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November 24, 2015

Like building Lego blocks, cell sheets used to treat heart disease

Inclusion of gelatin hydrogel microspheres (GHM) between sheets improves cell survival. Left, stacks of sheets without GHM. Right, stacks of sheets with GHM. Brown indicates cells that express cardiac troponin T, a heart cell marker. Scale bars, 50 µm.

The use of biodegradable microspheres makes for simple stem cell therapy against heart disease.

In cell therapies for heart disease, heart cells are transplanted as cell sheets that are laid over the heart. To minimize both the preparation time of the heart cells and the surgery time, several sheets are stacked onto each other and transplanted at the same time. However, in this scenario, the sheets in the inner layers of the stacks are deprived of oxygen and other nutrients, thus their cells will often die before or shortly after transplantation compromising the therapy.

A possible solution to this problem would be to insert tiny pillars between the sheets, which would create enough space between sheets so that all would have access to the surrounding environment and sustain cell survival. Researchers at the Center for iPS Cell Research and Application (CiRA), Kyoto University, have found that gelatin hydrogel microspheres could act as these pillars and show that transplanting stacks of cell sheets with these microspheres significantly increased the survival of mice with heart failure.

"The method uses new 3D tissue engineering that can be used in surgery and other research," says CiRA Professor Jun Yamashita, whose lab demonstrated the surgical benefits of this approach in cooperation with other labs at Kyoto University. Analogous to binding several blocks of Lego, Yamashita and his lab placed cell sheets on top of one another by building one sheet and then coating it with the microspheres before layering the next. Because of experimental space limitations, stacks only five sheets high could be made at a time, but larger stacks could be made by connecting three five-sheet stacks using the same hydrogel strategy.

The method was used to transplant cardiac cells into ill mice. As mice are relatively small animals, the number of cells needed for the transplantation is dwarfed by the number that will be required in humans, but there is reason to believe that the same system will apply. "We have already made these stacks using human heart cells and found better survival in Petri dishes," explains Yamashita. "But we have yet to transplant the cells into larger animals for confirmation."

The transplantation of cell sheets is used for organs besides the heart, such as the liver or kidneys, and the same problem of cell death in the inner layers of stacked sheets exists. For this reason Yamashita is eager to share his technique with other researchers. "My lab studies the heart, but there is no reason the same method cannot be used to study other organs," he said.

Paper Details
  • Journal: Scientific Reports
  • Title: Efficient long-term survival of cell grafts after myocardial infarction with thick viable cardiac tissue entirely from pluripotent stem cells
  • Authors: Takehiko Matsuo1,2,3, Hidetoshi Masumoto1,2,3, Shuhei Tajima2, Takeshi Ikuno1,2,3, Shirori Katayama1,2, Kenji Minakata3, Tadashi Ikeda3, Koehi Yamamizu1,2, Yasuhiko Tabata2, Ryuzo Sakata3, and Jun K Yamashita1,2
  • Author Affiliations:
    1. Center for iPS Cell Research and Application (CiRA), Kyoto University
    2. Graduate School of Medicine, Kyoto University
    3. Department of Cardiovascular Surgery, Kyoto University
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