Control of fibrosis and hypertrophic scar formation via glycolysis regulation with IR780

Abstract

Background: Hypertrophic scars (HS) represent one of the most common clinical challenges due to unsatisfactory therapeutic results. HS formation is associated with the abnormal activation of fibroblasts and their excessive fibrotic behavior. Glycolysis dysregulation has been shown to participate in the incidence and progression of various fibrotic diseases and shows potential as a means of controlling HS formation. This work aimed to discuss the impact of augmented glycolysis on HS and to propose a method for controlling HS formation through glycolysis regulation. Methods: Here, augmented glycolysis was confirmed together with enhanced fibrotic activity in both HS fibroblasts (HFs) and HS tissues, and the suppression of glycolysis also attenuated fibroblast activation. We also introduced IR780, a heptamethine cyanine dye, to regulate glycolysis for the control of HS formation. Results: In vitro, cell studies indicated that IR780 significantly down-regulated glycolysis and suppressed the fibrotic activity of HFs. In vivo, the intralesional injection of IR780 into rabbit HS models led to the downregulation of glycolysis and the control of HS formation. Furthermore, IR780 accumulated preferentially in activated fibroblasts in both in vitro and in vivo studies, and thus specifically downregulated glycolysis and efficiently controlled fibrosis by targeting activated fibroblasts. Conclusions: This work identified a strategy for controlling fibrosis and HS formation from the perspective of glycolysis regulation with IR780 targeting of activated fibroblasts.

Keywords

Hypertrophic scar / Glycolysis / Fibrosis / IR780 / Activated fibroblast

References

[1] English RS, Shenefelt PD. Keloids and hypertrophic scars. Dermatol Surg. 1999; 25: 631-8. https://doi.org/10.1046/j.1524-4725.1999.98257.x.

[2] Finnerty CC, Jeschke MG, Branski LK, Barret JP, Dziewulski P, Herndon DN. Hypertrophic scarring: the greatest unmet challenge after burn injury. Lancet. 2016; 388: 1427-36. https://doi.org/10.1016/s0140-6736(16)31406-4.

[3] Lee HJ, Jang YJ. Recent understandings of biology, prophylaxis and treatment strategies for hypertrophic scars and keloids. Int J Mol Sci. 2018; 19. https://doi.org/10.3390/ijms19030711.

[4] Berman B, Maderal A, Raphael B. Keloids and hypertrophic scars: pathophysiology, classification, and treatment. Dermatol Surg. 2017; 43: S3-18. https://doi.org/10.1097/dss.0000000000000819.

[5] Darby IA, Hewitson TD. Fibroblast differentiation in wound healing and fibrosis. Int Rev Cytol. 2007; 257: 143-79. https://doi.org/10.1016/S0074-7696(07)57004-X.

[6] Ding H, Jiang L, Xu J, Bai F, Zhou Y, Yuan Q, et al. Inhibiting aerobic glycolysis suppresses renal interstitial fibroblast activation and renal fibrosis. Am J Physiol Renal Physiol. 2017; 313: F561-75. https://doi.org/10.1152/ajprenal.00036.2017.

[7] Ma G, Samad I, Motz K, Yin LX, Duvvuri MV, Ding D, et al. Metabolic variations in normal and fibrotic human laryngotracheal-derived fibroblasts: a Warburg-like effect. Laryngoscope. 2017; 127: E107-13. https://doi.org/10.1002/lary.26254.

[8] Xie N, Tan Z, Banerjee S, Cui H, Ge J, Liu RM, et al. Glycolytic reprogramming in Myofibroblast differentiation and lung fibrosis. Am J Respir Crit Care Med. 2015; 192: 1462-74. https://doi.org/10.1164/rccm.201504-0780OC.

[9] Koppenol WH, Bounds PL, Dang CV. Otto Warburg’s contributions to current concepts of cancer metabolism. Nat Rev Cancer. 2011; 11: 325-37. https://doi.org/10.1038/nrc3038.

[10] Ganapathy-Kanniappan S, Geschwind J-FH. Tumor glycolysis as a target for cancer therapy: progress and prospects. Mol Cancer. 2013; 12: 152-2. https://doi.org/10.1186/1476-4598-12-152.

[11] Ward PS, Thompson CB. Metabolic reprogramming: a cancer hallmark even Warburg did not anticipate. Cancer Cell. 2012; 21: 297-308. https://doi.org/10.1016/j.ccr.2012.02.014.

[12] Li Q, Qin Z, Nie F, Bi H, Zhao R, Pan B, et al. Metabolic reprogramming in keloid fibroblasts: aerobic glycolysis and a novel therapeutic strategy. Biochem Biophys Res Commun. 2018; 496: 641-7. https://doi.org/10.1016/j.bbrc.2018.01.068.

