Notch activation enhances mesenchymal stem cell sheet osteogenic potential by inhibition of cellular senescence.
Our previous studies have confirmed the therapeutic effects of mesenchymal stem cell (MSC) monolayer sheet transplantation on allograft repair. A limiting factor in their application is the loss of MSC multi-potency as a result of high density sheet culture-induced senescence. In the study reported in this article, we tested whether Notch activation could be used to prevent or delay sheet culture-induced cell aging. Our results showed that, during in vitro long-term (5-day) cell sheet culture, MSCs progressively lose their progenitor characteristics. In contrast, Notch activation by Jagged1 in MSC sheet culture showed reduced cellular senescence and cell cycle arrest compared with control MSCs without Notch activation. Importantly, knockdown of Notch target gene Hes1 totally blocked the inhibition effect of Jagged1 on cellular senescence. Finally, the in vivo allograft transplantation data showed a significant enhanced callus formation and biomechanical properties in Notch activation cultured long-term sheet groups when compared with long-term cultured sheet without Notch activation. Our results suggest that Notch activation by Jagged1 could be used to overcome the stem cell aging caused by high density sheet culture, thereby increasing the therapeutic potential of MSC sheets for tissue regeneration.
Department of Orthopedics, Shengjing Hospital, China Medical University, Shenyang, China.
Ye
Y
Tian
Department of Anesthesiology, Shengjing Hospital, China Medical University, Shenyang, China.
Ying
Y
Xu
Department of Orthopedics, Shengjing Hospital, China Medical University, Shenyang, China.
Taiyang
T
Xue
Department of Orthopedics, Shengjing Hospital, China Medical University, Shenyang, China.
Longgang
L
Chen
Department of Orthopedics, Shengjing Hospital, China Medical University, Shenyang, China.
Bin
B
Shi
Department of Orthopedics, Spine Research Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Bing
B
Shu
Department of Orthopedics, University of Rochester Medical Center, Rochester, NY, USA.
Chao
C
Xie
Department of Orthopedic Surgery, Louisiana State University Health Sciences Center, Shreveport, LA, USA.
Massimo
M
Max Morandi
Department of Orthopedic Surgery, Louisiana State University Health Sciences Center, Shreveport, LA, USA.
Todd
T
Jaeblon
Department of Orthopedic Surgery, Louisiana State University Health Sciences Center, Shreveport, LA, USA.
John V
JV
Marymont
Department of Orthopedic Surgery, Louisiana State University Health Sciences Center, Shreveport, LA, USA.
Yufeng
Y
Dong
D000818:Animals; D059447:Cell Cycle Checkpoints / Q000502:physiology; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D006801:Humans; D000072100:Jagged-1 Protein / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D010012:Osteogenesis / Q000502:physiology*; D051880:Receptors, Notch / Q000378:metabolism*; D012038:Regeneration / Q000502:physiology; D000072056:Transcription Factor HES-1 / Q000378:metabolism
D000072100:Jagged-1 Protein; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1