Theranostics 2020; 10(8):3779-3792. doi:10.7150/thno.44115

Research Paper

Fasting before or after wound injury accelerates wound healing through the activation of pro-angiogenic SMOC1 and SCG2

Ming-Jie Luo1,2,3,4*, Shan-Shan Rao1,2,3*, Yi-Juan Tan1,3, Hao Yin1,3, Xiong-Ke Hu1,3, Yan Zhang3,5, Yi-Wei Liu3,5, Tao Yue1,3, Ling-Jiao Chen9, Li Li10, Ya-Rong Huang11, Yu-Xuan Qian1,3, Zheng-Zhao Liu3,5,8, Jia Cao1,3, Zhen-Xing Wang1,3, Zhong-Wei Luo1,3, Yi-Yi Wang1,3, Kun Xia1,3, Si-Yuan Tang2✉, Chun-Yuan Chen1,3✉, Hui Xie1,3,5,6,7,8✉

1. Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
2. Xiangya School of Nursing, Central South University, Changsha, Hunan 410013, China
3. Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
4. School of Nursing, Xinjiang Medical University, Urumqi, Xinjiang 830000, China
5. Department of Sports Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
6. Hunan Key Laboratory of Organ Injury, Aging and Regenerative Medicine, Changsha, Hunan 410008, China
7. Hunan Key Laboratory of Bone Joint Degeneration and Injury, Changsha, Hunan 410008, China
8. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
9. Department of Pathology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510220, China
10. The First Affiliated Hospital, Xinjiang Medical University, Urumqi, Xinjiang 830000, China
11. Changji Hospital of Traditional Chinese Medicine, Changji, Xinjiang 831100, China
*These authors contributed equally to this work.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Luo MJ, Rao SS, Tan YJ, Yin H, Hu XK, Zhang Y, Liu YW, Yue T, Chen LJ, Li L, Huang YR, Qian YX, Liu ZZ, Cao J, Wang ZX, Luo ZW, Wang YY, Xia K, Tang SY, Chen CY, Xie H. Fasting before or after wound injury accelerates wound healing through the activation of pro-angiogenic SMOC1 and SCG2. Theranostics 2020; 10(8):3779-3792. doi:10.7150/thno.44115. Available from https://www.thno.org/v10p3779.htm

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Abstract

Healing of the chronic diabetic ulceration and large burns remains a clinical challenge. Therapeutic fasting has been shown to improve health. Our study tested whether fasting facilitates diabetic and burn wound healing and explored the underlying mechanism.

Methods: The effects of fasting on diabetic and burn wound healing were evaluated by analyzing the rates of wound closure, re-epithelialization, scar formation, collagen deposition, skin cell proliferation and neovascularization using histological analyses and immunostaining. In vitro functional assays were conducted to assess fasting and refeeding on the angiogenic activities of endothelial cells. Transcriptome sequencing was employed to identify the differentially expressed genes in endothelial cells after fasting treatment and the role of the candidate genes in the fasting-induced promotion of angiogenesis was demonstrated.

Results: Two times of 24-h fasting in a week after but especially before wound injury efficiently induced faster wound closure, better epidermal and dermal regeneration, less scar formation and higher level of angiogenesis in mice with diabetic or burn wounds. In vitro, fasting alone by serum deprivation did not increase, but rather reduced the abilities of endothelial cell to proliferate, migrate and form vessel-like tubes. However, subsequent refeeding did not merely rescue, but further augmented the angiogenic activities of endothelial cells. Transcriptome sequencing revealed that fasting itself, but not the following refeeding, induced a prominent upregulation of a variety of pro-angiogenic genes, including SMOC1 (SPARC related modular calcium binding 1) and SCG2 (secretogranin II). Immunofluorescent staining confirmed the increase of SMOC1 and SCG2 expression in both diabetic and burn wounds after fasting treatment. When the expression of SMOC1 or SCG2 was down-regulated, the fasting/refeeding-induced pro-angiogenic effects were markedly attenuated.

Conclusion: This study suggests that fasting combined with refeeding, but not fasting solely, enhance endothelial angiogenesis through the activation of SMOC1 and SCG2, thus facilitating neovascularization and rapid wound healing.

Keywords: fasting, wound healing, angiogenesis, SMOC1, SCG2