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Background <p>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.</p> Methods <p>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 <i>ESRG</i>, we demonstrated that circ-OSK delivery alone is insufficient to transform MSCs into induced pluripotent stem cells (iPSCs).</p> Results <p>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.</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月26日

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

摘要

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.