糖尿病（DM）的高盛行率對醫療系統是一大挑戰，尤其又有慢性傷口癒合的併發症時，常常造成糖尿病足潰瘍（DFU）。由於DFU病因複雜，導致治療非常困難。傷口癒合遲緩的主要因素之一是纖維母細胞活性下降。CD248是一種第一型跨膜醣蛋白。CD248表達在纖維母細胞，並參與重要的細胞功能。在傷口癒合過程中CD248的表達明顯增加，而缺乏CD248的小鼠其傷口癒合速度明顯會減慢。因此本研究提出的假設是CD248在糖尿病傷口組織中的表達失調，將導致纖維母細胞功能下降和傷口癒合的速度變慢。經由本研究我們發現，在糖尿病的患者和小鼠的皮膚傷口中，CD248的表達顯著減少。透過單細胞轉錄組分析結果顯示CD248主要在secretory-reticular fibroblasts中表達，這些細胞參與細胞外基質的重建。另外本研究發現類胰島素生長因子-1（IGF-1）主要是透過Akt/mTOR信號通路和轉錄因子SP1，上調皮膚纖維母細胞中的CD248表達進而促進細胞爬行。此現象以siRNA抑制CD248表達時就會被抑制。經由免疫組化染色，進一步證實在糖尿病傷口部位的皮膚，SP1表達較低。且有CD248表達的secretory-reticular fibroblasts數量減少。此外本研究發現在糖尿病環境下，IGF-1治療傷口癒合的效果減弱，這可能是由於發炎因子TNFα在傷口的表達增加，引起細胞對IGF-1的抗性。總言之，本研究深入理解糖尿病傷口癒合的分子機制，並揭示了CD248及IGF-1調控CD248表達的途徑可作為潛在的治療靶點，以改善糖尿病傷口癒合。

The high prevalence of diabetes mellitus (DM) poses significant challenges to the healthcare system, particularly due to its complication of delayed wound healing, which leads to diabetic foot ulcers (DFUs). Treating DFUs is difficult due to their complex etiology, with reduced fibroblast activity being a key factor in impaired wound healing. CD248, a type I transmembrane glycoprotein, is mainly expressed by fibroblasts and is essential for their function. Its expression in the wound region increases during wound healing, and its deficiency impairs this process in mice. We hypothesized that CD248 expression is dysregulated in diabetic wounds, contributing to reduced fibroblast functionality and slower healing rates. Our findings indicate that CD248 expression is significantly decreased in skin wounds from both diabetic patients and mice. Through single-cell transcriptome analysis, we found that CD248 is enriched in secretory-reticular fibroblasts, which are involved in extracellular matrix remodeling. In addition, we demonstrated that insulin-like growth factor-1 (IGF-1) significantly upregulates CD248 expression in dermal fibroblasts via Akt/mTOR signaling pathway and the transcription factor SP1. Enhanced CD248 expression promotes cell motility, an effect that is inhibited when CD248 expression is knocked down using siRNA. Immunohistochemical staining confirmed lower SP1 expression and fewer CD248-positive secretory-reticular fibroblasts in diabetic wound sites. Furthermore, IGF-1 treatment showed reduced effectiveness in promoting wound healing in diabetic conditions, likely due to IGF-1 resistance caused by elevated levels of the pro-inflammatory cytokine Tumor necrosis factor α (TNFα). In summary, this study provides a deeper understanding of the molecular mechanisms underlying diabetic wound healing and identifies CD248 and its regulatory pathway in fibroblasts as potential therapeutic targets for improving diabetic wound treatment.

1. Gurtner GC, Werner S, Barrandon Y, Longaker MT. Wound repair and regeneration. Nature. 2008;453(7193):314-21.
2. Bainbridge P. Wound healing and the role of fibroblasts. J Wound Care. 2013;22(8):407-8.
3. Barrientos S, Stojadinovic O, Golinko MS, Brem H, Tomic-Canic M. Growth factors and cytokines in wound healing. Wound Repair Regen. 2008;16(5):585-601.