[13] Vincent AS, Phan TT, Mukhopadhyay A, Lim HY, Halliwell B, Wong KP. Human skin keloid fibroblasts display bioenergetics of cancer cells. J Invest Dermatol. 2008; 128: 702-9. https://doi.org/10.1038/sj.jid.5701107.

[14] Vinaik R, Barayan D, Auger C, Abdullahi A, Jeschke MG. Regulation of glycolysis and the Warburg effect in wound healing. JCI Insight. 2020; 5. https://doi.org/10.1172/jci.insight.138949.

[15] Qian Y. Inhibitors of glucose transport and glycolysis as novel anticancer therapeutics. World J Transl Med. 2014; 3. https://doi.org/10.5528/wjtm.v3.i2.37.

[16] Abdel-Wahab AF, Mahmoud W, Al-Harizy RM. Targeting glucose metabolism to suppress cancer progression: prospective of anti-glycolytic cancer therapy. Pharmacol Res. 2019; 150: 104511. https://doi.org/10.1016/j.phrs.2019.104511.

[17] Limandjaja GC, Niessen FB, Scheper RJ, Gibbs S. The keloid disorder: heterogeneity, histopathology, mechanisms and models. Front Cell Dev Biol. 2020; 8: 360. https://doi.org/10.3389/fcell.2020.00360.

[18] Zhang T, Wang XF, Wang ZC, Lou D, Fang QQ, Hu YY, et al. Current potential therapeutic strategies targeting the TGF-beta/Smad signaling pathway to attenuate keloid and hypertrophic scar formation. Biomed Pharmacother. 2020; 129: 110287. https://doi.org/10.1016/j.biopha.2020.110287.

[19] Chen Z, Wang Z, Jin T, Shen G, Wang Y, Tan X, et al. Fibrogenic fibroblast-selective near-infrared phototherapy to control scarring. Theranostics. 2019; 9: 6797-808. https://doi.org/10.7150/thno.36375.

[20] Luo M, Chen L, Zheng J, Wang Q, Huang Y, Liao F, et al. Mitigation of radiation-induced pulmonary fibrosis by small-molecule dye IR-780. Free Radic Biol Med. 2021; 164: 417-28. https://doi.org/10.1016/j.freeradbiomed.2020.12.435.

[21] Zhang E, Luo S, Tan X, Shi C. Mechanistic study of IR-780 dye as a potential tumor targeting and drug delivery agent. Biomaterials. 2014; 35: 771-8. https://doi.org/10.1016/j.biomaterials.2013.10.033.

[22] Wang Y, Liu T, Zhang E, Luo S, Tan X, Shi C. Preferential accumulation of the near infrared heptamethine dye IR-780 in the mitochondria of drug-resistant lung cancer cells. Biomaterials. 2014; 35: 4116-24. https://doi.org/10.1016/j.biomaterials.2014.01.061.

[23] Ogawa R, Akita S, Akaishi S, Aramaki-Hattori N, Dohi T, Hayashi T, et al. Diagnosis and treatment of keloids and hypertrophic scars-Japan scar workshop consensus document 2018. Burns Trauma. 2019; 7: 39. https://doi.org/10.1186/s41038-019-0175-y.

[24] Kierans SJ, Taylor CT. Regulation of glycolysis by the hypoxia-inducible factor (HIF): implications for cellular physiology. J Physiol. 2021; 599: 23-37. https://doi.org/10.1113/JP280572.

[25] Lindley LE, Stojadinovic O, Pastar I, Tomic-Canic M. Biology and biomarkers for wound healing. Plast Reconstr Surg. 2016; 138: 18S-28. https://doi.org/10.1097/PRS.0000000000002682.

[26] Qin Z, Chen F, Chen D, Wang Y, Tan Y, Ban J. Transdermal permeability of triamcinolone acetonide lipid nanoparticles. Int J Nanomedicine. 2019; 14: 2485-95. https://doi.org/10.2147/IJN.S195769.

[27] Xueqian Y, Malay C, Jeong-Han K, Kyle JS, Mi-Yeon J, Mahefatiana A, et al. Hexokinase 2 couples glycolysis with the profibrotic actions of TGF-β. Sci Signal. 2019; 12. https://doi.org/10.1126/scisignal.aax4067.

[28] Rodriguez-Garcia A, Samso P, Fontova P, Simon-Molas H, Manzano A, Castano E, et al. TGF-beta1 targets Smad, p38 MAPK, and PI3K/Akt signaling pathways to induce PFKFB3 gene expression and glycolysis in glioblastoma cells. FEBS J. 2017; 284: 3437-54. https://doi.org/10.1111/febs.14201.