Pre-activation of mesenchymal stem cells with TNF-α, IL-1β and nitric oxide enhances its paracrine effects on radiation-induced intestinal injury.
Conditioned medium from mesenchymal stem cells (MSC-CM) may represent a promising alternative to MSCs transplantation, however, the low concentrations of growth factors in non-activated MSC-CM hamper its clinical application. Recent data indicated that the paracrine potential of MSCs could be enhanced by inflammatory factors. Herein, we pre-activated bone-marrow-derived MSCs under radiation-induced inflammatory condition (MSC(IEC-6(IR))) and investigated the evidence and mechanism for the differential effects of MSC-CM(IEC-6(IR)) and non-activated MSC-CM on radiation-induced intestinal injury (RIII). Systemic infusion of MSC-CM(IEC-6(IR)), but not non-activated MSC-CM, dramatically improved intestinal damage and survival of irradiated rats. Such benefits may involve the modulation of epithelial regeneration and inflammation, as indicated by the regeneration of intestinal epithelial/stem cells, the regulation of the pro-/anti-inflammatory cytokine balance. The mechanism for the superior paracrine efficacy of MSC(IEC-6(IR)) is related to a higher secretion of regenerative, immunomodulatory and trafficking molecules, including the pivotal factor IGF-1, induced by TNF-α, IL-1β and nitric oxide partially via a heme oxygenase-1 dependent mechanism. Together, our findings suggest that pre-activation of MSCs with TNF-α, IL-1β and nitric oxide enhances its paracine effects on RIII via a heme oxygenase-1 dependent mechanism, which may help us to maximize the paracrine potential of MSCs.
1] Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China [2] Department of Gastroenterology, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China.
Hao
H
Chen
Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China.
Xiao-Hui
XH
Min
Department of Gastroenterology, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China.
Qi-Yi
QY
Wang
Division of Gastroenterology, David Geffen School of Medicine at University of California, Los Angeles, USA.
Felix W
FW
Leung
Department of Gastroenterology, Ganzhou People's Hospital, Ganzhou, People's Republic of China.
Liu
L
Shi
Department of Gastroenterology, Affiliated Hospital of Guangdong Medical College, Zhanjian, People's Republic of China.
Yu
Y
Zhou
Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China.
Tao
T
Yu
Department of Neurology, Shenzhen Sixth People's Hospital, Shenzhen, People's Republic of China.
Chuan-Ming
CM
Wang
Department of Reproductive Medicine Center, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, People's Republic of China.
Geng
G
An
Department of Gastroenterology, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China.
Wei-Hong
WH
Sha
Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China.
Qi-Kui
QK
Chen
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D017077:Culture Media, Conditioned / Q000494:pharmacology*; D051547:Heme Oxygenase-1 / Q000378:metabolism; D007249:Inflammation / Q000209:etiology / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism*; D007410:Intestinal Diseases / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D019899:Paracrine Communication; D011829:Radiation Dosage; D011833:Radiation Injuries, Experimental / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D051381:Rats; D012038:Regeneration / Q000187:drug effects; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D017077:Culture Media, Conditioned; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D007334:Insulin-Like Growth Factor I; D051547:Heme Oxygenase-1