Totipotent-like reprogramming: Molecular machineries and chemical manipulations

Embryonic stem cells (ESCs) exhibit remarkable pluripotency, possessing the dual abilities of self-renewal and differentiation into any cell type within the embryonic lineage. Among cultivated mouse ESCs, a subpopulation known as 2-cell-like cells (2CLCs) displays a transcriptomic signature reminiscent of the 2-cell embryonic stage, with the capacity to differentiate into both embryonic and extraembryonic tissues. These 2CLCs have served as an invaluable totipotent-like cell model for deciphering the cellular and molecular mechanisms underlying the establishment of totipotency. Accumulating evidence has indicated that a multitude of regulators including transcription factors, epigenetic modifications, and RNA regulators, exert crucial functions in the reprogramming of ESCs towards 2CLCs. In addition to 2CLCs, alternative totipotent-like cell types can be induced and maintained through the administration of single or combined chemical supplements, offering promising cell resources for regenerative medicine. In this review, we summarize the current advancements in the molecular regulations of 2CLCs and chemical manipulations of totipotent-like cells in mice, providing a foundation for understanding the regulatory networks underlying cell totipotency.