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Original Research

Smooth Muscle Cells Differentiated from Reprogrammed Embryonic Lung Fibroblasts Through DKK3 Signalling are Potent for Tissue Engineering of Vascular Grafts

Eirini Karamariti, Andriana Margariti, Bernhard Winker, Xiaocong Wang, Xuechong Hong, Dilair Baban, Jiannis Ragoussis, Yi Huang, Jing-Dong J Han, Mei Mei Wong, Can M Sag, Ajay M Shah, Yanhua Hu, Qingbo Xu
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https://doi.org/10.1161/CIRCRESAHA.111.300415
Circulation Research. 2013;CIRCRESAHA.112.300415
Originally published March 25, 2013
Eirini Karamariti
Cardiovascular, King's College London, Section on Vascular Biology and Medicine, 125 Coldharbour Lane, London, N/A, SE5 9NU, UNITED KINGDOM
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Andriana Margariti
Cardiovascular, King's College London, King's College London, James Black Centre, 125 Coldharbour Lane, London, SE5 9NU, UNITED KINGDOM
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Bernhard Winker
Cardiovascular, King's College London, Section on Vascular Biology and Medicine, 125 Coldharbour Lane, London, N/A, SE5 9NU, UNITED KINGDOM
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Xiaocong Wang
Cardiovascular, King's College London, 125 Coldharbour Lane, London, N/A, SE5 9NU, UNITED KINGDOM
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Xuechong Hong
Cardiovascular, King's College London, 125 Coldharbour Lane, London, N/A, SE5 9NU, UNITED KINGDOM
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Dilair Baban
WTCHG, University of Oxford, Roosevelt Drive, Oxford, N/A, OX3 7BN, UNITED KINGDOM
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Jiannis Ragoussis
University of Oxford
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Yi Huang
Shanghai Institutes for Biological Sciences, 320 Yueyang Road, Shanghai, N/A, 200031, CHINA
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Jing-Dong J Han
Shanghai Institutes for Biological Sciences, 320 Yueyang Road, Shanghai, N/A, CHINA
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Mei Mei Wong
Cardiology, King's College London, James Black Centre, 125 Coldharbour Lane, London, N/A, SE5 9NU, UNITED KINGDOM
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Can M Sag
Cardiology, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UNITED KINGDOM
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Ajay M Shah
Cardiovascular, King`s College London, James Black Centre, 125 Coldharbour Lane, London, N/A, SE5 9NU, UNITED KINGDOM
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Yanhua Hu
Cardiovascular, King's College London, Section on Vascular Biology and Medicine, 125 Coldharbour Lane, London, N/A, SE5 9NU, UNITED KINGDOM
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Qingbo Xu
Cardiovascular, King's College London, Section on Vascular Biology and Medicine, 125 Coldharbour Lane, London, N/A, SE5 9NU, UNITED KINGDOM
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  • For correspondence: qingbo.xu@kcl.ac.uk
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Abstract

Rationale: Smooth muscle cells (SMCs) are a key component of tissue-engineered vessels. However, the sources by which they can be isolated are limited.

Objective: We hypothesized that a large number of SMCs could be obtained by direct reprogramming of fibroblasts, i.e. direct differentiation of specific cell lineages prior to the cells reaching the pluripotent state.

Methods and Results: We designed a combined protocol of reprogramming and differentiation of human neonatal lung fibroblasts. Four reprogramming factors (OCT4, SOX2, KLF4, c-MYC) were overexpressed in fibroblasts under reprogramming conditions for 4 days with cells defined as partially induced pluripotent stem (PiPS) cells. PiPS cells did not form tumours in vivo after subcutaneous transplantation in SCID mice and differentiated into SMCs when seeded on collagen IV and maintained in differentiation media (DM). PiPS-SMCs expressed a panel of SMC markers at mRNA and protein levels. Furthermore, the gene DKK3 was found to be involved in the mechanism of PiPS-SMC differentiation. It was revealed that DKK3 transcriptionally regulated SM22 by potentiation of Wnt signalling and interaction with Kremen 1. Finally, PiPS-SMCs repopulated decellularised vessel grafts and ultimately gave rise to functional tissue-engineered vessels when combined with previously established PiPS-endothelial cells (PiPS-ECs), leading to increased survival of SCID mice after transplantation of the vessel as a vascular graft.

Conclusions: We developed a protocol to generate SMCs from PiPS cells through a DKK3 signalling pathway, useful for generating tissue-engineered vessels. These findings provide a new insight into the mechanisms of SMC differentiation with vast therapeutic potential.

  • animal models
  • progenitor cell
  • smooth muscle differentiation
  • tissue engineering
  • mouse
  • stem cell
  • Received October 29, 2012.
  • Revision received March 19, 2013.
  • Accepted March 25, 2013.
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    Smooth Muscle Cells Differentiated from Reprogrammed Embryonic Lung Fibroblasts Through DKK3 Signalling are Potent for Tissue Engineering of Vascular Grafts
    Eirini Karamariti, Andriana Margariti, Bernhard Winker, Xiaocong Wang, Xuechong Hong, Dilair Baban, Jiannis Ragoussis, Yi Huang, Jing-Dong J Han, Mei Mei Wong, Can M Sag, Ajay M Shah, Yanhua Hu and Qingbo Xu
    Circulation Research. 2013;CIRCRESAHA.112.300415, originally published March 25, 2013
    https://doi.org/10.1161/CIRCRESAHA.111.300415

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    Smooth Muscle Cells Differentiated from Reprogrammed Embryonic Lung Fibroblasts Through DKK3 Signalling are Potent for Tissue Engineering of Vascular Grafts
    Eirini Karamariti, Andriana Margariti, Bernhard Winker, Xiaocong Wang, Xuechong Hong, Dilair Baban, Jiannis Ragoussis, Yi Huang, Jing-Dong J Han, Mei Mei Wong, Can M Sag, Ajay M Shah, Yanhua Hu and Qingbo Xu
    Circulation Research. 2013;CIRCRESAHA.112.300415, originally published March 25, 2013
    https://doi.org/10.1161/CIRCRESAHA.111.300415
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  • Basic, Translational, and Clinical Research
    • Smooth Muscle Proliferation and Differentiation
    • Vascular Biology
    • Growth Factors/Cytokines
    • Animal Models of Human Disease

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