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Peer-reviewedCC BY-NC-ND 4.0Cell Reports Medicine

Enhanced liver regeneration via targeted mRNA delivery for partial in vivo reprogramming

  • Beom-Ki Jo1
  • Young Seok Song2
  • Woohyun Song3,4
  • Hee-Ji Eom1
  • Yon Jae Lee2
  • Jumee Kim5
  • Seunghee Hong3,4
  • Seung-Woo Cho2,6,7
  • Hyuk-Jin Cha1,8
8 affiliations
  1. 1College of Pharmacy, Seoul National University, Seoul, Republic of Korea
  2. 2Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea
  3. 3Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea
  4. 4Brain Korea 21 (BK21) FOUR Program, Yonsei Education & Research Center for Biosystems, Yonsei University, Seoul, Republic of Korea
  5. 5College of Pharmacy, Sookmyung Women’s University, Seoul, Republic of Korea
  6. 6Cellartgen, Seoul, Republic of Korea
  7. 7Center for Nanomedicine, Institute for Basic Science (IBS), Seoul, Republic of Korea
  8. 8Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
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Abstract

Recent studies indicate that injury-induced dedifferentiation generates transient regenerative progenitors (TRPs), which support tissue repair across multiple organs, including the liver. In vivo partial reprogramming using Yamanaka factors (Oct4, Sox2, Klf4, and c-Myc; OSKM) produces intestinal TRPs closely resembling those arising from injury-induced dedifferentiation, but transgenic or viral approaches raise safety concerns because of prolonged expression. Here, we show that transient OSKM induction generates two distinct liver progenitor-like cell (LPLC) populations without injury and with limited activation of injury-associated immune responses. Single-nucleus RNA sequencing shows that one population resembles injury-induced LPLCs observed in acetaminophen-injured mouse and human livers. To develop a temporally controlled regenerative strategy, we establish a liver-targeted lipid nanoparticle system for OSKM mRNA delivery. OSKM mRNA-LNP treatment induces hepatocyte dedifferentiation and Sox9+ LPLC-like cell formation and is associated with enhanced regeneration after acetaminophen-induced injury. Together, these findings identify transient hepatic reprogramming as a strategy for inducing regenerative plasticity and support liver-targeted OSKM mRNA delivery as a potential approach for acute liver injury.

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Cite

BibTeXRIS
BibTeX
@article{jo2026enhanced,
  title = {{Enhanced liver regeneration via targeted mRNA delivery for partial in vivo reprogramming}},
  author = {Beom-Ki Jo and Young Seok Song and Woohyun Song and Hee-Ji Eom and Yon Jae Lee and Jumee Kim and Seunghee Hong and Seung-Woo Cho and Hyuk-Jin Cha},
  journal = {Cell Reports Medicine},
  year = {2026},
  month = oct,
  doi = {10.1016/j.xcrm.2026.103084},
  url = {https://doi.org/10.1016/j.xcrm.2026.103084},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Enhanced liver regeneration via targeted mRNA delivery for partial in vivo reprogramming
AU  - Beom-Ki Jo
AU  - Young Seok Song
AU  - Woohyun Song
AU  - Hee-Ji Eom
AU  - Yon Jae Lee
AU  - Jumee Kim
AU  - Seunghee Hong
AU  - Seung-Woo Cho
AU  - Hyuk-Jin Cha
PY  - 2026
DA  - 2026/10/01
JO  - Cell Reports Medicine
DO  - 10.1016/j.xcrm.2026.103084
UR  - https://doi.org/10.1016/j.xcrm.2026.103084
AB  - Recent studies indicate that injury-induced dedifferentiation generates transient regenerative progenitors (TRPs), which support tissue repair across multiple organs, including the liver. In vivo partial reprogramming using Yamanaka factors (Oct4, Sox2, Klf4, and c-Myc; OSKM) produces intestinal TRPs closely resembling those arising from injury-induced dedifferentiation, but transgenic or viral approaches raise safety concerns because of prolonged expression. Here, we show that transient OSKM induction generates two distinct liver progenitor-like cell (LPLC) populations without injury and with limited activation of injury-associated immune responses. Single-nucleus RNA sequencing shows that one population resembles injury-induced LPLCs observed in acetaminophen-injured mouse and human livers. To develop a temporally controlled regenerative strategy, we establish a liver-targeted lipid nanoparticle system for OSKM mRNA delivery. OSKM mRNA-LNP treatment induces hepatocyte dedifferentiation and Sox9+ LPLC-like cell formation and is associated with enhanced regeneration after acetaminophen-induced injury. Together, these findings identify transient hepatic reprogramming as a strategy for inducing regenerative plasticity and support liver-targeted OSKM mRNA delivery as a potential approach for acute liver injury.
SN  - 2666-3791
ER  -