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Peer-reviewedCC BY-NC-NDStem cell research & therapy

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

  • Yumei Luo1,2,3
  • Detu Zhu1
  • Jinjin Tian1
  • Ping Li1
  • Xi Qin3
  • Junzhi Wang4,5
5 affiliations
  1. 1Department of Obstetrics and Gynecology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, Greater Bay Area Higher Education Joint Laboratory of Maternal- Fetal Medicine, The Third Affiliated Hospital, Guangzhou Medical University, 63 Duobao Road, Lwan District, 510150, Guangzhou, China.
  2. 2Biologics Testing and Evaluation Center, Guangzhou National Laboratory, 9 Xingdaohuan North Road, Haizhu District, 510320, Guangzhou, China.
  3. 3State Key Laboratory of Drug Regulatory Science, Institute of Biological Products, National Institutes for Food and Drug Control, 31 Huatuo Road, Daxing District,, 102629, Beijing, China.
  4. 4Biologics Testing and Evaluation Center, Guangzhou National Laboratory, 9 Xingdaohuan North Road, Haizhu District, 510320, Guangzhou, China. [email protected].
  5. 5State Key Laboratory of Drug Regulatory Science, Institute of Biological Products, National Institutes for Food and Drug Control, 31 Huatuo Road, Daxing District,, 102629, Beijing, China. [email protected].
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Abstract

Background

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.Methods

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).Results

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.Conclusions

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.

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Cite

BibTeXRIS
BibTeX
@article{luo2026circrna,
  title = {{A circRNA platform for safe partial reprogramming and rejuvenation of mesenchymal stem cells without pluripotent conversion.}},
  author = {Yumei Luo and Detu Zhu and Jinjin Tian and Ping Li and Xi Qin and Junzhi Wang},
  journal = {Stem cell research \& therapy},
  year = {2026},
  month = jul,
  doi = {10.1186/s13287-026-05193-0},
  url = {https://europepmc.org/article/MED/42907856},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - A circRNA platform for safe partial reprogramming and rejuvenation of mesenchymal stem cells without pluripotent conversion.
AU  - Yumei Luo
AU  - Detu Zhu
AU  - Jinjin Tian
AU  - Ping Li
AU  - Xi Qin
AU  - Junzhi Wang
PY  - 2026
DA  - 2026/07/01
JO  - Stem cell research & therapy
DO  - 10.1186/s13287-026-05193-0
UR  - https://europepmc.org/article/MED/42907856
AB  - Background  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.Methods  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).Results  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.Conclusions  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.
SN  - 1757-6512
ER  -