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Adv Healthc Mater. 2017 May;6(9). doi: 10.1002/adhm.201601340. Epub 2017 Feb 23.

Spatially Assembled Bilayer Cell Sheets of Stem Cells and Endothelial Cells Using Thermosensitive Hydrogels for Therapeutic Angiogenesis.

Jun I1,2, Ahmad T1,3, Bak S1,3, Lee JY1,3, Kim EM1,3, Lee J1,3, Lee YB1,3, Jeong H2, Jeon H2, Shin H1,3.

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Department of Bioengineering, Institute for Bioengineering and Biopharmaceutical Research, Hanyang University, Seoul, 04763, Republic of Korea.
Center for Biomaterials, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea.
BK21 Plus Future Biopharmaceutical Human Resources Training and Research Team, Hanyang University, Seoul, 04763, Republic of Korea.


Although the coculture of multiple cell types has been widely employed in regenerative medicine, in vivo transplantation of cocultured cells while maintaining the hierarchical structure remains challenging. Here, a spatially assembled bilayer cell sheet of human mesenchymal stem cells and human umbilical vein endothelial cells on a thermally expandable hydrogel containing fibronectin is prepared and its effect on in vitro proangiogenic functions and in vivo ischemic injury is investigated. The expansion of hydrogels in response to a temperature change from 37 to 4 °C allows rapid harvest and delivery of the bilayer cell sheet to two different targets (an in vitro model glass surface and in vivo tissue). The in vitro study confirms that the bilayer sheet significantly increases proangiogenic functions such as the release of nitric oxide and expression of vascular endothelial cell genes. In addition, transplantation of the cell sheet from the hydrogels into a hindlimb ischemia mice model demonstrates significant retardation of necrosis particularly in the group transplated with the bilayer sheet. Collectively, the bilayer cell sheet is readily transferrable from the thermally expandable hydrogel and represents an alternative approach for recovery from ischemic injury, potentially via improved cell-cell communication.


cell sheet engineering; cell-cell interaction; endothelial cells; stem cells; thermosensitive hydrogels

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