mRNA translational dynamics mediates totipotent-like reprogramming.

IRAK4 constrains cellular plasticity during chemically-induced cell fate reprogramming into multiple lineages

These findings establish IRAK4 as a regulator that constrains cellular plasticity potentially by coordinating chromatin accessibility and cell cycle dynamics, which may facilitate the establishment of multi-lineage states.

Translational cell fate reprogramming and regenerative medicine enabled by microphysiological systems.

This review discusses how organoids and OoC-based platforms are being leveraged to study and enhance cell fate reprogramming, repair, and regeneration across multiple tissues and outlines current limitations, including scalability, standardization, and biomaterial constraints.

A fast 2C-induction method reveals a barrier role of SP2 for totipotency

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

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.

Revisiting Pluripotency Acquisition: A Unified Framework for Reprogramming Strategies

The criteria for direct lineage reprogramming, atypical pluripotent reprogramming and noncanonical pluripotent reprogramming are delineated, and novel approaches like bacterial ribosome‐mediated cell fate conversion are explored like bacterial ribosome‐mediated cell fate conversion.

Canonical and isomiR products of miR-142 enhance dendritic cell reprogramming.

MicroRNAs (miRNAs) regulate gene expression and generate isoforms (isomiRs) with distinct targeting properties, but their roles in cellular specification and reprogramming remain poorly understood. Here, we investigated miRNAs and isomiRs during direct reprogramming to conventional type 1 dendritic cells (cDC1s), identifying miR-124 and miR-142 as facilitators of the process. The canonical miR-124-3p strand induced a permissive chromatin landscape enriched for cooperative transcription factor motifs, thereby transiently increasing reprogramming efficiency. In contrast, miR-142 enhanced lineage fidelity by repressing fibroblast identity and activating cDC1-specific programs through cooperating isomiRs that drove XCR1 expression and increased type 3 interferon production. In addition, miR-142 mimics enhanced cancer cell reprogramming and anti-tumor immunity in vivo. Finally, we developed RNA-based cDC1 reprogramming using transcription factor mRNAs combined with miRNA mimics. Together, these findings uncover miRNA isoform diversity as a programmable regulatory layer in immune cell specification and establish RNA-driven reprogramming as a non-viral strategy for cancer immunotherapy.