2. Academic Validation
  3. Vascular organoid model of Hutchinson-Gilford progeria syndrome uncovers repression of the SRF pathway in premature aging

Vascular organoid model of Hutchinson-Gilford progeria syndrome uncovers repression of the SRF pathway in premature aging

  • Dev Cell. 2025 Nov 27:S1534-5807(25)00690-2. doi: 10.1016/j.devcel.2025.10.019.
Xiaoyan Sun 1,  Shanshan Che 1,  Hengchao Wang 2,  Yanling Fan 2,  Yingjie Ding 1,  Ansheng Tan 3,  Kuan Yang 1,  Jianli Hu 1,  Yixin Zhang 4,  Miyang Ma 4,  Jinghao Hu 5,  Shuhui Sun 6,  Shuai Ma 4,  Si Wang 7,  Juan Carlos Izpisua Belmonte 8,  Jing Qu 9,  Weiqi Zhang 10,  Guang-Hui Liu 11
Affiliations

Affiliations

  • 1 China National Center for Bioinformation and Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 2 China National Center for Bioinformation and Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
  • 3 Beijing Friendship Hospital, Capital Medical University, Beijing 100000, China.
  • 4 University of Chinese Academy of Sciences, Beijing 100049, China; State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China.
  • 5 Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Aging Translational Medicine Center, Beijing Municipal Geriatric Medical Research Center, Beijing Key Laboratory of Environment and Aging, Xuanwu Hospital Capital Medical University, Beijing 100053, China.
  • 6 Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China.
  • 7 State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Aging Translational Medicine Center, Beijing Municipal Geriatric Medical Research Center, Beijing Key Laboratory of Environment and Aging, Xuanwu Hospital Capital Medical University, Beijing 100053, China; Aging Biomarker Consortium, Beijing 100101, China.
  • 8 Altos Labs, Inc., San Diego, CA 94022, USA.
  • 9 University of Chinese Academy of Sciences, Beijing 100049, China; State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; Aging Biomarker Consortium, Beijing 100101, China. Electronic address: [email protected].
  • 10 China National Center for Bioinformation and Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Aging Biomarker Consortium, Beijing 100101, China. Electronic address: [email protected].
  • 11 University of Chinese Academy of Sciences, Beijing 100049, China; State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Aging Translational Medicine Center, Beijing Municipal Geriatric Medical Research Center, Beijing Key Laboratory of Environment and Aging, Xuanwu Hospital Capital Medical University, Beijing 100053, China; Human Organ Physiopathology Emulation System, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Aging Biomarker Consortium, Beijing 100101, China. Electronic address: [email protected].
PMID: 41314218 DOI: 10.1016/j.devcel.2025.10.019
Abstract

Vascular aging is a key driver of Cardiovascular Disease, yet models capturing its complexity in humans are lacking. Hutchinson-Gilford progeria syndrome (HGPS), a premature aging disorder caused by the LMNA mutation, provides a model to study accelerated vascular decline. Here, we developed a blood vessel Organoid (BVO) model from HGPS-mutant human embryonic stem cells (hESCs). These BVOs model HGPS vascular defects and reveal significant downregulation of serum response factor (SRF), a trend also observed in the vasculature of naturally aged primates. We show that SRF regulates angiogenesis-related genes, and that its overexpression rescues endothelial function in HGPS organoids. In summary, we establish a 3D human Organoid model of vascular aging, identify SRF as a pivotal regulator and provide a powerful platform for discovering geroprotective therapies.

Keywords

Hutchinson-Gilford progeria syndrome; SRF; aging; angiogenesis; blood vessel; endothelial cell; organoid; premature aging; senescence; vascular aging.

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