Generation of functional mesothelial cells from human iPSCs that restore peritoneal integrity in experimental peritoneal injury

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Abstract
Long-term peritoneal injury results in loss of mesothelial integrity and impaired ultrafiltration, limiting the durability of peritoneal dialysis. Because primary human peritoneal mesothelial cells (PMCs) are difficult to obtain and expand, regenerative strategies for restoring peritoneal function have remained limited. We developed a protocol to differentiate human induced pluripotent stem cells (iPSCs) into functional peritoneal mesothelial-like cells (iPMCs). The molecular and functional characteristics of iPMCs were evaluated using gene expression analyses and functional assays, including comparison with a mesothelial cell model. The therapeutic effect of iPMCs was evaluated in a methylglyoxal-induced experimental peritoneal injury mouse model. iPMCs exhibited typical cobblestone morphology and expressed key mesothelial markers including CK18, WT1 and MSLN. Transcriptomic analysis demonstrated strong similarity between iPMCs and primary PMCs. In vivo, intraperitoneal administration of iPMCs partially improved peritoneal transport parameters in a mouse model of peritoneal injury. We successfully generated functional mesothelial cells from human iPSCs that reproduce mesothelial-like functional properties and suggest potential for restoring peritoneal integrity. This study demonstrates the feasibility of iPSC-derived mesothelial cells as a regenerative cell source for peritoneal repair and provides a foundation for future peritoneal regeneration therapy.
Funding Information
  • Japan Society for the Promotion of Science (25K11550)
  • Japan Society for the Promotion of Science (20K08598)
  • Japan Society for the Promotion of Science (21K08292)
  • Baxter Healthcare Corporation as an investigator-initiated research (IIR) program,
  • Kansai Medical University Molecular Imaging Center of Diseases
  • Katano Alumni Research Grant
  • Sanju Alumni Research Grant

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