A circRNA platform for safe partial reprogramming and rejuvenation of mesenchymal stem cells without pluripotent conversion.

Authors

Yumei Luo, Detu Zhu, Jinjin Tian, Ping Li, Xi Qin, Junzhi Wang

Published in

Stem cell research & therapy. Volume 17. Issue 1. Jul 26, 2026. Epub Jul 26, 2026.

Abstract

Mesenchymal stem cells (MSCs) are widely used in cell therapies; however, replicative senescence during in vitro expansion limits their potency and consistency. Partial reprogramming has emerged as a promising strategy to rejuvenate aged cells, yet concerns regarding unintended pluripotent conversion have hindered its translational application.
Here we developed a circular RNA (circRNA)-based platform enabling safe partial reprogramming and rejuvenation of MSCs. We generated a lipid nanoparticle (LNP)-delivered circRNA co-expressing OCT4, SOX2, and KLF4 (circ-OSK) to achieve transient and coordinated expression of partial reprogramming factors without genomic modification in MSCs. Using a rigorously validated droplet digital PCR (ddPCR) system targeting the pluripotency marker ESRG, we demonstrated that circ-OSK delivery alone is insufficient to transform MSCs into induced pluripotent stem cells (iPSCs).
Circ-OSK-mediated partial reprogramming significantly rejuvenated senescent late-passage MSCs by reducing senescence-associated β-galactosidase activity, DNA damage markers, and inflammatory cytokine secretion, while preserving canonical MSC surface markers and genome stability, and restoring proliferative, migratory and tri-lineage differentiation capacities at a level comparable to early-passage MSCs. The rejuvenated MSCs generated through this process are defined as partially reprogrammed MSCs (prMSCs). Further RNA-seq analysis revealed that prMSCs restored youthful gene expression and promoted a stress resilient and regenerative transcriptional program via repressing the PI3K-Akt signaling pathway. Combined RNA-seq and SNP array analysis confirmed circ-OSK-mediated partial reprogramming retained MSC identity and genome integrity without pluripotent conversion.
Our study has established a circRNA-mediated partial reprogramming strategy that rejuvenates MSCs without pluripotent conversion, offering a safety-oriented approach to enhance the potency and quality of MSC-based cell therapy products.

PMID:
42907856
Bibliographic data and abstract were imported from PubMed on 23 Oct 2026.

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