Tonsil-derived mesenchymal stem cells incorporated in reactive oxygen species-releasing hydrogel promote bone formation by increasing the translocation of cell surface GRP78

Da Hyeon Choi, Kyeong Eun Lee, Se Young Oh, Si Min Lee, Beom Soo Jo, Jue Yeon Lee, Jong Chul Park, Yoon Jeong Park, Ki Dong Park, Inho Jo, Yoon Shin Park

Research output: Contribution to journalArticlepeer-review

Abstract

Controlling the senescence of mesenchymal stem cells (MSCs) is essential for improving the efficacy of MSC-based therapies. Here, a model of MSC senescence was established by replicative subculture in tonsil-derived MSCs (TMSCs) using senescence-associated β-galactosidase, telomere-length related genes, stemness, and mitochondrial metabolism. Using transcriptomic and proteomic analyses, we identified glucose-regulated protein 78 (GRP78) as a unique MSC senescence marker. With increasing cell passage number, GRP78 gradually translocated from the cell surface and cytosol to the (peri)nuclear region of TMSCs. A gelatin-based hydrogel releasing a sustained, low level of reactive oxygen species (ROS-hydrogel) was used to improve TMSC quiescence and self-renewal. TMSCs expressing cell surface-specific GRP78 (csGRP78+), collected by magnetic sorting, showed better stem cell function and higher mitochondrial metabolism than unsorted cells. Implantation of csGRP78+ cells embedded in ROS-hydrogel in rats with calvarial defects resulted in increased bone regeneration. Thus, csGRP78 is a promising biomarker of senescent TMSCs, and the combined use of csGRP78+ cells and ROS-hydrogel improved the regenerative capacity of TMSCs by regulating GRP78 translocation.

Original languageEnglish
Article number121156
JournalBiomaterials
Volume278
DOIs
StatePublished - Nov 2021

Keywords

  • Bone regeneration
  • Cell surface GRP78+
  • Glucose-regulated protein 78
  • ROS releasing hydrogel
  • Senescence
  • Tonsil-derived mesenchymal stem cells

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