mercaptoethanol+ 3 mM CHIR99021+ 1 mM PD0325901+ 10 ng/ml mouse LIF) Chemically induced pluripotent stem cells (CiPSCs) Ye et al., 2016
5 Mouse fibroblasts Stage 1: 0.5 mM VPA, 10 mM CHIR, 10 mM 616452, 10 mM Parnate, 10 mM forskolin, 0.05 mM AM580.Stage 2: from day 20, 0.05 mM DZNep was added into the stage 1 chemical reprogramming medium. 2i-medium (with DMEM/F-12 containing N2 and B27 supplements) from day 40. Chemically induced pluripotent stem cells (CiPSCs) Ye et al., 2016
6 Mouse small intestinal epithelial cells (IECs) Stage 1: 0.5 mM VPA, 10 mM CHIR, 20 mM 616452, 10 mM Parnate, 10 mM forskolin, 0.05 mM AM 580).Stage 2: From day 16, 0.05 mM DZNep was added into the stage 1 chemical reprogramming medium, and AM580 was withdrawn. 2i-medium (with DMEM/F-12 containing N2 and B27 supplements) from day 40. Chemically induced pluripotent stem cells (CiPSCs) Ye et al., 2016
Tab.1  Different protocols that have been used for chemical-only induction of pluripotency
Small-molecule Effect Role in generation of Necessity reference
Forskolin (F) Activator of adenylate cyclase Mouse CiPSC Essential inducer Hou et al., 2013; Long et al., 2015; Zhao et al., 2015;Ye et al., 2016
TTNPB (T) A synthetic retinoic acid receptor (RAR) ligand; activates retinoic acid receptors Mouse CiPSC Enhancer Hou et al., 2013; Long et al., 2015
Parnate (P, Tranylcypromine) An epigenetic modifier that inhibits lysine-specific demethylase 1 (LSD1) Mouse CiPSC Essential inducer Hou et al., 2013; Long et al., 2015; Zhao et al., 2015;Ye et al., 2016
5-aza-dc (5-Aza-2′-deoxycytidine) Inhibitor of DNA methyltransferase Mouse CiPSC Enhancer Zhao et al., 2015
VPA (V, valproic acid) an inhibitor of histone deacetylase (HDACs) Mouse CiPSC Essential inducer Hou et al., 2013; Long et al., 2015; Zhao et al., 2015;Ye et al., 2016
CHIR99021 An inhibitor of GSK-3 kinases Mouse CiPSC Essential inducer Hou et al., 2013; Long et al., 2015; Zhao et al., 2015;Ye et al., 2016
RepSox (6, or 616452) An inhibitor of TGF-b pathways Mouse CiPSC Essential inducer Hou et al., 2013; Long et al., 2015; Zhao et al., 2015;Ye et al., 2016
DZNep (Z, 3-Deazaneplanocin A) An S-adenosylhomocysteine synthesis inhibitor and a histone methyltransferase EZH2 inhibitor Mouse CiPSC Essential inducer (Hou et al., 2013) andEnhancer (Long et al., 2015)(Ye et al., 2016) Hou et al., 2013; Long et al., 2015; Zhao et al., 2015;Ye et al., 2016
PD0325901 (P) An inhibitor of the MEK/ERK pathway Mouse CiPSC A component of maturation medium Ye et al., 2016
BrdU (B, Bromodeoxyuridine) A synthetic analog of the nucleoside thymidine Mouse CiPSC Essential inducer Long et al., 2015
EPZ004777 (E) An inhibitor DOT1L methyltransferase Mouse CiPSC Essential inducer Zhao et al., 2015
AM580 (A) An agonist of retinoic acid receptor a (RARa) Mouse CiPSC Enhancer Zhao et al., 2015
SGC0946 (S) An inhibitor DOT1L methyltransferase Mouse CiPSC Enhancer Zhao et al., 2015
LIF (Leukemia inhibitory factor) An interleukin 6 class cytokine that inhibits differentiation of mouse embryonic stem cells and iPSCs Mouse CiPSC A component of maturation medium Zhao et al., 2015; Ye et al., 2016
Tab.2  Different small molecules and factors that have been used in chemical-only reprogramming to pluripotency
Fig.1  Pluripotent reprogramming of somatic cells using small molecules alone. Generally, three steps have been exploited by different authors for chemical-only reprogramming to pluripotency. Abbreviations are explained in Table 1 and Table 2. MM indicates maturation medium.
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