期刊
STEM CELLS
卷 36, 期 9, 页码 1393-1403出版社
WILEY
DOI: 10.1002/stem.2853
关键词
Spheroid; Preconditioning; Mesenchymal stem cell; Bone; Hydrogel
资金
- National Institute of Dental and Craniofacial Research of the National Institutes of Health [R01DE025475]
- T32 Animal Models of Infectious Disease Training Program Kirschstein-NRSA [T32 AI060555]
Cell-based approaches for musculoskeletal tissue repair are limited by poor cell survival and engraftment. Short-term hypoxic preconditioning of mesenchymal stem cells (MSCs) can prolong cell viability in vivo, while the aggregation of MSCs into spheroids increases cell survival, trophic factor secretion, and tissue formation in vivo. We hypothesized that preconditioning MSCs in hypoxic culture before spheroid formation would increase cell viability, proangiogenic potential, and resultant bone repair compared with that of individual MSCs. Human MSCs were preconditioned in 1% O-2 in monolayer culture for 3 days (PC3) or kept in ambient air (PC0), formed into spheroids of increasing cell density, and then entrapped in alginate hydrogels. Hypoxia-preconditioned MSC spheroids were more resistant to apoptosis than ambient air controls and this response correlated with duration of hypoxia exposure. Spheroids of the highest cell density exhibited the greatest osteogenic potential in vitro and vascular endothelial growth factor (VEGF) secretion was greatest in PC3 spheroids. PC3 spheroids were then transplanted into rat critical-sized femoral segmental defects to evaluate their potential for bone healing. Spheroid-containing gels induced significantly more bone healing compared with gels containing preconditioned individual MSCs or acellular gels. These data demonstrate that hypoxic preconditioning represents a simple approach for enhancing the therapeutic potential of MSC spheroids when used for bone healing.
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