Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6.
Quantitative assays for human DNA and mRNA were used to examine the paradox that intravenously (i.v.) infused human multipotent stromal cells (hMSCs) can enhance tissue repair without significant engraftment. After 2 x 10(6) hMSCs were i.v. infused into mice, most of the cells were trapped as emboli in lung. The cells in lung disappeared with a half-life of about 24 hr, but <1000 cells appeared in six other tissues. The hMSCs in lung upregulated expression of multiple genes, with a large increase in the anti-inflammatory protein TSG-6. After myocardial infarction, i.v. hMSCs, but not hMSCs transduced with TSG-6 siRNA, decreased inflammatory responses, reduced infarct size, and improved cardiac function. I.v. administration of recombinant TSG-6 also reduced inflammatory responses and reduced infarct size. The results suggest that improvements in animal models and patients after i.v. infusions of MSCs are at least in part explained by activation of MSCs to secrete TSG-6.
Lee
Ryang Hwa
RH
Center for Gene Therapy, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
Pulin
Andrey A
AA
Seo
Min Jeong
MJ
Kota
Daniel J
DJ
Ylostalo
Joni
J
Larson
Benjamin L
BL
Semprun-Prieto
Laura
L
Delafontaine
Patrice
P
Prockop
Darwin J
DJ
D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D054443:Cell Migration Assays; D020869:Gene Expression Profiling; D006321:Heart / Q000503:physiopathology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007262:Infusions, Intravenous; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D039902:Multipotent Stem Cells / Q000378:metabolism / Q000637:transplantation*; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D011655:Pulmonary Embolism / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism
D015815:Cell Adhesion Molecules; D018836:Inflammation Mediators; C513057:Tnfaip6 protein, mouse