"Cell identity is established during development to acquire and maintain specialized cellular functions in somatic cells. Cellular reprogramming can manipulate cell identity, enabling the generation of desired cell types that provide broad applications in disease modelling, drug discovery and regenerative medicine. Using cellular factors, including oocyte components and transcription factors, mouse and human somatic cells can be reprogrammed into pluripotent stem (PS) cells.
Alternatively, we demonstrated that chemical stimulation can reprogram mouse somatic cells to PS cells by simple exposure to small molecules. This chemical reprogramming approach synergistically targets cell signalling pathways and epigenetic modifiers without gene manipulation, and offers considerable advantages for the development of pharmacological and therapeutic strategies. Moreover, this approach also enables lineage conversion between functional somatic cell types.
Nevertheless, previous attempts in chemical reprogramming have been unable to induce human PS (hPS) cells from somatic cells, which requires a full reset of the somatic epigenome. This failure may be related to the fact that human somatic cells have evolved to have a more stable epigenetic landscape to protect its cell identities from chemical-based perturbation.
A clue to overcome this barrier is provided by the remarkably versatile dedifferentiation processes in certain lower animals. For example, injured somatic cells in the axolotl can respond to external signals to initiate cell dedifferentiation, yielding a plastic state characterized by the loss of somatic cell identity, increased cell proliferation and reactivation of development-associated genes. Importantly, such a plastic state often has relatively open chromatin architecture with increased accessibility, which is essential for inducing a new cell fate. Thus, we hypothesize that recreating such a plastic state is key for small molecules to unlock the restricted potency of human somatic cells and to permit the generation of hPS cells.
Chemically induced dedifferentiation
To induce human somatic cell dedifferentiation, we focused on identifying small molecules to disrupt fibroblast cell identity, promote cell proliferation and reactivate dedifferentiation-related genes. First, we tested the small molecules used in mouse chemical reprogramming, and identified a small molecule combination (CHIR99021, 616452 and TTNPB) that converted human fibroblasts into epithelial-like cells. An additional screening of chemical libraries found that Y27632, ABT869 and SAG further promoted the generation of the epithelial-like cells. Consistently, this treatment upregulated epithelial cell-related genes (KRT8, KRT18 and KRT19) and downregulated a panel of fibroblast marker genes , suggesting a loss of fibroblast identity. Immunofluorescence and quantitative PCR with reverse transcription (RT–qPCR) analysis showed LIN28A expression in the culture , an important gene that regulates dedifferentiation and regeneration in different species." [1]
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1. Nature volume 605, pages 325–331 (2022)
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