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April 02, 2021

Enhanced muscle regeneration using stem cells

The Hidetoshi Sakurai laboratory reports two new markers that should advance iPS cell therapies for muscle degeneration.

Muscular dystrophy describes a group of muscle degenerative congenital diseases. The severity and rates differ between disease and patient, but in all cases the degeneration progresses, sometimes leaving patients in wheelchairs and unable to breathe without artificial respiration. With no present cure, scientists are experimenting with the transplantation of muscle progenitor cells, but the amounts needed can only be made from stem cells such as iPS cells. A new study by CiRA Associate Professor Hidetoshi Sakurai and colleagues report two cell surface receptors, CDH13 and FGFR4, that are expected to advance iPS cell therapies for these diseases.

Muscles are constantly torn and damaged through exercise and other activities. In healthy bodies, the muscle is quickly regenerated by muscle stem cells. In congenital diseases like muscular dystrophy, however, the rate of damage is too high. Scientists have therefore explored the transplantation of muscle progenitor cells as a form of regenerative cell therapy.

The development of skeletal muscle is known as myogenesis, and the gene MYF5 is one of four myogenic regulator factors that control this process. The activation of MYF5 in iPS cells is believed to mark the differentiation of iPS cells into muscle progenitor cells.

"MYF5 is the first myogenic regulator factor expressed in muscle development. It characterizes iPS cells that have differentiated into muscle progenitor cells. We can genetically modify cells to identify MYF5 expression in iPS cell differentiation, but this method is not an option for cell therapies because it risks mutations," said Minas Nalbandian, who earned his Ph.D. from the study.

Several groups have shown how to produce muscle progenitor cells from iPS cells. The problem, however, is the purity. Much like how a light bulb generates not just light, but heat and noise, iPS cell differentiation leads to a mixture of cells that include muscle progenitor cells.

"The challenge is to find markers that allow us to separate muscle progenitor cells from the other cell types," continued Nalbandian.

To purify a cell population, scientists commonly rely on receptors expressed on the surface of the cell. However, receptors that are exclusive for muscle progenitor cells are missing.

"We did a transcriptome analysis of cells purified by using a MYF5 reporter line and found that they expressed CDH13 and FGFR4. Cells that did not express MYF5 did not express these two receptors," Nalbandian said.

Using a standard cell sorter that separates cells based on their surface receptors, the scientists isolated cells that expressed either CDH13 or FGFR4 and then transplanted them into mice with damaged muscle. Good regeneration of the muscle was observed, unlike the transplantation of cells not expressing these receptors.

Other markers for muscle progenitor cells have been identified in the past, but the purity of the cells is not as high as with CDH13 or FGFR4. Sakurai, whose career has been devoted to using iPS cells for the regeneration of muscle, said that it is not enough to transplant cells with good regenerative properties. Purity is also to be considered.

"We know other markers for the differentiation of iPS cells into muscle progenitor cells. The problem is that other cells express these markers too. Along with good regeneration, purity is important, because it affects the quality of the regeneration. We expect the identification of CDH13 and FGFR4 will advance efforts for cell therapies to treat muscular dystrophy," he explained.

Paper Details
  • Journal: Stem Cell Reports
  • Title: Characterization of hiPSC-Derived Muscle Progenitors Reveals Distinctive Markers for Myogenic Cell Purification Toward Cell Therapy
  • Authors: Minas Nalbandian1, Mingming Zhao1, Naoshi Sugimoto1, Mitsuru Sasaki-Honda1,
    Tatsuya Jonouchi1, Antonio Lucena-Cacace2, Takuma Mizusawa3, Masahiko Yasuda3, Yoshinori Yoshida2,
    Akitsu Hotta1, and Hidetoshi Sakurai1
  • Author Affiliations:
    1. Department of Clinical Application, CiRA, Kyoto University, Kyoto, Japan
    2. Department of Cell Growth and Differentiation, CiRA, Kyoto University, Kyoto, Japan
    3. Central Institute for Experimental Animals, Kawasaki, Japan
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