Lymphangiogenesis: novel strategies to promote cutaneous wound healing

Abstract

The cutaneous lymphatic system regulates tissue inflammation, fluid balance and immunological responses. Lymphangiogenesis or lymphatic dysfunction may lead to lymphedema, immune deficiency, chronic inflammation etc. Tissue regeneration and healing depend on angiogenesis and lymphangiogenesis during wound healing. Tissue oedema and chronic inflammation can slow wound healing due to impaired lymphangiogenesis or lymphatic dysfunction. For example, impaired lymphangiogenesis or lymphatic dysfunction has been detected in nonhealing wounds such as diabetic ulcers, venous ulcers and bedsores. This review summarizes the structure and function of the cutaneous lymphatic vessel system and lymphangiogenesis in wounds. Furthermore, we review wound lymphangiogenesis processes and remodelling, especially the influence of the inflammatory phase. Finally, we outline how to control lymphangiogenesis to promote wound healing, assess the possibility of targeting lymphangiogenesis as a novel treatment strategy for chronic wounds and provide an analysis of the possible problems that need to be addressed.

Keywords

Lymphangiogenesis / Wound healing / Growth factor / Lymphatic vessels / Skin / Inflammation / Chronic wound

References

[1] Morfoisse F, Noel A. Lymphatic and blood systems: identical or fraternal twins? Int J Biochem Cell Biol 2019; 114: 105562. https://doi.org/10.1016/j.biocel.2019.105562.

[2] Petrova TV, Koh GY. Organ-specific lymphatic vasculature: from development to pathophysiology. J Exp Med 2018; 215: 35-49. https://doi.org/10.1084/jem.20171868.

[3] Potente M, Mäkinen T. Vascular heterogeneity and specialization in development and disease. Nat Rev Mol Cell Biol 2017; 18: 477-94. https://doi.org/10.1038/nrm.2017.36.

[4] Oliver G, Kipnis J, Randolph GJ, Harvey NL. The lymphatic vasculature in the 21(st) century: novel functional roles in homeostasis and disease. Cell 2020; 182: 270-96. https://doi.org/10.1016/j.cell.2020.06.039.

[5] Petrova TV, Koh GY. Biological functions of lymphatic vessels. Science 2020; 369: eaax4063. https://doi.org/10.1126/science.aax4063.

[6] Breslin JW, Yang Y, Scallan JP, Sweat RS, Adderley SP, Murfee WL. Lymphatic vessel network structure and physiology. Compr Physiol 2018; 9: 207-99. https://doi.org/10.1002/cphy.c180015.

[7] Ahn JH, Cho H, Kim JH, Kim SH, Ham JS, Park I, et al. Meningeal lymphatic vessels at the skull base drain cerebrospinal fluid. Nature 2019; 572: 62-6. https://doi.org/10.1038/s41586-019-1419-5.

[8] Klaourakis K, Vieira JM, Riley PR. The evolving cardiac lymphatic vasculature in development, repair and regeneration. Nat Rev Cardiol 2021; 18: 368-79. https://doi.org/10.1038/s41569-020-00489-x.

[9] Liu X, De la Cruz E, Gu X, Balint L, Oxendine-Burns M, Terrones T, et al. Lymphoangiocrine signals promote cardiac growth and repair. Nature 2020; 588: 705-11. https://doi.org/10.1038/s41586-020-2998-x.

[10] Biswas L, Chen J, De Angelis J, Singh A, Owen-Woods C, Ding Z, et al. Lymphatic vessels in bone support regeneration after injury. Cell 2023; 186: 382-397.e24. https://doi.org/10.1016/j.cell.2022.12.031.

[11] Clahsen T, Hadrian K, Notara M, Schlereth SL, Howaldt A, Prokosch V, et al. The novel role of lymphatic vessels in the pathogenesis of ocular diseases. Prog Retin Eye Res 2023; 96: 101157. https://doi.org/10.1016/j.preteyeres.2022.101157.

[12] Renò F, Sabbatini M. Breaking a vicious circle: Lymphangiogenesis as a new therapeutic target in wound healing. Biomedicines 2023; 11: 656. https://doi.org/10.3390/biomedicines11030656.

[13] Gur-Cohen S, Yang H, Baksh SC, Miao Y, Levorse J, Kataru RP, et al. Stem cell-driven lymphatic remodeling coordinates tissue regeneration. Science 2019; 366: 1218-25. https://doi.org/10.1126/science.aay4509.

[14] Murray RZ, West ZE, Cowin AJ, Farrugia BL. Development and use of biomaterials as wound healing therapies. Burns Trauma 2019; 7: 2. https://doi.org/10.1186/s41038-018-0139-7.

[15] Huang C, Dong L, Zhao B, Lu Y, Huang S, Yuan Z, et al. Anti-inflammatory hydrogel dressings and skin wound healing. Clin Transl Med 2022; 12: e1094. https://doi.org/10.1002/ctm2.1094.

[16] Norahan MH, Pedroza-González SC, Sánchez-Salazar MG, Álvarez MM, Trujillo de Santiago G. Structural and biological engineering of 3D hydrogels for wound healing. Bioact Mater 2023; 24: 197-235. https://doi.org/10.1016/j.bioactmat.2022.11.019.

[17] Weng T, Wang J, Yang M, Zhang W, Wu P, You C, et al. Nanomaterials for the delivery of bioactive factors to enhance angiogenesis of dermal substitutes during wound healing. Burns Trauma 2022; 10: tkab049. https://doi.org/10.1093/burnst/tkab049.

