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  • Decoupling Cellular Rejuvenation from Oncogenic Plasticity: A Single-Cell and Multi-Omic Framework for Identity-Preserving Partial Reprogramming

  • Maryam Heydari,1 Shirin Farivar,2,*
    1. Department of Cell and Molecular Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, 1983969411, Evin, Tehran, Iran
    2. Department of Cell and Molecular Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, 1983969411, Evin, Tehran, Iran


  • Introduction: Partial reprogramming can reverse selected molecular features of aging and improve tissue function without establishing pluripotency, but its interpretation requires separating molecular age, lineage identity, plasticity depth, and cellular or clonal fate. These dimensions can change asynchronously: rejuvenation may precede overt dedifferentiation, accompany temporary suppression of mature identity, or emerge through regenerative progenitor-like states. Conversely, incomplete recovery, organ dysfunction, or unfavorable clonal behavior may remain invisible to molecular clocks or identity markers. This review examines how single-cell, multi-omic, lineage, and cancer-genetic evidence can distinguish identity-preserving rejuvenation from oncogenic plasticity.
  • Methods: This integrative review synthesizes direct evidence from partial, transient, cyclic, and targeted reprogramming with mechanistic studies, single-cell and multi-omic lineage approaches, and cancer-plasticity comparators. Findings were organized around temporal remodeling, lineage fidelity and reversibility, heterogeneity, provenance, genotype, clonal dynamics, functional recovery, and long-term oncologic or systemic outcomes. Direct partial-reprogramming findings were distinguished from methodological or cancer-derived comparators, and computationally inferred trajectories were not equated with experimentally observed ancestry or fate.
  • Results: Evidence shows that molecular rejuvenation, identity remodeling, developmental depth, and fate are related but non-equivalent. DNA-methylation age and youthful molecular features can improve before major somatic-identity loss, whereas deeper bounded exposure can transiently suppress mature programs followed by regulatory and functional recovery. Beneficial regeneration may also involve fetal- or progenitor-like states in heart, liver, intestine, epidermis, muscle, and neural systems. Thus, uninterrupted mature identity is not required for every useful outcome; the critical issue is whether appropriate lineage competence is durably maintained or restored after withdrawal. A key conceptual distinction concerns age-associated mesenchymal drift versus epithelial–mesenchymal transition (EMT). Mesenchymal drift is an aging-associated program observed across tissues and may include stromal-composition effects, whereas EMT denotes epithelial-state remodeling toward partial, hybrid, or more mesenchymal states. Although they can share extracellular-matrix and mesenchymal-associated features, they are not mechanistically or operationally equivalent; reversal of mesenchymal drift should therefore not be interpreted as demonstrated EMT suppression or cancer prevention. Single-cell profiling resolves heterogeneous responses and separates within-cell remodeling from shifts in cell-type abundance, but a molecular snapshot cannot establish ancestry, persistence, reversibility, or malignant potential. Pseudotime, optimal transport, and RNA velocity can nominate trajectories, yet do not directly record parent–descendant relationships. Lineage tracing, lineage barcodes, genotype-linked transcriptomics, and multimodal lineage methods provide provenance needed to test whether apparently rejuvenated states generate appropriately constrained descendants. Spatial profiling adds location but cannot substitute for lineage provenance. Cancer studies show that high-plasticity states, hybrid epithelial–mesenchymal states, and lineage switching become consequential when persistent, heritable, selectively advantageous, or linked to malignant initiation, dissemination, drug resistance, or recurrence. These properties define warning criteria rather than proving equivalence between cancer states and partial-reprogramming intermediates. Genotype and exposure further modify risk. TP53/RB1-deficient cancer models demonstrate genotype-dependent lineage plasticity, while full-reprogramming studies show selection against damaged cells and enrichment of pre-existing mutation-bearing clones. These findings motivate baseline genotyping and serial clonal surveillance without establishing identical selection during partial rejuvenation. Safety also extends beyond cancer: sustained systemic OSKM can cause hepatocyte dedifferentiation, oxidative stress, DNA-damage signaling, apoptosis, and lethal liver dysfunction without tumors. Antioxidant rescue reduces stress and improves survival without abolishing reprogramming-associated plasticity, separating acute stress-mediated toxicity from plasticity itself. We therefore propose an eight-domain operational framework integrating molecular rejuvenation, functional restoration, lineage fidelity, reversibility, genomic integrity, clonal stability, plasticity containment, and long-term oncologic and systemic safety. Implementation requires baseline characterization, controlled induction, intermediate sampling, withdrawal, recovery, and long-term follow-up, with state measurements linked to provenance, genotype, clone behavior, tissue function, and pathology. The central evidence gap is the scarcity of experiments connecting those signatures to the subsequent behavior of the same lineages.
  • Conclusion: Identity-preserving partial reprogramming should be defined by durable molecular and functional benefit carried by cells whose lineage competence and clonal behavior remain appropriately constrained after the initiating stimulus is withdrawn. Single-cell and multi-omic profiling are necessary but insufficient unless state is connected to provenance and longitudinal fate. The most defensible translational objective is the least disruptive reprogramming trajectory that achieves durable rejuvenation while avoiding persistent lineage diversion, unfavorable clonal selection, organ dysfunction, and oncogenic escape. Future studies should prioritize genotype-aware lineage tracing, withdrawal and recovery analyses, and long-latency functional and pathological validation.
  • Keywords: Partial reprogramming single-cell multi-omics lineage tracing oncogenic plasticity

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