Browse > Article
http://dx.doi.org/10.4062/biomolther.2019.131

Melatonin-Induced PGC-1α Improves Angiogenic Potential of Mesenchymal Stem Cells in Hindlimb Ischemia  

Lee, Jun Hee (Medical Science Research Institute, Soonchunhyang University Seoul Hospital)
Han, Yong-Seok (Medical Science Research Institute, Soonchunhyang University Seoul Hospital)
Lee, Sang Hun (Medical Science Research Institute, Soonchunhyang University Seoul Hospital)
Publication Information
Biomolecules & Therapeutics / v.28, no.3, 2020 , pp. 240-249 More about this Journal
Abstract
Despite the therapeutic effect of mesenchymal stem cells (MSCs) in ischemic diseases, pathophysiological conditions, including hypoxia, limited nutrient availability, and oxidative stress restrict their potential. To address this issue, we investigated the effect of melatonin on the bioactivities of MSCs. Treatment of MSCs with melatonin increased the expression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α). Melatonin treatment enhanced mitochondrial oxidative phosphorylation in MSCs in a PGC-1α-dependent manner. Melatonin-mediated PGC-1α expression enhanced the proliferative potential of MSCs through regulation of cell cycle-associated protein activity. In addition, melatonin promoted the angiogenic ability of MSCs, including migration and invasion abilities and secretion of angiogenic cytokines by increasing PGC-1α expression. In a murine hindlimb ischemia model, the survival of transplanted melatonin-treated MSCs was significantly increased in the ischemic tissues, resulting in improvement of functional recovery, such as blood perfusion, limb salvage, neovascularization, and protection against necrosis and fibrosis. These findings indicate that the therapeutic effect of melatonin-treated MSCs in ischemic diseases is mediated via regulation of PGC-1α level. This study suggests that melatonin-induced PGC-1α might serve as a novel target for MSC-based therapy of ischemic diseases, and melatonin-treated MSCs could be used as an effective cell-based therapeutic option for patients with ischemic diseases.
Keywords
Melatonin; Mesenchymal stem cells; $PGC-1{\alpha}$; Hindlimb ischemia; Cell-based therapy;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Chamberlain, G., Fox, J., Ashton, B. and Middleton, J. (2007) Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells 25, 2739-2749.   DOI
2 Deblois, G., St-Pierre, J. and Giguere, V. (2013) The PGC-1/ERR signaling axis in cancer. Oncogene 32, 3483-3490.   DOI
3 Fernandez, A., Ordonez, R., Reiter, R. J., Gonzalez-Gallego, J. and Mauriz, J. L. (2015) Melatonin and endoplasmic reticulum stress: relation to autophagy and apoptosis. J. Pineal Res. 59, 292-307.   DOI
4 Garcia, J. J., Lopez-Pingarron, L., Almeida-Souza, P., Tres, A., Escudero, P., Garcia-Gil, F. A., Tan, D. X., Reiter, R. J., Ramirez, J. M. and Bernal-Perez, M. (2014) Protective effects of melatonin in reducing oxidative stress and in preserving the fluidity of biological membranes: a review. J. Pineal Res. 56, 225-237.   DOI
5 Han, D., Huang, W., Li, X., Gao, L., Su, T., Li, X., Ma, S., Liu, T., Li, C., Chen, J., Gao, E. and Cao, F. (2016) Melatonin facilitates adiposederived mesenchymal stem cells to repair the murine infarcted heart via the SIRT1 signaling pathway. J. Pineal Res. 60, 178-192.   DOI
6 Han, Y. S., Kim, S. M., Lee, J. H., Jung, S. K., Noh, H. and Lee, S. H. (2019) Melatonin protects chronic kidney disease mesenchymal stem cells against senescence via PrP(C)-dependent enhancement of the mitochondrial function. J. Pineal Res. 66, e12535.   DOI
7 Hock, M. B. and Kralli, A. (2009) Transcriptional control of mitochondrial biogenesis and function. Annu. Rev. Physiol. 71, 177-203.   DOI
8 Jan, J. E., Reiter, R. J., Wasdell, M. B. and Bax, M. (2009) The role of the thalamus in sleep, pineal melatonin production, and circadian rhythm sleep disorders. J. Pineal Res. 46, 1-7.   DOI
9 Lee, J. H., Han, Y. S. and Lee, S. H. (2017) Potentiation of biological effects of mesenchymal stem cells in ischemic conditions by melatonin via upregulation of cellular prion protein expression. J. Pineal Res. 62, doi: 10.1111/jpi.12385.
10 Lee, J. H., Lee, S. H., Choi, S. H., Asahara, T. and Kwon, S. M. (2015) The sulfated polysaccharide fucoidan rescues senescence of endothelial colony-forming cells for ischemic repair. Stem Cells 33, 1939-1951.   DOI
11 Lee, J. H., Yoon, Y. M., Han, Y. S., Jung, S. K. and Lee, S. H. (2019) Melatonin protects mesenchymal stem cells from autophagy-mediated death under ischaemic ER-stress conditions by increasing prion protein expression. Cell Prolif. 52, e12545.   DOI
12 Lee, J. H., Yun, C. W., Hur, J. and Lee, S. H. (2018) Fucoidan rescues p-cresol-induced cellular senescence in mesenchymal stem cells via FAK-Akt-TWIST axis. Mar. Drugs 16, E121.
13 Li, S., Liu, C., Li, N., Hao, T., Han, T., Hill, D. E., Vidal, M. and Lin, J. D. (2008) Genome-wide coactivation analysis of PGC-1alpha identifies BAF60a as a regulator of hepatic lipid metabolism. Cell Metab. 8, 105-117.   DOI
14 Lin, J., Handschin, C. and Spiegelman, B. M. (2005) Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab. 1, 361-370.   DOI
15 Lv, F. J., Tuan, R. S., Cheung, K. M. and Leung, V. Y. (2014) Concise review: the surface markers and identity of human mesenchymal stem cells. Stem Cells 32, 1408-1419.   DOI
16 Mauriz, J. L., Collado, P. S., Veneroso, C., Reiter, R. J. and Gonzalez-Gallego, J. (2013) A review of the molecular aspects of melatonin's anti-inflammatory actions: recent insights and new perspectives. J. Pineal Res. 54, 1-14.   DOI
17 Pugh, C. W. and Ratcliffe, P. J. (2003) Regulation of angiogenesis by hypoxia: role of the HIF system. Nat. Med. 9, 677-684.   DOI
18 Reiter, R. J., Mayo, J. C., Tan, D. X., Sainz, R. M., Alatorre-Jimenez, M. and Qin, L. (2016) Melatonin as an antioxidant: under promises but over delivers. J. Pineal Res. 61, 253-278.   DOI
19 Reiter, R. J., Tan, D. X., Manchester, L. C., Paredes, S. D., Mayo, J. C. and Sainz, R. M. (2009) Melatonin and reproduction revisited. Biol. Reprod. 81, 445-456.   DOI
20 Saint-Geniez, M., Jiang, A., Abend, S., Liu, L., Sweigard, H., Connor, K. M. and Arany, Z. (2013) PGC-1alpha regulates normal and pathological angiogenesis in the retina. Am. J. Pathol. 182, 255-265.   DOI
21 Sano, M., Wang, S. C., Shirai, M., Scaglia, F., Xie, M., Sakai, S., Tanaka, T., Kulkarni, P. A., Barger, P. M., Youker, K. A., Taffet, G. E., Hamamori, Y., Michael, L. H., Craigen, W. J. and Schneider, M. D. (2004) Activation of cardiac Cdk9 represses PGC-1 and confers a predisposition to heart failure. EMBO J. 23, 3559-3569.   DOI
22 Scarpulla, R. C. (2011) Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochim. Biophys. Acta 1813, 1269-1278.   DOI
23 St-Pierre, J., Drori, S., Uldry, M., Silvaggi, J. M., Rhee, J., Jager, S., Handschin, C., Zheng, K., Lin, J., Yang, W., Simon, D. K., Bachoo, R. and Spiegelman, B. M. (2006) Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell 127, 397-408.   DOI
24 Su, S. C., Hsieh, M. J., Yang, W. E., Chung, W. H., Reiter, R. J. and Yang, S. F. (2017) Cancer metastasis: mechanisms of inhibition by melatonin. J. Pineal Res. 62, doi: 10.1111/jpi.12370.
25 Reiter, R. J. (1991) Pineal melatonin: cell biology of its synthesis and of its physiological interactions. Endocr. Rev. 12, 151-180.   DOI
26 Yip, H. K., Chang, Y. C., Wallace, C. G., Chang, L. T., Tsai, T. H., Chen, Y. L., Chang, H. W., Leu, S., Zhen, Y. Y., Tsai, C. Y., Yeh, K. H., Sun, C. K. and Yen, C. H. (2013) Melatonin treatment improves adiposederived mesenchymal stem cell therapy for acute lung ischemiareperfusion injury. J. Pineal Res. 54, 207-221.   DOI
27 Yu, B., Huo, L., Liu, Y., Deng, P., Szymanski, J., Li, J., Luo, X., Hong, C., Lin, J. and Wang, C. Y. (2018) PGC-1alpha controls skeletal stem cell fate and bone-fat balance in osteoporosis and skeletal aging by inducing TAZ. Cell Stem Cell 23, 193-209.e5.   DOI
28 Zhang, L., Hao, J., Zheng, Y., Su, R., Liao, Y., Gong, X., Liu, L. and Wang, X. (2018) Fucoidan protects dopaminergic neurons by enhancing the mitochondrial function in a rotenone-induced rat model of Parkinson's disease. Aging Dis. 9, 590-604.   DOI
29 Zhou, Y., Lu, T. and Xie, T. (2011) A PGC-1 tale: healthier intestinal stem cells, longer life. Cell Metab. 14, 571-572.   DOI
30 Adhihetty, P. J., O'Leary, M. F., Chabi, B., Wicks, K. L. and Hood, D. A. (2007) Effect of denervation on mitochondrially mediated apoptosis in skeletal muscle. J. Appl. Physiol. 102, 1143-1151.   DOI
31 Arany, Z., Foo, S. Y., Ma, Y., Ruas, J. L., Bommi-Reddy, A., Girnun, G., Cooper, M., Laznik, D., Chinsomboon, J., Rangwala, S. M., Baek, K. H., Rosenzweig, A. and Spiegelman, B. M. (2008) HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1alpha. Nature 451, 1008-1012.   DOI
32 Austin, S. and St-Pierre, J. (2012) PGC1alpha and mitochondrial metabolism--emerging concepts and relevance in ageing and neurodegenerative disorders. J. Cell Sci. 125, 4963-4971.   DOI
33 Caplan, A. I. and Correa, D. (2011) The MSC: an injury drugstore. Cell Stem Cell 9, 11-15.   DOI