[18] Wei Y, Li J, Huang Y, Lei X, Zhang L, Yin M, et al. The clinical effectiveness and safety of using epidermal growth factor, fibroblast growth factor and granulocyte-macrophage colony stimulating factor as therapeutics in acute skin wound healing: a systematic review and meta-analysis. Burns Trauma 2022; 10: tkac002. https://doi.org/10.1093/burnst/tkac002.

[19] Azari Z, Nazarnezhad S, Webster TJ, Hoseini SJ, Brouki Milan P, Baino F, et al. Stem cell-mediated angiogenesis in skin tissue engineering and wound healing. Wound Repair Regen 2022; 30: 421-35. https://doi.org/10.1111/wrr.13033.

[20] Yamakawa S, Hayashida K. Advances in surgical applications of growth factors for wound healing. Burns Trauma 2019; 7: 10. https://doi.org/10.1186/s41038-019-0148-1.

[21] Veith AP, Henderson K, Spencer A, Sligar AD, Baker AB. Therapeutic strategies for enhancing angiogenesis in wound healing. Adv Drug Deliv Rev 2019; 146: 97-125. https://doi.org/10.1016/j.addr.2018.09.010.

[22] Metcalf DG, Bowler PG. Biofilm delays wound healing: a review of the evidence. Burns Trauma 2013; 1: 5-12. https://doi.org/10.4103/2321-3868.113329.

[23] Eliot R. Clark ELC. Further observations on living lymphatic vessels in the transparent chamber in the rabbit’s ear-their relation to the tissue spaces. Dev Dyn 1933; 52: 273-305. https://doi.org/10.1002/aja.1000520204.

[24] Eliot R. Clark ELC. Observations on the new growth of lymphatic vessels as seen in transparent chambers introduced into the rabbit’s ear. Dev Dyn 1932; 51: 49-87. https://doi.org/10.1002/aja.1000510104.

[25] McMaster PD, Hudack SS. The participation of skin lymphatics in repair of the lesions due to incisions and burns. J Exp Med 1934; 60: 479-501. https://doi.org/10.1084/jem.60.4.479.

[26] Saaristo A, Tammela T, Farkkil¯a A, Kärkkäinen M, Suominen E, Yla-Herttuala S, et al. Vascular endothelial growth factor-C accelerates diabetic wound healing. Am J Pathol 2006; 169: 1080-7. https://doi.org/10.2353/ajpath.2006.051251.

[27] Paavonen K, Puolakkainen P, Jussila L, Jahkola T, Alitalo K. Vascular endothelial growth factor receptor-3 in lymphangiogenesis in wound healing. Am J Pathol 2000; 156: 1499-504. https://doi.org/10.1016/S0002-9440(10)65021-3.

[28] Zhou J, Wei T, He Z. ADSCs enhance VEGFR3-mediated lymphangiogenesis via METTL3-mediated VEGF-C m(6)a modification to improve wound healing of diabetic foot ulcers. Mol Med 2021; 27: 146. https://doi.org/10.1186/s10020-021-00406-z.

[29] Wu M, Matar DY, Yu Z, Chen Z, Knoedler S, Ng B, et al. Modulation of Lymphangiogenesis in incisional murine diabetic wound healing using negative pressure wound therapy. Adv Wound Care (New Rochelle) 2023; 12: 483-97. https://doi.org/10.1089/wound.2022.0074.

[30] Wu M, Liu Q, Yu Z, Karvar M, Aoki S, Hamaguchi R, et al. Negative pressure wound therapy induces Lymphangiogenesis in murine diabetic wound healing. Plast Reconstr Surg 2023; 151: 779-90. https://doi.org/10.1097/PRS.0000000000009997.

[31] Brunner LM, He Y, Cousin N, Scholl J, Albin LK, Schmucki B, et al. Promotion of Lymphangiogenesis by targeted delivery of VEGF-C improves diabetic wound healing. Cells 2023; 12: 472. https://doi.org/10.3390/cells12030472.

[32] Amann-Vesti BR, Ruesch C, Gitzelmann G, Hafner J, Koppensteiner R. Microangiopathy of split-skin grafts in venous ulcers. Dermatologic Surg 2004; 30: 399-402.

[33] Labanaris AP, Polykandriotis E, Horch RE. The effect of vacuum-assisted closure on lymph vessels in chronic wounds. J Plast Reconstr Aesthet Surg 2009; 62: 1068-75. https://doi.org/10.1016/j.bjps.2008.01.006.

[34] Maruyama K, Asai J, Ii M, Thorne T, Losordo DW, D’Amore PA. Decreased macrophage number and activation lead to reduced lymphatic vessel formation and contribute to impaired diabetic wound healing. Am J Pathol 2007; 170: 1178-91. https://doi.org/10.2353/ajpath.2007.060018.

[35] Bianchi A, Painter KJ, Sherratt JA. A mathematical model for lymphangiogenesis in normal and diabetic wounds. J Theor Biol 2015; 383: 61-86. https://doi.org/10.1016/j.jtbi.2015.07.023.

[36] Tammela T, Alitalo K. Lymphangiogenesis: molecular mechanisms and future promise. Cell 2010; 140: 460-76. https://doi.org/10.1016/j.cell.2010.01.045.

[37] Alitalo K, Tammela T, Petrova TV. Lymphangiogenesis in development and human disease. Nature 2005; 438: 946-53. https://doi.org/10.1038/nature04480.

[38] Randolph GJ, Ivanov S, Zinselmeyer BH, Scallan JP. The lymphatic system: integral roles in immunity. Annu Rev Immunol 2017; 35: 31-52. https://doi.org/10.1146/annurev-immunol-041015-055354.

[39] Baluk P, Fuxe J, Hashizume H, Romano T, Lashnits E, Butz S, et al. Functionally specialized junctions between endothelial cells of lymphatic vessels. J Exp Med 2007; 204: 2349-62. https://doi.org/10.1084/jem.20062596.

[40] Danussi C, Spessotto P, Petrucco A, Wassermann B, Sabatelli P, Montesi M, et al. Emilin1 deficiency causes structural and functional defects of lymphatic vasculature. Mol Cell Biol 2008; 28: 4026-39. https://doi.org/10.1128/MCB.02062-07.

[41] Choi I, Lee S, Hong YK. The new era of the lymphatic system: no longer secondary to the blood vascular system. Cold Spring Harb Perspect Med 2012; 2: a006445. https://doi.org/10.1101/cshperspect.a006445.

[42] Jia W, Hitchcock-Szilagyi H, He W, Goldman J, Zhao F. Engineering the lymphatic network: a solution to lymphedema. Adv Healthc Mater 2021; 10: e2001537. https://doi.org/10.1002/adhm.202001537.

[43] Moore JE, Bertram CD. Lymphatic System Flows. Annu Rev Fluid Mech 2018; 50: 459-82. https://doi.org/10.1146/annurev-fluid-122316-045259.

[44] Bazigou E, Xie S, Chen C, Weston A, Miura N, Sorokin L, et al. Integrin-alpha9 is required for fibronectin matrix assembly during lymphatic valve morphogenesis. Dev Cell 2009; 17: 175-86. https://doi.org/10.1016/j.devcel.2009.06.017.

[45] von Andrian UH, Mempel TR. Homing and cellular traffic in lymph nodes. Nat Rev Immunol 2003; 3: 867-78. https://doi.org/10.1038/nri1222.

[46] Huggenberger R, Siddiqui SS, Brander D, Ullmann S, Zimmermann K, Antsiferova M, et al. An important role of lymphatic vessel activation in limiting acute inflammation. Blood 2011; 117: 4667-78. https://doi.org/10.1182/blood-2010-10-316356.

[47] Kim H, Kataru RP, Koh GY. Regulation and implications of inflammatory lymphangiogenesis. Trends Immunol 2012; 33: 350-6. https://doi.org/10.1016/j.it.2012.03.006.

[48] Wang Z, Wang W, Chai Q, Zhu M. Langerhans cells control lymphatic vessel function during inflammation via LIGHT-LTβR Signaling. J Immunol 2019; 202: 2999-3007. https://doi.org/10.4049/jimmunol.1801578.

[49] Schwager S, Detmar M. Inflammation and lymphatic function. Front Immunol 2019; 10: 308. https://doi.org/10.3389/fimmu.2019.00308.

[50] Henno A, Blacher S, Lambert C, Colige A, Seidel L, Noël A, et al. Altered expression of angiogenesis and lymphangiogenesis markers in the uninvolved skin of plaque-type psoriasis. Br J Dermatol 2009; 160: 581-90. https://doi.org/10.1111/j.1365-2133.2008.08889.x.

[51] Kajiya K, Hirakawa S, Detmar M. Vascular endothelial growth factor-a mediates ultraviolet B-induced impairment of lymphatic vessel function. Am J Pathol 2006; 169: 1496-503. https://doi.org/10.2353/ajpath.2006.060197.

[52] Kajiya K, Sawane M, Huggenberger R, Detmar M. Activation of the VEGFR-3 pathway by VEGF-C attenuates UVB-induced edema formation and skin inflammation by promoting lymphangiogenesis. J Invest Dermatol 2009; 129: 1292-8. https://doi.org/10.1038/jid.2008.351.

[53] Ohl L, Mohaupt M, Czeloth N, Hintzen G, Kiafard Z, Zwirner J, et al. CCR7 governs skin dendritic cell migration under inflammatory and steady-state conditions. Immunity 2004; 21: 279-88. https://doi.org/10.1016/j.immuni.2004.06.014.

[54] Lynskey NN, Banerji S, Johnson LA, Holder KA, Reglinski M, Wing PA, et al. Rapid lymphatic dissemination of encapsulated group a streptococci via lymphatic vessel endothelial Receptor-1 interaction. PLoS Pathog 2015; 11: e1005137. https://doi.org/10.1371/journal.ppat.1005137.

[55] Johnson LA, Banerji S, Lawrance W, Gileadi U, Prota G, Holder KA, et al. Dendritic cells enter lymph vessels by hyaluronan-mediated docking to the endothelial receptor LYVE-1. Nat Immunol 2017; 18: 762-70. https://doi.org/10.1038/ni.3750.

[56] Lawrance W, Banerji S, Day AJ, Bhattacharjee S, Jackson DG. Binding of Hyaluronan to the native lymphatic vessel endothelial receptor LYVE-1 is critically dependent on receptor clustering and Hyaluronan organization. J Biol Chem 2016; 291: 8014-30. https://doi.org/10.1074/jbc.M115.708305.

[57] Jackson DG.Hyaluronan in the lymphatics: the key role of the hyaluronan receptor LYVE-1 in leucocyte trafficking. Matrix Biol 2019; 78-79: 219-35. https://doi.org/10.1016/j.matbio.2018.02.001.

[58] Peña-Jimenez D, Fontenete S, Megias D, Fustero-Torre C, Graña-Castro O, Castellana D, et al. Lymphatic vessels interact dynamically with the hair follicle stem cell niche during skin regeneration in vivo. EMBO J 2019; 38: e101688. https://doi.org/10.15252/embj.2019101688.

[59] Yoon SY, Dieterich LC, Karaman S, Proulx ST, Bachmann SB, Sciaroni C, et al. An important role of cutaneous lymphatic vessels in coordinating and promoting anagen hair follicle growth. PLoS One 2019; 14: e0220341. https://doi.org/10.1371/journal.pone.0220341.

[60] Yang Y, Wang X, Wang P. Signaling mechanisms underlying lymphatic vessel dysfunction in skin aging and possible antiaging strategies. Biogerontology 2023; 24: 727-40. https://doi.org/10.1007/s10522-023-10016-3.

[61] Hromada C, Hartmann J, Oesterreicher J, Stoiber A, Daerr A, Schädl B, et al. Occurrence of Lymphangiogenesis in peripheral nerve autografts contrasts Schwann cell-induced apoptosis of lymphatic endothelial cells In vitro. Biomolecules 2022; 12: 820. https://doi.org/10.3390/biom12060820.

[62] Meng FW, Jing XN, Song GH, Jie LL, Shen FF. Prox1 induces new lymphatic vessel formation and promotes nerve reconstruction in a mouse model of sciatic nerve crush injury. J Anat 2020; 237: 933-40. https://doi.org/10.1111/joa.13247.

[63] Martínez-Corral I, Olmeda D, Diéguez-Hurtado R, Tammela T, Alitalo K, Ortega S. In vivo imaging of lymphatic vessels in development, wound healing, inflammation, and tumor metastasis. Proc Natl Acad Sci USA 2012; 109: 6223-8. https://doi.org/10.1073/pnas.1115542109.

[64] Bianchi A, Painter KJ, Sherratt JA. Spatio-temporal models of Lymphangiogenesis in wound healing. Bull Math Biol 2016; 78: 1904-41. https://doi.org/10.1007/s11538-016-0205-x.

[65] Rutkowski JM, Boardman KC, Swartz MA. Characterization of lymphangiogenesis in a model of adult skin regeneration. Am J Physiol Heart Circ Physiol 2006; 291: H1402-10. https://doi.org/10.1152/ajpheart.00038.2006.

[66] Boardman KC, Swartz MA. Interstitial flow as a guide for lymphangiogenesis. Circ Res 2003; 92: 801-8. https://doi.org/10.1161/01.RES.0000065621.69843.49.

[67] Swartz MA, Boardman KC, Jr.. The role of interstitial stress in lymphatic function and lymphangiogenesis. Ann N Y Acad Sci 2002; 979: 197-210discussion 229-134. https://doi.org/10.1111/j.1749-6632.2002.tb04880.x.

[68] Goldman J, Conley KA, Raehl A, Bondy DM, Pytowski B, Swartz MA, et al. Regulation of lymphatic capillary regeneration by interstitial flow in skin. Am J Physiol Heart Circ Physiol 2007; 292: H2176-83. https://doi.org/10.1152/ajpheart.01011.2006.

[69] Kim S, Chung M, Jeon NL. Three-dimensional biomimetic model to reconstitute sprouting lymphangiogenesis in vitro. Biomaterials 2016; 78: 115-28. https://doi.org/10.1016/j.biomaterials.2015.11.019.

[70] Ji RC, Miura M, Qu P, Kato S. Expression of VEGFR-3 and 5′-nase in regenerating lymphatic vessels of the cutaneous wound healing. Microsc Res Tech 2004; 64: 279-86. https://doi.org/10.1002/jemt.20082.

[71] Nogami M, Hoshi T, Arai T, Toukairin Y, Takama M, Takahashi I. Morphology of lymphatic regeneration in rat incision wound healing in comparison with vascular regeneration. Leg Med (Tokyo) 2009; 11: 213-8. https://doi.org/10.1016/j.legalmed.2009.05.001.

[72] Karkkainen MJ, Haiko P, Sainio K, Partanen J, Taipale J, Petrova TV, et al. Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat Immunol 2004; 5: 74-80. https://doi.org/10.1038/ni1013.

[73] Martin P.. Wound healing-aiming for perfect skin regeneration. Science 1997; 276: 75-81. https://doi.org/10.1126/science.276.5309.75.

[74] Suzuki-Inoue K, Tsukiji N, Shirai T, Osada M, Inoue O, Ozaki Y. Platelet CLEC-2: roles beyond Hemostasis. Semin Thromb Hemost 2018; 44: 126-34. https://doi.org/10.1055/s-0037-1604090.

[75] Walsh TG, Metharom P, Berndt MC. The functional role of platelets in the regulation of angiogenesis. Platelets 2015; 26: 199-211. https://doi.org/10.3109/09537104.2014.909022.

[76] Suzuki-Inoue K, Tsukiji N, Otake S. Crosstalk between hemostasis and lymphangiogenesis. J Thromb Haemost 2020; 18: 767-70. https://doi.org/10.1111/jth.14726.

[77] Wang Z, Qi F, Luo H, Xu G, Wang D. Inflammatory microenvironment of skin wounds. Front Immunol 2022; 13: 789274. https://doi.org/10.3389/fimmu.2022.789274.

[78] Lim L, Bui H, Farrelly O, Yang J, Li L, Enis D, et al. Hemostasis stimulates lymphangiogenesis through release and activation of VEGFC. Blood 2019; 134: 1764-75. https://doi.org/10.1182/blood.2019001736.

[79] Hur J, Jang JH, Oh IY, Choi JI, Yun JY, Kim J, et al. Human podoplanin-positive monocytes and platelets enhance lymphangiogenesis through the activation of the podoplanin/CLEC-2 axis. Mol Ther 2014; 22: 1518-29. https://doi.org/10.1038/mt.2014.61.

[80] Suzuki-Inoue K, Inoue O, Ding G, Nishimura S, Hokamura K, Eto K, et al. Essential in vivo roles of the C-type lectin receptor CLEC-2: embryonic/neonatal lethality of CLEC-2-deficient mice by blood/lymphatic misconnections and impaired thrombus formation of CLEC-2-deficient platelets. J Biol Chem 2010; 285: 24494-507. https://doi.org/10.1074/jbc.M110.130575.

[81] Langan SA, Navarro-Núñez L, Watson SP, Nash GB. Modulation of VEGF-induced migration and network formation by lymphatic endothelial cells: roles of platelets and podoplanin. Platelets 2018; 29: 486-95. https://doi.org/10.1080/09537104.2017.1336210.

[82] Sato H, Higashiyama M, Hozumi H, Sato S, Furuhashi H, Takajo T, et al. Platelet interaction with lymphatics aggravates intestinal inflammation by suppressing lymphangiogenesis. Am J Physiol Gastrointest Liver Physiol 2016; 311: G276-85. https://doi.org/10.1152/ajpgi.00455.2015.

[83] Kim H, Kataru RP, Koh GY. Inflammation-associated lymphangiogenesis: a double-edged sword? J Clin Invest 2014; 124: 936-42. https://doi.org/10.1172/JCI71607.

[84] Kataru RP, Jung K, Jang C, Yang H, Schwendener RA, Baik JE, et al. Critical role of CD11b+ macrophages and VEGF in inflammatory lymphangiogenesis, antigen clearance, and inflammation resolution. Blood 2009; 113: 5650-9. https://doi.org/10.1182/blood-2008-09-176776.

[85] Kerjaschki D.The crucial role of macrophages in lymphangiogenesis. J Clin Invest 2005; 115: 2316-9. https://doi.org/10.1172/JCI26354.

[86] Huggenberger R, Ullmann S, Proulx ST, Pytowski B, Alitalo K, Detmar M. Stimulation of lymphangiogenesis via VEGFR-3 inhibits chronic skin inflammation. J Exp Med 2010; 207: 2255-69. https://doi.org/10.1084/jem.20100559.

[87] Varricchi G, Loffredo S, Galdiero MR, Marone G, Cristinziano L, Granata F, et al. Innate effector cells in angiogenesis and lymphangiogenesis. Curr Opin Immunol 2018; 53: 152-60. https://doi.org/10.1016/j.coi.2018.05.002.

[88] Marone G, Varricchi G, Loffredo S, Granata F. Mast cells and basophils in inflammatory and tumor angiogenesis and lymphangiogenesis. Eur J Pharmacol 2016; 778: 146-51. https://doi.org/10.1016/j.ejphar.2015.03.088.

[89] Singer AJ. Healing mechanisms in cutaneous wounds: tipping the balance. Tissue Eng Part B Rev 2022; 28: 1151-67. https://doi.org/10.1089/ten.teb.2021.0114.

[90] Massena S, Christoffersson G, Vågesjö E, Seignez C, Gustafsson K, Binet F, et al. Identification and characterization of VEGF-A-responsive neutrophils expressing CD49d, VEGFR1, and CXCR4 in mice and humans. Blood 2015; 126: 2016-26. https://doi.org/10.1182/blood-2015-03-631572.

[91] Hong YK, Lange-Asschenfeldt B, Velasco P, Hirakawa S, Kunstfeld R, Brown LF, et al. VEGF-A promotes tissue repair-associated lymphatic vessel formation via VEGFR-2 and the alpha1beta1 and alpha2beta1 integrins. FASEB J 2004; 18: 1111-3. https://doi.org/10.1096/fj.03-1179fje.

[92] Detmar M, Brown LF, Schön MP, Elicker BM, Velasco P, Richard L, et al. Increased microvascular density and enhanced leukocyte rolling and adhesion in the skin of VEGF transgenic mice. J Invest Dermatol 1998; 111: 1-6. https://doi.org/10.1046/j.1523-1747.1998.00262.x.

[93] Durré T, Morfoisse F, Erpicum C, Ebroin M, Blacher S, García-Caballero M, et al. uPARAP/Endo180 receptor is a gatekeeper of VEGFR-2/VEGFR-3 heterodimerisation during pathological lymphangiogenesis. Nat Commun 2018; 9: 5178. https://doi.org/10.1038/s41467-018-07514-1.

[94] Wada I, Nakao S, Yamaguchi M, Kaizu Y, Arima M, Sawa S, et al. Retinal VEGF-A overexpression is not sufficient to induce Lymphangiogenesis regardless of VEGF-C upregulation and Lyve1+ macrophage infiltration. Invest Ophthalmol Vis Sci 2021; 62: 17. https://doi.org/10.1167/iovs.62.13.17.

[95] Cursiefen C, Chen L, Borges LP, Jackson D, Cao J, Radziejewski C, et al. VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment. J Clin Invest 2004; 113: 1040-50. https://doi.org/10.1172/JCI20465.

[96] Halin C, Tobler NE, Vigl B, Brown LF, Detmar M. VEGF-A produced by chronically inflamed tissue induces lymphangiogenesis in draining lymph nodes. Blood 2007; 110: 3158-67. https://doi.org/10.1182/blood-2007-01-066811.

[97] Corliss BA, Azimi MS, Munson JM, Peirce SM, Murfee WL. Macrophages: an inflammatory link between angiogenesis and Lymphangiogenesis. Microcirculation 2016; 23: 95-121. https://doi.org/10.1111/micc.12259.

[98] Kataru RP, Baik JE, Park HJ, Wiser I, Rehal S, Shin JY, et al. Regulation of immune function by the lymphatic system in lymphedema. Front Immunol 2019; 10: 470. https://doi.org/10.3389/fimmu.2019.00470.

[99] Willenborg S, Injarabian L, Eming SA. Role of macrophages in wound healing. Cold Spring Harb Perspect Biol 2022; 14:a041216. https://doi.org/10.1101/cshperspect.a041216.

[100] Glinton KE, Ma W, Lantz C, Grigoryeva LS, DeBerge M, Liu X, et al. Macrophage-produced VEGFC is induced by efferocytosis to ameliorate cardiac injury and inflammation. J Clin Invest 2022; 132: e140685. https://doi.org/10.1172/JCI140685.

[101] Maruyama K, Ii M, Cursiefen C, Jackson DG, Keino H, Tomita M, et al. Inflammation-induced lymphangiogenesis in the cornea arises from CD11b-positive macrophages. J Clin Invest 2005; 115: 2363-72. https://doi.org/10.1172/JCI23874.

[102] Gordon EJ, Rao S, Pollard JW, Nutt SL, Lang RA, Harvey NL. Macrophages define dermal lymphatic vessel calibre during development by regulating lymphatic endothelial cell proliferation. Development 2010; 137: 3899-910. https://doi.org/10.1242/dev.050021.

[103] Clavin NW, Avraham T, Fernandez J, Daluvoy SV, Soares MA, Chaudhry A, et al. TGF-beta1 is a negative regulator of lymphatic regeneration during wound repair. Am J Physiol Heart Circ Physiol 2008; 295: H2113-27. https://doi.org/10.1152/ajpheart.00879.2008.

[104] Avraham T, Daluvoy S, Zampell J, Yan A, Haviv YS, Rockson SG, et al. Blockade of transforming growth factor-beta1 accelerates lymphatic regeneration during wound repair. Am J Pathol 2010; 177: 3202-14. https://doi.org/10.2353/ajpath.2010.100594.

[105] Shimamura K, Nakatani T, Ueda A, Sugama J, Okuwa M. Relationship between lymphangiogenesis and exudates during the wound-healing process of mouse skin full-thickness wound. Wound Repair Regen 2009; 17: 598-605. https://doi.org/10.1111/j.1524-475X.2009.00512.x.

[106] Hall MA, Robinson H, Chan W, Sevick-Muraca EM. Detection of lymphangiogenesis by near-infrared fluorescence imaging and responses to VEGF-C during healing in a mouse full-dermis thickness wound model. Wound Repair Regen 2013; 21: 604-15. https://doi.org/10.1111/wrr.12063.

[107] Ji RC. Lymphatic endothelial cells, inflammatory lymphangiogenesis, and prospective players. Curr Med Chem 2007; 14: 2359-68. https://doi.org/10.2174/092986707781745541.

[108] Gerald D, Adini I, Shechter S, Perruzzi C, Varnau J, Hopkins B, et al. RhoB controls coordination of adult angiogenesis and lymphangiogenesis following injury by regulating VEZF1-mediated transcription. Nat Commun 2013; 4: 2824. https://doi.org/10.1038/ncomms3824.

[109] Paupert J, Sounni NE, Noël A. Lymphangiogenesis in post-natal tissue remodeling: lymphatic endothelial cell connection with its environment. Mol Asp Med 2011; 32: 146-58. https://doi.org/10.1016/j.mam.2011.04.002.

[110] Avraham T, Clavin NW, Daluvoy SV, Fernandez J, Soares MA, Cordeiro AP, et al. Fibrosis is a key inhibitor of lymphatic regeneration. Plast Reconstr Surg 2009; 124: 438-50. https://doi.org/10.1097/PRS.0b013e3181adcf4b.

[111] Saaristo A, Tammela T, Timonen J, Yla-Herttuala S, Tukiainen E, Asko-Seljavaara S, et al. Vascular endothelial growth factor-C gene therapy restores lymphatic flow across incision wounds. FASEB J 2004; 18: 1707-9. https://doi.org/10.1096/fj.04-1592fje.

[112] Epstein SE, Kornowski R, Fuchs S, Dvorak HF. Angiogenesis therapy: amidst the hype, the neglected potential for serious side effects. Circulation 2001; 104: 115-9. https://doi.org/10.1161/01.CIR.104.1.115.

[113] Saaristo A, Veikkola T, Enholm B, Hytönen M, Arola J, Pajusola K, et al. Adenoviral VEGF-C overexpression induces blood vessel enlargement, tortuosity, and leakiness but no sprouting angiogenesis in the skin or mucous membranes. FASEB J 2002; 16: 1041-9. https://doi.org/10.1096/fj.01-1042com.

[114] Isaka N, Padera TP, Hagendoorn J, Fukumura D, Jain RK.Peritumor lymphatics induced by vascular endothelial growth factor-C exhibit abnormal function. Cancer Res 2004; 64: 4400-4. https://doi.org/10.1158/0008-5472.CAN-04-0752.

[115] Güç E, Briquez PS, Foretay D, Fankhauser MA, Hubbell JA, Kilarski WW, et al. Local induction of lymphangiogenesis with engineered fibrin-binding VEGF-C promotes wound healing by increasing immune cell trafficking and matrix remodeling. Biomaterials 2017; 131: 160-75. https://doi.org/10.1016/j.biomaterials.2017.03.033.

[116] Goldman J, Le TX, Skobe M, Swartz MA. Overexpression of VEGF-C causes transient lymphatic hyperplasia but not increased lymphangiogenesis in regenerating skin. Circ Res 2005; 96: 1193-9. https://doi.org/10.1161/01.RES.0000168918.27576.78.

[117] Cho CH, Sung HK, Kim KT, Cheon HG, Oh GT, Hong HJ, et al. COMP-angiopoietin-1 promotes wound healing through enhanced angiogenesis, lymphangiogenesis, and blood flow in a diabetic mouse model. Proc Natl Acad Sci USA 2006; 103: 4946-51. https://doi.org/10.1073/pnas.0506352103.

[118] He ZY, Huang MT, Cui X, Zhou ST, Wu Y, Zhang PH, et al. Long noncoding RNA GAS5 accelerates diabetic wound healing and promotes lymphangiogenesis via miR-217/Prox1 axis. Mol Cell Endocrinol 2021; 532: 111283. https://doi.org/10.1016/j.mce.2021.111283.

[119] He ZY, Wei TH, Zhang PH, Zhou J, Huang XY. Long noncoding RNA-antisense noncoding RNA in the INK4 locus accelerates wound healing in diabetes by promoting lymphangiogenesis via regulating miR-181a/Prox1 axis. J Cell Physiol 2019; 234: 4627-40. https://doi.org/10.1002/jcp.27260.

[120] Rezvanian M, Ng SF, Alavi T, Ahmad W. In-vivo evaluation of alginate-pectin hydrogel film loaded with simvastatin for diabetic wound healing in Streptozotocin-induced diabetic rats. Int J Biol Macromol 2021; 171: 308-19. https://doi.org/10.1016/j.ijbiomac.2020.12.221.

[121] Liu C, Zhu J, Hai B, Zhang W, Wang H, Leng H, et al. Single intraosseous injection of simvastatin promotes endothelial progenitor cell mobilization, neovascularization, and wound healing in diabetic rats. Plast Reconstr Surg 2020; 145: 433-43. https://doi.org/10.1097/PRS.0000000000006502.

[122] Asai J, Takenaka H, Hirakawa S, Sakabe J, Hagura A, Kishimoto S, et al. Topical simvastatin accelerates wound healing in diabetes by enhancing angiogenesis and lymphangiogenesis. Am J Pathol 2012; 181: 2217-24. https://doi.org/10.1016/j.ajpath.2012.08.023.

[123] Choi J, Park YG, Yun MS, Seol JW. Effect of herbal mixture composed of Alchemilla vulgaris and Mimosa on wound healing process. Biomed Pharmacother 2018; 106: 326-32. https://doi.org/10.1016/j.biopha.2018.06.141.

[124] Lafuente H, Jaunarena I, Ansuategui E, Lekuona A, Izeta A. Cell therapy as a treatment of secondary lymphedema: a systematic review and meta-analysis. Stem Cell Res Ther 2021; 12: 578. https://doi.org/10.1186/s13287-021-02632-y.

[125] Shimizu Y, Shibata R, Shintani S, Ishii M, Murohara T. Therapeutic lymphangiogenesis with implantation of adipose-derived regenerative cells. J Am Heart Assoc 2012; 1: e000877. https://doi.org/10.1161/JAHA.112.000877.

[126] Campbell KT, Curtis MB, Massey JM, Wysoczynski K, Hadley DJ, George SC, et al. Isolating and characterizing lymphatic endothelial progenitor cells for potential therapeutic lymphangiogenic applications. Acta Biomater 2021; 135: 191-202. https://doi.org/10.1016/j.actbio.2021.08.005.

[127] Li ZJ, Yang E, Li YZ, Liang ZY, Huang JZ, Yu NZ, et al. Application and prospect of adipose stem cell transplantation in treating lymphedema. World J Stem Cells 2020; 12: 676-87. https://doi.org/10.4252/wjsc.v12.i7.676.

[128] Robering JW, Weigand A, Pfuhlmann R, Horch RE, Beier JP, Boos AM. Mesenchymal stem cells promote lymphangiogenic properties of lymphatic endothelial cells. J Cell Mol Med 2018; 22: 3740-50. https://doi.org/10.1111/jcmm.13590.

[129] Conrad C, Niess H, Huss R, Huber S, von Luettichau I, Nelson PJ, et al. Multipotent mesenchymal stem cells acquire a lymphendothelial phenotype and enhance lymphatic regeneration in vivo. Circulation 2009; 119: 281-9. https://doi.org/10.1161/CIRCULATIONAHA.108.793208.

[130] Fuchs B, Birt A, Moellhoff N, Kuhlmann C, Giunta RE, Wiggenhauser PS. Adipose-derived stem cells improve angiogenesis and Lymphangiogenesis in a hypoxic dermal regeneration model In vitro. Medicina (Kaunas) 2023; 59: 706. https://doi.org/10.3390/medicina59040706.

[131] Yamada H, Naito R, Nishimura M, Kawakami R, Morinaga E, Morita Y, et al. Xenotransplantation of neonatal porcine bone marrow-derived mesenchymal stem cells improves diabetic wound healing by promoting angiogenesis and lymphangiogenesis. Xenotransplantation 2022; 29:e12739. https://doi.org/10.1111/xen.12739.

[132] Beerens M, Aranguren XL, Hendrickx B, Dheedene W, Dresselaers T, Himmelreich U, et al. Multipotent adult progenitor cells support lymphatic regeneration at multiple anatomical levels during wound healing and lymphedema. Sci Rep 2018; 8: 3852. https://doi.org/10.1038/s41598-018-21610-8.

[133] Lee SJ, Park C, Lee JY, Kim S, Kwon PJ, Kim W, et al. Generation of pure lymphatic endothelial cells from human pluripotent stem cells and their therapeutic effects on wound repair. Sci Rep 2015; 5: 11019. https://doi.org/10.1038/srep11019.

[134] Alderfer L, Hall E, Hanjaya-Putra D. Harnessing biomaterials for lymphatic system modulation. Acta Biomater 2021; 133: 34-45. https://doi.org/10.1016/j.actbio.2021.06.006.

[135] Frueh FS, Sanchez-Macedo N, Calcagni M, Giovanoli P, Lindenblatt N. The crucial role of vascularization and Lymphangiogenesis in skin reconstruction. Eur Surg Res 2018; 59: 242-54. https://doi.org/10.1159/000492413.

[136] Marino D, Luginbühl J, Scola S, Meuli M, Reichmann E. Bioengineering dermo-epidermal skin grafts with blood and lymphatic capillaries. Sci Transl Med 2014; 6: 221ra14. https://doi.org/10.1126/scitranslmed.3006894.

[137] Kong AM, Lim SY, Palmer JA, Rixon A, Gerrand YW, Yap KK, et al. Engineering transplantable human lymphatic and blood capillary networks in a porous scaffold. J Tissue Eng 2022; 13: 204173142211409. https://doi.org/10.1177/20417314221140979.

[138] Jiang J, Kraneburg U, Dornseifer U, Schilling AF, Hadjipanayi E, Machens HG, et al. Hypoxia preconditioned serum (HPS)-hydrogel can accelerate dermal wound healing in mice-an In vivo pilot study. Biomedicines 2022; 10: 176. https://doi.org/10.3390/biomedicines10010176.

[139] Frueh FS, Später T, Lindenblatt N, Calcagni M, Giovanoli P, Scheuer C, et al. Adipose tissue-derived microvascular fragments improve vascularization, Lymphangiogenesis, and integration of dermal skin substitutes. J Invest Dermatol 2017; 137: 217-27. https://doi.org/10.1016/j.jid.2016.08.010.

[140] Frueh FS, Spáter T, Körbel C, Scheuer C, Simson AC, Lindenblatt N, et al. Prevascularization of dermal substitutes with adipose tissue-derived microvascular fragments enhances early skin grafting. Sci Rep 2018; 8: 10977. https://doi.org/10.1038/s41598-018-29252-6.

[141] Chávez MN, Fuchs B, Moellhoff N, Hofmann D, Zhang L, Selão TT, et al. Use of photosynthetic transgenic cyanobacteria to promote lymphangiogenesis in scaffolds for dermal regeneration. Acta Biomater 2021; 126: 132-43. https://doi.org/10.1016/j.actbio.2021.03.033.

[142] Hsiao HY, Hsieh WC, Chang FC, Liu JW, Kuo WL, Cheong DC, et al. The effect of negative pressure on wound healing and regeneration in closed incisions under high tension: evidence from animal studies and clinical experience. J Clin Med 2022; 12: 106. https://doi.org/10.3390/jcm12010106.

[143] Cherubino M, Pellegatta I, Tamborini F, Cerati M, Sessa F, Valdatta L. Evaluation of lymphangiogenesis in acellular dermal matrix. Indian J Plast Surg 2014; 47: 318-24. https://doi.org/10.4103/0970-0358.146578.

[144] Wong AK, Schonmeyer BH, Singh P, Carlson DL, Li S, Mehrara BJ. Histologic analysis of angiogenesis and lymphangiogenesis in acellular human dermis. Plast Reconstr Surg 2008; 121: 1144-52. https://doi.org/10.1097/01.prs.0000302505.43942.07.

[145] Rockson SG. Advances in lymphedema. Circ Res 2021; 128: 2003-16. https://doi.org/10.1161/CIRCRESAHA.121.318307.

[146] Yoshida S, Koshima I, Hamada Y, Sasaki A, Fujioka Y, Nagamatsu S, et al. Lymphovenous anastomosis aids wound healing in lymphedema: relationship between lymphedema and delayed wound healing from a view of immune mechanisms. Adv Wound Care (New Rochelle) 2019; 8: 263-9. https://doi.org/10.1089/wound.2018.0871.

[147] Cigna E, Pierazzi DM, Sereni S, Marcasciano M, Losco L, Bolletta A. Lymphatico-venous anastomosis in chronic ulcer with venous insufficiency: a case report. Microsurgery 2021; 41: 574-8. https://doi.org/10.1002/micr.30753.