Simultaneous silencing of TGF-β1 and COX-2 reduces human skin hypertrophic scar through activation of fibroblast apoptosis
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Jia Zhou1,*, Yixuan Zhao1,*, Vera Simonenko2,*, John J. Xu3, Kai Liu1, Deling Wang3, Jingli Shi3, Tianyi Zhong3, Lixia Zhang3, Lun Zeng4, Bin Huang4, Shenggao Tang5, Alan Y. Lu5, A. James Mixson6, Yangbai Sun1, Patrick Y. Lu2 and Qingfeng Li1
1Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
2Sirnaomics, Inc., Gaithersburg, MD, USA
3Suzhou Sirnaomics Pharmaceuticals, Ltd., Biobay, Suzhou, China
4Guangzhou Xiangxue Pharmaceuticals, Co. Ltd., Guangzhou, China
5Guangzhou Nanotides Pharmaceuticals, Co. Ltd., Guangzhou, China
6Department of Pathology, School of Medicine, University of Maryland, Baltimore, MD, USA
*These authors contributed equally to this work and share co-first authorship
Qingfeng Li, email: [email protected]
Patrick Y. Lu, email: [email protected]
Yangbai Sun, email: [email protected]
Keywords: siRNA therapeutics, hypertrophic scar, TGF-β1, COX-2, synergistic effect
Received: November 16, 2016 Accepted: August 26, 2017 Published: September 14, 2017
Excessive skin scars due to elective operations or trauma represent a challenging clinical problem. Pathophysiology of hypertrophic scars entails a prolonged inflammatory and proliferative phase of wound healing. Over expression of TGF-β1 and COX-2 play key regulatory roles of the aberrant fibrogenic responses and proinflammatory mediators. When we silenced TGF-β1 and COX-2 expression simultaneously in primary human fibroblasts, a marked increase in the apoptotic cell population occurred in contrast to those only treated with either TGF-β1 or COX-2 siRNA alone. Furthermore, using human hypertrophic scar and skin graft implant models in mice, we observed significant size reductions of the implanted tissues following intra-scar administration of TGF-β1/COX-2 specific siRNA combination packaged with Histidine Lysine Polymer (HKP). Gene expression analyses of those treated tissues revealed silencing of the target gene along with down regulations of pro-fibrotic factors such as α-SMA, hydroxyproline acid, Collagen 1 and Collagen 3. Using TUNEL assay detection, we found that the human fibroblasts in the implanted tissues treated with the TGF-β1/COX-2siRNAs combination exhibited significant apoptotic activity. Therefore we conclude that a synergistic effect of the TGF-β1/COX-2siRNAs combination contributed to the size reductions of the hypertrophic scar implants, through activation of fibroblast apoptosis and re-balancing between scar tissue deposition and degradation.
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