The Centriole as a Structural Ratchet That Restricts Cellular Reprogramming to Totipotency

Abstract

Somatic cell nuclear transfer succeeds (Wilmut et al., 1997) but depends on oocyte cytoplasm that has undergone natural centriole elimination. No method using transcription factors, small molecules, or culture conditions alone has produced sustained totipotency from a fully differentiated somatic cell—though transient totipotent-like states can be induced from pluripotent stem cells, and stable totipotent-like stem cells (TLSCs) have been derived from mouse embryonic stem cells through chemical chromatin remodeling (Yang et al., 2022). Here we propose the centriole functions as a structural stabilizer of the differentiated state. Through conservative replication, asymmetric inheritance, and active regulatory roles, the mother centriole physically maintains the somatic gene regulatory network. Oocytes eliminate centrioles before totipotency in every metazoan examined; the germline resets the hardware at each generation, but the soma cannot. We outline a three-phase protocol—Eliminate (PLK4 PROTAC-mediated centriole removal), Reprogram (Tet-On DUX4 plus TPRX1), and Rebuild (de novo centriole assembly)—and predict that centriole elimination combined with totipotency factors will yield stable, self-renewing totipotent cells, distinct from transient 8C-like cells. We specify six quantitative falsification criteria, compare four alternative models, and propose a two-phase experimental design with a composite totipotency index as the primary endpoint.