Small Molecule Epigenetic Modulators in Pure Chemical Cell Fate Conversion

Abstract

Although innovative technologies for somatic cell reprogramming and transdifferentiation provide new strategies for the research of translational medicine, including disease modeling, drug screening, artificial organ development, and cell therapy, recipient safety remains a concern due to the use of exogenous transcription factors during induction. To resolve this problem, new induction approaches containing clinically applicable small molecules have been explored. Small molecule epigenetic modulators such as DNA methylation writer inhibitors, histone methylation writer inhibitors, histone acylation reader inhibitors, and histone acetylation eraser inhibitors could overcome epigenetic barriers during cell fate conversion. In the past few years, significant progress has been made in reprogramming and transdifferentiation of somatic cells with small molecule approaches. In the present review, we systematically discuss recent achievements of pure chemical reprogramming and transdifferentiation.

Application of Small Molecules in the Central Nervous System Direct Neuronal Reprogramming

“…For the treatment of some neurological disorders, subtype-specific neurons should be induced in appropriate regions of the brain ( Smith et al, 2016 ). Recently, it has been proposed that some in vitro chemical-induced stable neurons could be constructed for brains by a three-dimensional (3D) bioprinting technology, which prints biodegradable materials with cells as 3D tissue ( Ho and Hsu, 2018 ; Yuan et al, 2020 ). In 2021, a lab bioprinted MSC-derived neural tissues successfully using a fibrin-based bioink and the RX1 bioprinter with the aid of SB431542, LDN-193189, purmorphamine, fibroblast growth factor 8 (FGF8), fibroblast growth factor-basic (bFGF), and brain-derived neurotrophic factor (BDNF) ( Restan Perez et al, 2021 ).…”

“…Furthermore, the increased intracellular levels of cAMP by Forskolin provide neurotrophic effects, reduce oxidant stress injury, and improve cellular survivability ( Xu et al, 2019 ). It has also been found that small molecules that target the cAMP/PKA pathway can overcome the interference of in vivo environment on transdifferentiation ( Yuan et al, 2020 ).…”

“…There are two types of neuronal reprogramming: indirect reprogramming and direct reprogramming ( Figure 1 ) ( Sato et al, 2019 ). The former is a two-step process, in which differentiated somatic cells are first reprogrammed into intermediated states such as induced pluripotent stem cells (iPSCs) or multipotent neural stem cells (iNSCs), followed by differentiation into neurons ( Kim et al, 2011 ; Ladewig et al, 2013 ; Liu et al, 2016 ; Yuan et al, 2020 ). The latter is the direct transformation of terminally differentiated cells into target mature cells without passing through the stages of pluripotent or multipotent cells, which is also known as transdifferentiation ( Kim et al, 2011 ; Ladewig et al, 2013 ; Liu et al, 2016 ; Mollinari et al, 2018 ; Yang et al, 2020a ; Yuan et al, 2020 ; Wang et al, 2021a ).…”

“…The former is a two-step process, in which differentiated somatic cells are first reprogrammed into intermediated states such as induced pluripotent stem cells (iPSCs) or multipotent neural stem cells (iNSCs), followed by differentiation into neurons ( Kim et al, 2011 ; Ladewig et al, 2013 ; Liu et al, 2016 ; Yuan et al, 2020 ). The latter is the direct transformation of terminally differentiated cells into target mature cells without passing through the stages of pluripotent or multipotent cells, which is also known as transdifferentiation ( Kim et al, 2011 ; Ladewig et al, 2013 ; Liu et al, 2016 ; Mollinari et al, 2018 ; Yang et al, 2020a ; Yuan et al, 2020 ; Wang et al, 2021a ). Since direct lineage reprogramming does not go through an intermediate stem cell state, it possesses the appealing features of a low likelihood of tumor formation, no age-resetting, a high conversion speed, and an efficient cell differentiation ( Yang et al, 2011 ; Li and Chen, 2016 ; Ma et al, 2019 ; Mollinari and Merlo, 2021 ).…”

Cell Fate Reprogramming in the Era of Cancer Immunotherapy

“…In an attempt to develop transgene-free reprogramming methods, neuronal reprogramming in glioma was recently induced with ROCK and mTOR inhibitors ( 199 ). Alternatively, Yuan et al induced a similar conversion with a small compound cocktail composed of forskolin, ISX9, DAPT, CHIR99021, and I-BET 151 ( 200 ).…”