Nonsenescent Hsp27-upregulated MSCs implantation promotes neuroplasticity in stroke model.
Cellular senescence induces changes in cellular physiology, morphology, proliferative capacity, and gene expression. Stem cell senescence might be one of the major issues of limited efficacy of stem cell transplantation. In this study, we demonstrated that implantation of human umbilical cord mesenchymal stem cells (hUCMSCs) cultured in human umbilical cord serum (hUCS) significantly enhanced neuroplasticity and angiogenesis in stroke and ischemic limb models. Immunophenotypic analysis indicated that hUCMSCs cultured in hUCS had more small and rapidly self-renewing cells than those expanded in FCS. The main cause of greater senescence in FCS-cultured cells was increased generation of reactive oxygen species (ROS). Proteome profiling showed significantly more senescence-associated vimentin in FCS-cultured hUCMSCs than in hUCS-cultured hUCMSCs. In contrast, there was significant upregulation of heat shock protein 27 (Hsp27) in the hUCS-cultured hUCMSCs. By gene targeting, we found that overexpression of Hsp27 may downregulate vimentin expression through inhibition of the nuclear translocation of p65 (NF-κB signaling). Thus, an interaction between Hsp27 and vimentin may modulate the degree of senescence in hUCS- and FCS-cultured hUCMSCs. In summary, hUCMSCs exhibiting senescence are detrimental to cell engraftment and differentiation in animal models via activation of NF-κB pathway. Human stem cells incubated in hUCS might reduce the senescent process through upregulation of Hsp27 to increase implantation efficiency.
Liu
Shih-Ping
SP
Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan.
Ding
Dah-Ching
DC
Wang
Hsiao-Jung
HJ
Su
Ching-Yuan
CY
Lin
Shinn-Zong
SZ
Li
Hung
H
Shyu
Woei-Cherng
WC
D000818:Animals; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005312:Fetal Blood / Q000502:physiology; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D009473:Neuronal Plasticity; D010641:Phenotype; D020543:Proteome / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D020521:Stroke / Q000628:therapy*; D051996:Transcription Factor RelA / Q000378:metabolism; D014470:Umbilical Cord / Q000166:cytology; D015854:Up-Regulation; D014746:Vimentin / Q000378:metabolism
D055551:HSP27 Heat-Shock Proteins; D020543:Proteome; D017382:Reactive Oxygen Species; D051996:Transcription Factor RelA; D014746:Vimentin