Short-term memory of danger signals or environmental stimuli in mesenchymal stem cells: implications for therapeutic potential.
Mesenchymal stem/stromal cells (MSCs) possess some characteristics of immune cells, including a pro-inflammatory phenotype, an immunosuppressive phenotype, antibacterial properties and the expression of Toll-like receptor proteins. Here we show that, similar to immune cells, MSCs retain information from danger signals or environmental stimuli for a period of time. When treated with the pro-inflammatory factors lipopolysaccharide (LPS) or tumor necrosis factor-α (TNF-α), MSCs display increased expression of IL-6, IL-8 and MCP-1. Following re-plating and several rounds of cell division in the absence of stimulating factors, the expression of IL-6, IL-8 and MCP-1 remained higher than in untreated cells for over 7 days. A spike in cytokine secretion occurred when cells were exposed to a second round of stimulation. We primed MSCs with LPS and LPS-primed MSCs had better therapeutic efficacy at promoting skin flap survival in a diabetic rat model than did unprimed MSCs. Finally, we found that several microRNAs, including miR146a, miR150 and miR155, along with the modification of DNA by 5-hydroxymethylcytosine (5hmC), mediate the MSC response to LPS and TNF-α stimulation. Collectively, our data suggest that MSCs have a short-term memory of environmental signals, which may impact their therapeutic potential.
Key Laboratory of Systems Bioengineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin, China.
Guang-Yang
GY
Liu
Beijing Institute of Radiation Medicine (BIRM), Beijing, China.
Yang
Y
Liu
307 Hospital of the Chinese People's Liberation Army, Beijing, China.
Ying
Y
Lu
Beijing Institute of Radiation Medicine (BIRM), Beijing, China.
Ya-Ru
YR
Qin
Beijing Institute of Radiation Medicine (BIRM), Beijing, China.
Guo-Hu
GH
Di
301 Hospital of the Chinese People's Liberation Army, Beijing, China.
Yong-Hong
YH
Lei
301 Hospital of the Chinese People's Liberation Army, Beijing, China.
Hu-Xian
HX
Liu
Key Laboratory of Systems Bioengineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin, China.
Yan-Qi
YQ
Li
Key Laboratory of Systems Bioengineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin, China.|Beijing Institute of Radiation Medicine (BIRM), Beijing, China.
Chutse
C
Wu
Beijing Institute of Biotechnology (BIB), Beijing, China.
Xian-Wen
XW
Hu
Beijing Institute of Radiation Medicine (BIRM), Beijing, China.
Hai-Feng
HF
Duan
D044503:5-Methylcytosine / Q000031:analogs & derivatives / Q000378:metabolism; D000273:Adipose Tissue / Q000166:cytology; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D018932:Chemokine CCL2 / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D007156:Immunologic Memory / Q000187:drug effects; D016130:Immunophenotyping; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013524:Surgical Flaps / Q000502:physiology; D014022:Tissue Survival / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D018932:Chemokine CCL2; D015850:Interleukin-6; D016209:Interleukin-8; D008070:Lipopolysaccharides; D035683:MicroRNAs; D014409:Tumor Necrosis Factor-alpha; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine