Pterostilbene accelerates wound healing by modulating diabetes-induced estrogen receptor β suppression in hematopoietic stem cells

Abstract

Background: Delayed wound healing is one of the major complications of diabetes mellitus and is characterized by prolonged inflammation, delayed re-epithelialization and consistent oxidative stress, although the detailed mechanism remains unknown. In this study, we aimed to investigate the potential role and effect of pterostilbene (PTE) and hematopoietic stem cells (HSCs) on diabetic wound healing. Methods: Diabetic rats were used to measure the epigenetic changes in both HSCs and peripheral blood mononuclear cells (PBMCs). A cutaneous burn injury was induced in the rats and PTE-treated diabetic HSCs were transplanted for evaluation of wound healing. In addition, several biomedical parameters, including gene expression, oxidative stress, mitochondrial function and inflammation in macrophages, were also measured. Results: Our data showed that PTE had a much stronger effect than resveratrol on accelerating diabetic wound healing, likely because PTE can ameliorate diabetes-induced epigenetic changes to estrogen receptor β promoter in HSCs, while resveratrol cannot. Further investigation showed that bone marrow transplantation of PTE-treated diabetic HSCs restores diabetes-induced suppression of estrogen receptor β and its target genes, including nuclear respiratory factor-1 and superoxide dismutase 2, and protects against diabetes-induced oxidative stress, mitochondrial dysfunction and elevated pro-inflammatory cytokines in both PBMCs and macrophages, subsequently accelerating cutaneous wound healing. Conclusions: HSC may play an important role in wound healing through transferring epigenetic modifications to subsequent PBMCs and macrophages by differentiation, while PTE accelerates diabetic wound healing by modulating diabetes-induced epigenetic changes in HSCs. Thus, PTE may be a novel therapeutic strategy for diabetic wound healing.

Keywords

Hematopoietic stem cells / Inflammation / Oxidative stress / Pterostilbene / Wound healing

References

[1] King A, Balaji S, Keswani SG, Crombleholme TM. The role of stem cells in wound angiogenesis. Adv Wound Care (New Rochelle). 2014; 3: 614-25.

[2] Cerqueira MT, Pirraco RP, Marques AP. Stem cells in skin wound healing: are we there yet? Adv Wound Care (New Rochelle). 2016; 5: 164-75.

[3] Dhall S, Do DC, Garcia M, Kim J, Mirebrahim SH, Lyubovitsky J, et al. Generating and reversing chronic wounds in diabetic mice by manipulating wound redox parameters. J Diabetes Res. 2014; 562625. https://doi.org/10.1155/2014/562625.

[4] Singh N, Armstrong DG, Lipsky BA. Preventing foot ulcers in patients with diabetes. JAMA. 2005; 293: 217-28.

[5] Noor S, Zubair M, Ahmad J. Diabetic foot ulcer-a review on pathophysiology, classification and microbial etiology. Diabetes Metab Syndr. 2015; 9: 192-9.

[6] Esposito K, Nappo F, Marfella R, Giugliano G, Giugliano F, Ciotola M, et al. Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress. Circulation. 2002; 106: 2067-72.

[7] Thangarajah H, Yao D, Chang EI, Shi Y, Jazayeri L, Vial IN, et al. The molecular basis for impaired hypoxia-induced VEGF expression in diabetic tissues. Proc Natl Acad Sci U S A. 2009; 106: 13505-10.

[8] McInnes RL, Cullen BM, Hill KE, Price PE, Harding KG, Thomas DW, et al. Contrasting host immuno-inflammatory responses to bacterial challenge within venous and diabetic ulcers. Wound Repair Regen. 2014; 22: 58-69.

[9] El-Osta A, Brasacchio D, Yao D, Pocai A, Jones PL, Roeder RG, et al. Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia. J Exp Med. 2008; 205: 2409-17.

[10] Kunkemoeller B, Kyriakides TR. Redox Signaling in diabetic wound healing regulates extracellular matrix deposition. Antioxid Redox Signal. 2017; 27: 823-38.

[11] Cullen SM, Mayle A, Rossi L, Goodell MA. Hematopoietic stem cell development: an epigenetic journey. Curr Top Dev Biol. 2014; 107: 39-75.

[12] Trowbridge JJ, Snow JW, Kim J, Orkin SH. DNA methyltransferase 1 is essential for and uniquely regulates hematopoietic stem and progenitor cells. Cell Stem Cell. 2009; 5: 442-9.

[13] Yan J, Tie G, Wang S, Tutto A, DeMarco N, Khair L, et al. Diabetes impairs wound healing by Dnmt1-dependent dysregulation of hematopoietic stem cells differentiation towards macrophages. Nat Commun. 2018; 9: 33.

[14] Dzierzak E, Bigas A. Blood development: hematopoietic stem cell dependence and independence. Cell Stem Cell. 2018; 22: 639-51.

[15] Haas S, Trumpp A, Milsom MD. Causes and consequences of hematopoietic stem cell heterogeneity. Cell Stem Cell. 2018; 22: 627-38.

[16] Placek K, Schultze JL, Aschenbrenner AC. Epigenetic reprogramming of immune cells in injury, repair, and resolution. J Clin Invest. 2019; 129:2994-3005.

[17] Wang X, Lu J, Xie W, Lu X, Liang Y, Li M, et al. Maternal diabetes induces autism-like behavior by hyperglycemia-mediated persistent oxidative stress and suppression of superoxide dismutase 2. Proc Natl Acad Sci U S A. 2019; 116: 23743-52.

[18] Klinge CM. Estrogenic control of mitochondrial function. Redox Biol. 2020. https://doi.org/10.1016/j.redox.2020.101435.

[19] Klinge CM. Estrogenic control of mitochondrial function and biogenesis. J Cell Biochem. 2008; 105: 1342-51.

[20] Liu Z, Gou Y, Zhang H, Zuo H, Zhang H, Liu Z, et al. Estradiol improves cardiovascular function through up-regulation of SOD2 on vascular wall. Redox Biol. 2014; 3: 88-99.

[21] Zhan Y, Liu Z, Li M, Ding T, Zhang L, Lu Q, et al. ER β expression in the endothelium ameliorates ischemia/reperfusion-mediated oxidative burst and vascular injury. Free Radic Biol Med. 2016; 96: 223-33.

[22] Kong D, Zhan Y, Liu Z, Ding T, Li M, Yu H, et al. SIRT1-mediated ER β suppression in the endothelium contributes to vascular aging. Aging Cell. 2016; 15: 1092-102.

[23] Zou Y, Lu Q, Zheng D, Chu Z, Liu Z, Chen H, et al. Prenatal levonorgestrel exposure induces autism-like behavior in offspring through ER β suppression in the amygdala. Mol Autism. 2017. https://doi.org/10.1186/s13229-017-0159-3.

[24] Xie W, Ge X, Li L, Yao A, Wang X, Li M, et al. Resveratrol ameliorates prenatal progestin exposure-induced autism-like behavior through ER β activation. Mol Autism. 2018. https://doi.org/10.1186/s13229-018-0225-5.

[25] Campbell L, Emmerson E, Davies F, Gilliver SC, Krust A, Chambon P, et al. Estrogen promotes cutaneous wound healing via estrogen receptor beta independent of its antiinflammatory activities. J Exp Med. 2010; 207: 1825-33.

[26] Zhang Y, Zhang Y. Pterostilbene, a novel natural plant conduct, inhibits high fat-induced atherosclerosis inflammation via NF-κB signaling pathway in toll-like receptor 5 (TLR5) deficient mice. Biomed Pharmacother. 2016; 81: 345-55.

[27] Sun H, Liu X, Long SR, Teng W, Ge H, Wang Y, et al. Antidiabetic effects of pterostilbene through PI3K/Akt signal pathway in high fat diet and STZ-induced diabetic rats. Eur J Pharmacol. 2019. https://doi.org/10.1016/j.ejphar.2019.172526.

[28] Sirerol JA, Feddi F, Mena S, Rodriguez ML, Sirera P, Aupi M, et al. Topical treatment with pterostilbene, a natural phytoalexin, effectively protects hairless mice against UVB radiation-induced skin damage and carcinogenesis. Free Radic Biol Med. 2015; 85: 1-11.

[29] Dellinger RW, Garcia AM, Meyskens FL Jr. Differences in the glucuronidation of resveratrol and pterostilbene: altered enzyme specificity and potential gender differences. Drug Metab Pharmacokinet. 2014; 29: 112-9.

[30] Erasalo H, Hamalainen M, Leppanen T, Maki-Opas I, Laavola M, Haavikko R, et al. Natural Stilbenoids have anti-inflammatory properties in vivo and down-regulate the production of inflammatory mediators NO, IL6, and MCP1 possibly in a PI3K/Akt-dependent manner. J Nat Prod. 2018; 81: 1131-42.

[31] Li M, Yu H, Pan H, Zhou X, Ruan Q, Kong D, et al. Nrf2 suppression delays diabetic wound healing through sustained oxidative stress and inflammation. Front Pharmacol. 2019. https://doi.org/10.3389/fphar.2019.01099.

[32] Zhou X, Li M, Xiao M, Ruan Q, Chu Z, Ye Z, et al. ER β accelerates diabetic wound healing by ameliorating hyperglycemia-induced persistent oxidative stress. Front Endocrinol (Lausanne). 2019. https://doi.org/10.3389/fendo.2019.00499.

[33] Rossi L, Challen GA, Sirin O, Lin KK, Goodell MA. Hematopoietic stem cell characterization and isolation. Methods Mol Biol. 2011; 750: 47-59.

[34] Xie W, Ren M, Li L, Zhu Y, Chu Z, Zhu Z, et al. Perinatal testosterone exposure potentiates vascular dysfunction by ER β suppression in endothelial progenitor cells. PLoS One. 2017. https://doi.org/10.1371/journal.pone.0182945.

[35] Ii M, Nishimura H, Iwakura A, Wecker A, Eaton E, Asahara T, et al. Endothelial progenitor cells are rapidly recruited to myocardium and mediate protective effect of ischemic preconditioning via "imported" nitric oxide synthase activity. Circulation. 2005; 111: 1114-20.

[36] Zhang H, Li L, Chen Q, Li M, Feng J, Sun Y, et al. PGC1beta regulates multiple myeloma tumor growth through LDHA-mediated glycolytic metabolism. Mol Oncol. 2018; 12: 1579-95.

[37] Yu T, Gao M, Yang P, Liu D, Wang D, Song F, et al. Insulin promotes macrophage phenotype transition through PI3K/Akt and PPAR-gamma signaling during diabetic wound healing. J Cell Physiol. 2019; 234: 4217-31.

[38] Ray A, Dittel BN. Isolation of mouse peritoneal cavity cells. J Vis Exp. 2010. https://doi.org/10.3791/1488.

[39] Kimball AS, Joshi A, WFt C, Boniakowski AE, Schaller M, Allen R, et al. The histone methyltransferase MLL1 directs macrophage-mediated inflammation in wound healing and is altered in a murine model of obesity and type 2 diabetes. Diabetes. 2017; 66: 2459-71.

[40] Kobayashi EH, Suzuki T, Funayama R, Nagashima T, Hayashi M, Sekine H, et al. Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Nat Commun. 2016. https://doi.org/10.1038/ncomms11624.

[41] Li H, Liu Z, Gou Y, Yu H, Siminelakis S, Wang S, et al. Estradiol mediates vasculoprotection via ERR α-dependent regulation of lipid and ROS metabolism in the endothelium. J Mol Cell Cardiol. 2015; 87: 92-101.

[42] Wilkinson AC, Igarashi KJ, Nakauchi H. Haematopoietic stem cell self-renewal in vivo and ex vivo. Nat Rev Genet. 2020; 21: 541-54.