pp 1–14 | Cite as

Mitochondrial fission protein 1 up-regulation ameliorates senescence-related endothelial dysfunction of human endothelial progenitor cells

  • Hsueh-Hsiao WangEmail author
  • Yih-Jer Wu
  • Ya-Ming Tseng
  • Cheng-Huang Su
  • Chin-Ling Hsieh
  • Hung-I Yeh
Original Paper



We investigated the contribution of mitochondrial dysfunction to the senescence of human endothelial progenitor cells (EPCs) expanded in vitro and the underlying molecular mechanism.

Methods and results

Serial passage increased cell doubling time and those cells reaching the doubling time for more than 100% were defined as senescent EPCs, of which the activity of therapeutic angiogenesis was attenuated in mouse ischemic hindlimbs. The senescent cells, in medium free of glucose and bicarbonate, showed impaired activity in migration and tube formation. Flow cytometry indicated increased content of reactive oxygen species, mitochondria, and calcium, while bioenergetic analysis showed increased oxygen consumption and reduced ATP content. Examination of mitochondrial network showed that senescence increased the length of the network and ultrastructure analysis exhibited elongated mitochondria. Immunoblotting of the senescent EPCs demonstrated decreased expression level of fission protein1 (Fis1). In rat EPCs, the Fis1 level was decreased in the animals aged 24 months or older, compared to those of 3 months. Silencing of Fis1 in the young EPCs using Fis1-specific siRNA leads to appearance of phenotype resembling those of senescent cells, including elevated oxidative stress, disturbed mitochondrial network, reduced mitochondria membrane potential, decreasing ATP content, lower proliferation activity, and loss of therapeutic potential in ischemic hindlimbs. Fis1 over-expression in senescent EPCs reduced the oxidative stress, increased the proliferation, and restored the cobble stone-like morphology, senescence, bioenergetics, angiogenic potential, and therapeutic activity.


In human EPCs, down-regulation of Fis1 is involved in mitochondrial dysfunction and contributes to the impaired activity of EPCs during the senescence process. Enhanced expression of Fis1 in senescent EPCs restores the youthful phenotype.


Angiogenesis Endothelial progenitor cells Mitochondrial fission protein 1 Senescence 



2′,7′-dichlorofluorescin diacetate




Dynamin-related protein 1


Endothelial progenitor cells


Fission protein 1




Mitochondrial deoxyribonucleic acid


MitoTracker Red CMXRos


Nonyl acridine orange


Optic atrophy 1


Oxygen consumption rate


Peripheral blood mononuclear cells


Reactive oxygen species


Voltage-dependent anion channel


Senescence-associated β-galactosidase



The authors acknowledge the supported provided from the Ministry of Science and Technology, Taiwan (Grant Nos. MOST 103-2320-B-715-004, MOST 104-2320-B-715-008-MY2, MOST 105-2632-B-715-001, MOST 106-2632-B-715-001, and MOST 107-2632-B-715-001), MacKay Memorial Hospital (Grant Nos. MMH-E-102003, MMH-MM-10703, and MMH-MM-10810), and Mackay Medical College (Grant Nos. 1041B16 and 1061B21), Taiwan.

Supplementary material

10456_2019_9680_MOESM1_ESM.pdf (7.7 mb)
Supplementary material 1 (PDF 7839 kb)
10456_2019_9680_MOESM2_ESM.pdf (3.1 mb)
Supplementary material 2 (PDF 3196 kb)


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Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Department of MedicineMackay Medical CollegeNew Taipei CityTaiwan
  2. 2.Departments of Internal Medicine and Medical ResearchMacKay Memorial HospitalTaipeiTaiwan

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