4. Darby IA, Laverdet B, Bonte F, Desmouliere A. Fibroblasts and myofibroblasts in wound healing. Clin Cosmet Investig Dermatol. 2014;7:301-11.
5. Falanga V. Wound healing and its impairment in the diabetic foot. The Lancet. 2005;366(9498):1736-43.
6. Zou ML, Teng YY, Wu JJ, Liu SY, Tang XY, Jia Y, et al. Fibroblasts: Heterogeneous Cells With Potential in Regenerative Therapy for Scarless Wound Healing. Front Cell Dev Biol. 2021;9:713605.
7. Harper RA, Grove G. Human skin fibroblasts derived from papillary and reticular dermis: differences in growth potential in vitro. Science. 1979;204(4392):526-7.
8. Haydont V, Neiveyans V, Perez P, Busson É, Lataillade J, Asselineau D, et al. Fibroblasts from the Human Skin Dermo-Hypodermal Junction are Distinct from Dermal Papillary and Reticular Fibroblasts and from Mesenchymal Stem Cells and Exhibit a Specific Molecular Profile Related to Extracellular Matrix Organization and Modeling. Cells. 2020;9(2).
9. Janson DG, Saintigny G, van Adrichem A, Mahé C, El Ghalbzouri A. Different gene expression patterns in human papillary and reticular fibroblasts. J Invest Dermatol. 2012;132(11):2565-72.
10. Feldman SR, Trojanowska M, Smith EA, Leroy EC. Differential responses of human papillary and reticular fibroblasts to growth factors. Am J Med Sci. 1993;305(4):203-7.
11. Driskell RR, Lichtenberger BM, Hoste E, Kretzschmar K, Simons BD, Charalambous M, et al. Distinct fibroblast lineages determine dermal architecture in skin development and repair. Nature. 2013;504(7479):277-81.
12. Pageon H, Zucchi H, Asselineau D. Distinct and complementary roles of papillary and reticular fibroblasts in skin morphogenesis and homeostasis. Eur J Dermatol. 2012;22(3):324-32.
13. Philippeos C, Telerman SB, Oulès B, Pisco AO, Shaw TJ, Elgueta R, et al. Spatial and Single-Cell Transcriptional Profiling Identifies Functionally Distinct Human Dermal Fibroblast Subpopulations. J Invest Dermatol. 2018;138(4):811-25.
14. Solé-Boldo L, Raddatz G, Schütz S, Mallm JP, Rippe K, Lonsdorf AS, et al. Single-cell transcriptomes of the human skin reveal age-related loss of fibroblast priming. Commun Biol. 2020;3(1):188.
15. Hantash BM, Zhao L, Knowles JA, Lorenz HP. Adult and fetal wound healing. Front Biosci. 2008;13:51-61.
16. Hung CF, Rohani MG, Lee SS, Chen P, Schnapp LM. Role of IGF-1 pathway in lung fibroblast activation. Respir Res. 2013;14:102.
17. Yin Y, Han Y, Shi C, Xia Z. IGF-1 regulates the growth of fibroblasts and extracellular matrix deposition in pelvic organ prolapse. Open medicine (Warsaw, Poland). 2020;15(1):833-40.
18. Grazul-Bilska AT, Johnson ML, Bilski JJ, Redmer DA, Reynolds LP, Abdullah A, et al. Wound healing: the role of growth factors. Drugs Today (Barc). 2003;39(10):787-800.
19. Raja, Sivamani K, Garcia MS, Isseroff RR. Wound re-epithelialization: modulating keratinocyte migration in wound healing. Front Biosci. 2007;12:2849-68.
20. Patel S, Srivastava S, Singh MR, Singh D. Mechanistic insight into diabetic wounds: Pathogenesis, molecular targets and treatment strategies to pace wound healing. Biomed Pharmacother. 2019;112:108615.
21. Brem H, Tomic-Canic M. Cellular and molecular basis of wound healing in diabetes. J Clin Invest. 2007;117(5):1219-22.
22. Zubair M, Ahmad J. Role of growth factors and cytokines in diabetic foot ulcer healing: A detailed review. Rev Endocr Metab Disord. 2019;20(2):207-17.
23. Siqueira MF, Li J, Chehab L, Desta T, Chino T, Krothpali N, et al. Impaired wound healing in mouse models of diabetes is mediated by TNF-α dysregulation and associated with enhanced activation of forkhead box O1 (FOXO1). Diabetologia. 2010;53:378-88.
24. Goren I, Müller E, Pfeilschifter J, Frank S. Severely impaired insulin signaling in chronic wounds of diabetic ob/ob mice: a potential role of tumor necrosis factor-alpha. Am J Pathol. 2006;168(3):765-77.
25. Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science. 1996;271(5249):665-8.
26. Liu R, Bal HS, Desta T, Behl Y, Graves DT. Tumor necrosis factor-α mediates diabetes-enhanced apoptosis of matrix-producing cells and impairs diabetic healing. The American journal of pathology. 2006;168(3):757-64.
27. Corredor J, Yan F, Shen CC, Tong W, John SK, Wilson G, et al. Tumor necrosis factor regulates intestinal epithelial cell migration by receptor-dependent mechanisms. American Journal of Physiology-Cell Physiology. 2003;284(4):C953-C61.
28. Xu F, Zhang C, Graves DT. Abnormal cell responses and role of TNF-α in impaired diabetic wound healing. BioMed research international. 2013;2013:754802.
29. Agren MS, Steenfos HH, Dabelsteen S, Hansen JB, Dabelsteen E. Proliferation and mitogenic response to PDGF-BB of fibroblasts isolated from chronic venous leg ulcers is ulcer-age dependent. J Invest Dermatol. 1999;112(4):463-9.
30. Kim BC, Kim HT, Park SH, Cha JS, Yufit T, Kim SJ, et al. Fibroblasts from chronic wounds show altered TGF-beta-signaling and decreased TGF-beta Type II receptor expression. J Cell Physiol. 2003;195(3):331-6.
31. Wilkinson HN, Clowes C, Banyard KL, Matteuci P, Mace KA, Hardman MJ. Elevated Local Senescence in Diabetic Wound Healing Is Linked to Pathological Repair via CXCR2. J Invest Dermatol. 2019;139(5):1171-81 e6.
32. Wilkinson HN, Hardman MJ. Senescence in Wound Repair: Emerging Strategies to Target Chronic Healing Wounds. Frontiers in cell and developmental biology. 2020;8:773.
33. Yamakawa S, Hayashida K. Advances in surgical applications of growth factors for wound healing. Burns Trauma. 2019;7:10.
34. Smiell JM, Wieman TJ, Steed DL, Perry BH, Sampson AR, Schwab BH. Efficacy and safety of becaplermin (recombinant human platelet‐derived growth factor‐BB) in patients with nonhealing, lower extremity diabetic ulcers: a combined analysis of four randomized studies. Wound Repair Regen. 1999;7(5):335-46.
35. Papanas D, Maltezos E. Benefit-risk assessment of becaplermin in the treatment of diabetic foot ulcers. Drug Saf. 2010;33(6):455-61.
36. Khan KA, McMurray JL, Mohammed F, Bicknell R. C-type lectin domain group 14 proteins in vascular biology, cancer and inflammation. FEBS J. 2019;286(17):3299-332.
37. Rettig WJ, Garin-Chesa P, Healey JH, Su SL, Jaffe EA, Old LJ. Identification of endosialin, a cell surface glycoprotein of vascular endothelial cells in human cancer. Proc Natl Acad Sci U S A. 1992;89(22):10832-6.
38. Valdez Y, Maia M, M Conway E. CD248: reviewing its role in health and disease. Curr Drug Targets. 2012;13(3):432-9.
39. Christian S, Winkler R, Helfrich I, Boos AM, Besemfelder E, Schadendorf D, et al. Endosialin (Tem1) is a marker of tumor-associated myofibroblasts and tumor vessel-associated mural cells. Am J Pathol. 2008;172(2):486-94.
40. Tomkowicz B, Rybinski K, Foley B, Ebel W, Kline B, Routhier E, et al. Interaction of endosialin/TEM1 with extracellular matrix proteins mediates cell adhesion and migration. Proc Natl Acad Sci U S A. 2007;104(46):17965-70.
41. Khan KA, Naylor AJ, Khan A, Noy PJ, Mambretti M, Lodhia P, et al. Multimerin-2 is a ligand for group 14 family C-type lectins CLEC14A, CD93 and CD248 spanning the endothelial pericyte interface. Oncogene. 2017;36(44):6097-108.
42. Maia M, de Vriese A, Janssens T, Moons M, van Landuyt K, Tavernier J, et al. CD248 and its cytoplasmic domain: a therapeutic target for arthritis. Arthritis Rheum. 2010;62(12):3595-606.
43. Maia M, DeVriese A, Janssens T, Moons M, Lories RJ, Tavernier J, et al. CD248 facilitates tumor growth via its cytoplasmic domain. BMC Cancer. 2011;11(1):162.
44. Wilhelm A, Aldridge V, Haldar D, Naylor AJ, Weston CJ, Hedegaard D, et al. CD248/endosialin critically regulates hepatic stellate cell proliferation during chronic liver injury via a PDGF-regulated mechanism. Gut. 2016;65(7):1175-85.
45. Di Benedetto P, Liakouli V, Ruscitti P, Berardicurti O, Carubbi F, Panzera N, et al. Blocking CD248 molecules in perivascular stromal cells of patients with systemic sclerosis strongly inhibits their differentiation toward myofibroblasts and proliferation: a new potential target for antifibrotic therapy. Arthritis Res Ther. 2018;20(1):223.
46. Tomkowicz B, Rybinski K, Sebeck D, Sass P, Nicolaides NC, Grasso L, et al. Endosialin/TEM-1/CD248 regulates pericyte proliferation through PDGF receptor signaling. Cancer Biol Ther. 2014;9(11):908-15.
47. Hong YK, Lee YC, Cheng TL, Lai CH, Hsu CK, Kuo CH, et al. Tumor Endothelial Marker 1 (TEM1/Endosialin/CD248) Enhances Wound Healing by Interacting with Platelet-Derived Growth Factor Receptors. J Invest Dermatol. 2019;139(10):2204-14.e7.
48. Christian S, Ahorn H, Koehler A, Eisenhaber F, Rodi HP, Garin-Chesa P, et al. Molecular cloning and characterization of endosialin, a C-type lectin-like cell surface receptor of tumor endothelium. J Biol Chem. 2001;276(10):7408-14.
49. Ohradanova A, Gradin K, Barathova M, Zatovicova M, Holotnakova T, Kopacek J, et al. Hypoxia upregulates expression of human endosialin gene via hypoxia-inducible factor 2. Br J Cancer. 2008;99(8):1348-56.
50. Opavsky R, Haviernik P, Jurkovicova D, Garin MT, Copeland NG, Gilbert DJ, et al. Molecular characterization of the mouse Tem1/endosialin gene regulated by cell density in vitro and expressed in normal tissues in vivo. J Biol Chem. 2001;276(42):38795-807.
51. Babu SS, Valdez Y, Xu A, O’Byrne AM, Calvo F, Lei V, et al. TGFβ-mediated suppression of CD248 in non-cancer cells via canonical Smad-dependent signaling pathways is uncoupled in cancer cells. BMC Cancer. 2014;14(1):113.
52. Hong YK, Lin YC, Cheng TL, Lai CH, Chang YH, Huang YL, et al. TEM1/endosialin/CD248 promotes pathologic scarring and TGF-β activity through its receptor stability in dermal fibroblasts. J Biomed Sci. 2024;31(1):12.
53. Chen HC. Boyden chamber assay. Methods Mol Biol. 2005;294:15-22.
54. Park J, Gill KS, Aghajani AA, Heredia JD, Choi H, Oberstein A, et al. Engineered receptors for human cytomegalovirus that are orthogonal to normal human biology. PLoS Pathog. 2020;16(6):e1008647.
55. Sawaya AP, Stone RC, Brooks SR, Pastar I, Jozic I, Hasneen K, et al. Deregulated immune cell recruitment orchestrated by FOXM1 impairs human diabetic wound healing. Nat Commun. 2020;11(1):4678.
56. Davis FM, Tsoi LC, Wasikowski R, denDekker A, Joshi A, Wilke C, et al. Epigenetic regulation of the PGE2 pathway modulates macrophage phenotype in normal and pathologic wound repair. JCI insight. 2020;5(17):e138443.
57. Mascharak S, desJardins-Park HE, Longaker MT. Fibroblast Heterogeneity in Wound Healing: Hurdles to Clinical Translation. Trends Mol Med. 2020;26(12):1101-6.
58. Theocharidis G, Baltzis D, Roustit M, Tellechea A, Dangwal S, Khetani RS, et al. Integrated Skin Transcriptomics and Serum Multiplex Assays Reveal Novel Mechanisms of Wound Healing in Diabetic Foot Ulcers. Diabetes. 2020;69(10):2157-69.
59. Chitnis MM, Yuen JS, Protheroe AS, Pollak M, Macaulay VM. The type 1 insulin-like growth factor receptor pathway. Clin Cancer Res. 2008;14(20):6364-70.
60. Girnita A, Girnita L, del Prete F, Bartolazzi A, Larsson O, Axelson M. Cyclolignans as inhibitors of the insulin-like growth factor-1 receptor and malignant cell growth. Cancer Res. 2004;64(1):236-42.
61. Favata MF, Horiuchi KY, Manos EJ, Daulerio AJ, Stradley DA, Feeser WS, et al. Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J Biol Chem. 1998;273(29):18623-32.
62. Muhl L, Genové G, Leptidis S, Liu J, He L, Mocci G, et al. Single-cell analysis uncovers fibroblast heterogeneity and criteria for fibroblast and mural cell identification and discrimination. Nat Commun. 2020;11(1):3953.
63. Broussard SR, MCCusker RH, Novakofski JE, Strle K, Hong Shen W, Johnson RW, et al. Cytokine-Hormone Interactions: Tumor Necrosis Factor α Impairs Biologic Activity and Downstream Activation Signals of the Insulin-Like Growth Factor I Receptor in Myoblasts. Endocrinology. 2003;144(7):2988-96.
64. Choukair D, Hügel U, Sander A, Uhlmann L, Tönshoff B. Inhibition of IGF-I–related intracellular signaling pathways by proinflammatory cytokines in growth plate chondrocytes. Pediatr Res. 2014;76(3):245-51.
65. Aguirre V, Werner ED, Giraud J, Lee YH, Shoelson SE, White MF. Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action. J Biol Chem. 2002;277(2):1531-7.
66. Stephens JM, Lee J, Pilch PF. Tumor Necrosis Factor-α-induced Insulin Resistance in 3T3-L1 Adipocytes Is Accompanied by a Loss of Insulin Receptor Substrate-1 and GLUT4 Expression without a Loss of Insulin Receptor-mediated Signal Transduction*. J Biol Chem. 1997;272(2):971-6.
67. Akash MSH, Rehman K, Liaqat A. Tumor Necrosis Factor-Alpha: Role in Development of Insulin Resistance and Pathogenesis of Type 2 Diabetes Mellitus. J Cell Biochem. 2018;119(1):105-10.
68. Plomgaard P, Bouzakri K, Krogh-Madsen R, Mittendorfer B, Zierath JR, Pedersen BK. Tumor Necrosis Factor-α Induces Skeletal Muscle Insulin Resistance in Healthy Human Subjects via Inhibition of Akt Substrate 160 Phosphorylation. Diabetes. 2005;54(10):2939-45.
69. Tanti J-F, Jager J. Cellular mechanisms of insulin resistance: role of stress-regulated serine kinases and insulin receptor substrates (IRS) serine phosphorylation. Curr Opin Pharmacol. 2009;9(6):753-62.
70. Stunova A, Vistejnova L. Dermal fibroblasts-A heterogeneous population with regulatory function in wound healing. Cytokine Growth Factor Rev. 2018;39:137-50.
71. Janson DG, Saintigny G, van Adrichem A, Mahé C, El Ghalbzouri A. Different Gene Expression Patterns in Human Papillary and Reticular Fibroblasts. J Invest Dermatol. 2012;132(11):2565-72.
72. Tabib T, Morse C, Wang T, Chen W, Lafyatis R. SFRP2/DPP4 and FMO1/LSP1 Define Major Fibroblast Populations in Human Skin. J Invest Dermatol. 2018;138(4):802-10.
73. Vorstandlechner V, Laggner M, Kalinina P, Haslik W, Radtke C, Shaw L, et al. Deciphering the functional heterogeneity of skin fibroblasts using single-cell RNA sequencing. FASEB J. 2020;34(3):3677-92.
74. Solé-Boldo L, Raddatz G, Schütz S, Mallm J-P, Rippe K, Lonsdorf AS, et al. Single-cell transcriptomes of the human skin reveal age-related loss of fibroblast priming. Communications Biology. 2020;3(1):188.
75. Theocharidis G, Thomas BE, Sarkar D, Mumme HL, Pilcher WJR, Dwivedi B, et al. Single cell transcriptomic landscape of diabetic foot ulcers. Nat Commun. 2022;13(1):181.
76. Brown DL, Kane CD, Chernausek SD, Greenhalgh DG. Differential expression and localization of insulin-like growth factors I and II in cutaneous wounds of diabetic and nondiabetic mice. The American journal of pathology. 1997;151(3):715.
77. Bitar MS. Insulin and glucocorticoid-dependent suppression of the IGF-I system in diabetic wounds. Surgery. 2000;127(6):687-95.
78. Velander P, Theopold C, Hirsch T, Bleiziffer O, Zuhaili B, Fossum M, et al. Impaired wound healing in an acute diabetic pig model and the effects of local hyperglycemia. Wound Repair Regen. 2008;16(2):288-93.
79. Blakytny R, Jude EB, Martin Gibson J, Boulton AJ, Ferguson MW. Lack of insulin‐like growth factor 1 (IGF1) in the basal keratinocyte layer of diabetic skin and diabetic foot ulcers. J Pathol. 2000;190(5):589-94.
80. Toulon A, Breton L, Taylor KR, Tenenhaus M, Bhavsar D, Lanigan C, et al. A role for human skin-resident T cells in wound healing. J Exp Med. 2009;206(4):743-50.
81. Mirza RE, Fang MM, Ennis WJ, Koh TJ. Blocking interleukin-1β induces a healing-associated wound macrophage phenotype and improves healing in type 2 diabetes. Diabetes. 2013;62(7):2579-87.
82. Wang J, Kang M, Qin Y-T, Wei Z-X, Xiao J-J, Wang R-S. Sp1 is over-expressed in nasopharyngeal cancer and is a poor prognostic indicator for patients receiving radiotherapy. Int J Clin Exp Pathol. 2015;8(6):6936.
83. Liao S, Lin X, Mo C. Integrated analysis of circRNA-miRNA-mRNA regulatory network identifies potential diagnostic biomarkers in diabetic foot ulcer. Non-coding RNA research. 2020;5(3):116-24.
84. Wang W, Yang C, Wang Xy, Zhou Ly, Lao Gj, Liu D, et al. MicroRNA-129 and -335 Promote Diabetic Wound Healing by Inhibiting Sp1-Mediated MMP-9 Expression. Diabetes. 2018;67(8):1627-38.
85. Park JW, Hwang SR, Yoon IS. Advanced Growth Factor Delivery Systems in Wound Management and Skin Regeneration. Molecules. 2017;22(8).
86. Mueller RV, Hunt TK, Tokunaga A, Spencer EM. The effect of insulinlike growth factor I on wound healing variables and macrophages in rats. Arch Surg. 1994;129(3):262-5.
87. Gong F, Zhao F, Cheng SL, Ding D, Zhang BW, Li XL, et al. Effect of insulin-like growth factor-1 on promoting healing of skin ulcers in diabetic rats. J Biol Regul Homeost Agents. 2019;33(3):687-94.
88. denDekker AD, Davis FM, Joshi AD, Wolf SJ, Allen R, Lipinski J, et al. TNF-α regulates diabetic macrophage function through the histone acetyltransferase MOF. JCI insight. 2020;5(5):e132306.
89. Liu T, Zhang L, Joo D, Sun S-C. NF-κB signaling in inflammation. Signal Transduction and Targeted Therapy. 2017;2(1):17023.
90. Gao Z, Hwang D, Bataille F, Lefevre M, York D, Quon MJ, et al. Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa B kinase complex. J Biol Chem. 2002;277(50):48115-21.
91. Anderson K, Wherle L, Park M, Nelson K, Nguyen L. Salsalate, an old, inexpensive drug with potential new indications: a review of the evidence from 3 recent studies. American health & drug benefits. 2014;7(4):231-5.
92. Cheng TL, Wu YT, Lai CH, Kao YC, Kuo CH, Liu SL, et al. Thrombomodulin regulates keratinocyte differentiation and promotes wound healing. J Invest Dermatol. 2013;133(6):1638-45.
93. Cheng TL, Chen PK, Huang WK, Kuo CH, Cho CF, Wang KC, et al. Plasminogen/thrombomodulin signaling enhances VEGF expression to promote cutaneous wound healing. J Mol Med (Berl). 2018;96(12):1333-44.
94. Cheng TL, Wu YT, Lin HY, Hsu FC, Liu SK, Chang BI, et al. Functions of rhomboid family protease RHBDL2 and thrombomodulin in wound healing. J Invest Dermatol. 2011;131(12):2486-94.
95. Cheng TL, Lai CH, Chen PK, Cho CF, Hsu YY, Wang KC, et al. Thrombomodulin promotes diabetic wound healing by regulating toll-like receptor 4 expression. J Invest Dermatol. 2015;135(6):1668-75.
96. Hsu YY, Liu KL, Yeh HH, Lin HR, Wu HL, Tsai JC. Sustained release of recombinant thrombomodulin from cross-linked gelatin/hyaluronic acid hydrogels potentiate wound healing in diabetic mice. Eur J Pharm Biopharm. 2019;135:61-71.
97. Hsueh YS, Shyong YJ, Yu HC, Jheng SJ, Lin SW, Wu HL, et al. Nanostructured Lipid Carrier Gel Formulation of Recombinant Human Thrombomodulin Improve Diabetic Wound Healing by Topical Administration. Pharmaceutics. 2021;13(9):1386.
98. Cheng TL, Lin YS, Hong YK, Ma CY, Tsai HW, Shi GY, et al. Role of tumor endothelial marker 1 (Endosialin/CD248) lectin-like domain in lipopolysaccharide-induced macrophage activation and sepsis in mice. Transl Res. 2021;232:150-62.
99. Romero G, von Zastrow M, Friedman PA. 9 - Role of PDZ Proteins in Regulating Trafficking, Signaling, and Function of GPCRs: Means, Motif, and Opportunity. In: Neubig RR, editor. Adv Pharmacol. 62: Academic Press; 2011. p. 279-314.