Research advances on stem cell-based treatments in animal studies and clinical trials of lymphedema_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

CHEN Junzhe ¹ ,  DENG Chengliang ^1,2

1. Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi Guizhou, 563003, P. R. China;
2. Collaborative Innovation Center of Tissue Repair and Regenerative Medicine, Zunyi Guizhou, 563003, P. R. China;

Corresponding author：

DENG Chengliang, Email: cheliadeng@sina.com

Keywords：

Stem cells; lymphedema; lymphatic regeneration; tissue engineering; regenerative medicine

DOI：

10.7507/1002-1892.202309045

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To summarize the progress of the roles and mechanisms of various types of stem cell-based treatments and their combination therapies in both animal studies and clinical trials of lymphedema. Methods The literature on stem cell-based treatments for lymphedema in recent years at home and abroad was extensively reviewed, and the animal studies and clinical trials on different types of stem cells for lymphedema were summarized.Results Various types of stem cells have shown certain effects in animal studies and clinical trials on the treatment of lymphedema, mainly through local differentiation into lymphoid endothelial cells and paracrine cytokines with different functions. Current research focuses on two cell types, adipose derived stem cells and bone marrow mesenchymal stem cells, both of which have their own advantages and disadvantages, mainly reflected in the therapeutic effect of stem cells, the difficulty of obtaining stem cells and the content in vivo. In addition, stem cells can also play a synergistic role in combination with other treatments, such as conservative treatment, surgical intervention, cytokines, biological scaffolds, and so on. However, it is still limited to the basic research stage, and only a small number of studies have completed clinical trials. Conclusion Stem cells have great transformation potential in the treatment of lymphedema, but there is no unified standard in the selection of cell types, the amount of transplanted cells, and the timing of transplantation.

Citation： CHEN Junzhe, DENG Chengliang. Research advances on stem cell-based treatments in animal studies and clinical trials of lymphedema. Chinese Journal of Reparative and Reconstructive Surgery, 2024, 38(1): 99-106. doi: 10.7507/1002-1892.202309045 Copy

1.	Brown S, Dayan JH, Kataru RP, et al. The vicious circle of stasis, inflammation, and fibrosis in lymphedema. Plast Reconstr Surg, 2023, 151(2): 330e-341e.
2.	Schulze H, Nacke M, Gutenbrunner C, et al. Worldwide assessment of healthcare personnel dealing with lymphoedema. Health Econ Rev, 2018, 8(1): 10.
3.	McLaughlin SA, Brunelle CL, Taghian A. Breast cancer-related lymphedema: Risk factors, screening, management, and the impact of locoregional treatment. J Clin Oncol, 2020, 38(20): 2341-2350.
4.	Ogino R, Yokooji T, Hayashida M, et al. Emerging anti-inflammatory pharmacotherapy and cell-based therapy for lymphedema. Int J Mol Sci, 2022, 23(14): 7614.
5.	Barufi S, Pereira de Godoy HJ, Pereira de Godoy JM, et al. Exercising and compression mechanism in the treatment of lymphedema. Cureus, 2021, 13(7): e16121.
6.	Donahue PMC, MacKenzie A, Filipovic A, et al. Advances in the prevention and treatment of breast cancer-related lymphedema. Breast Cancer Res Treat, 2023, 200(1): 1-14.
7.	Nicenboim J, Malkinson G, Lupo T, et al. Lymphatic vessels arise from specialized angioblasts within a venous niche. Nature, 2015, 522(7554): 56-61.
8.	Oliver G, Kipnis J, Randolph GJ, et al. The lymphatic vasculature in the 21^st century: Novel functional roles in homeostasis and disease. Cell, 2020, 182(2): 270-296.
9.	Baluk P, Fuxe J, Hashizume H, et al. Functionally specialized junctions between endothelial cells of lymphatic vessels. J Exp Med, 2007, 204(10): 2349-2362.
10.	Tammela T, Alitalo K. Lymphangiogenesis: Molecular mechanisms and future promise. Cell, 2010, 140(4): 460-476.
11.	Rockson SG. Advances in lymphedema. Circ Res, 2021, 128(12): 2003-2016.
12.	Ly CL, Nores GDG, Kataru RP, et al. T helper 2 differentiation is necessary for development of lymphedema. Transl Res, 2019, 206: 57-70.
13.	Henderson NC, Rieder F, Wynn TA. Fibrosis: from mechanisms to medicines. Nature, 2020, 587(7835): 555-566.
14.	Zhao W, Zhang H, Liu R, et al. Advances in immunomodulatory mechanisms of mesenchymal stem cells-derived exosome on immune cells in scar formation. Int J Nanomedicine, 2023, 18: 3643-3662.
15.	Ogino R, Hayashida K, Yamakawa S, et al. Adipose-derived stem cells promote intussusceptive lymphangiogenesis by restricting dermal fibrosis in irradiated tissue of mice. Int J Mol Sci, 2020, 21(11): 3885.
16.	Baik JE, Park HJ, Kataru RP, et al. TGF-β₁ mediates pathologic changes of secondary lymphedema by promoting fibrosis and inflammation. Clin Transl Med, 2022, 12(6): e758.
17.	Yoon SH, Kim KY, Wang Z, et al. EW-7197, a transforming growth factor-beta type Ⅰ receptor kinase inhibitor, ameliorates acquired lymphedema in a mouse tail model. Lymphat Res Biol, 2020, 18(5): 433-438.
18.	Levy D, Abadchi SN, Shababi N, et al. Induced pluripotent stem cell-derived extracellular vesicles promote wound repair in a diabetic mouse model via an anti-inflammatory immunomodulatory mechanism. Adv Healthc Mater, 2023, 12(26): e2300879.
19.	Huethorst E, Krebber MM, Fledderus JO, et al. Lymphatic vascular regeneration: The next step in tissue engineering. Tissue Eng Part B Rev, 2016, 22(1): 1-14.
20.	Saijo H, Suzuki K, Yoshimoto H, et al. Paracrine effects of adipose-derived stem cells promote lymphangiogenesis in irradiated lymphatic endothelial cells. Plast Reconstr Surg, 2019, 143(6): 1189e-1200e.
21.	Cao R, Ji H, Feng N, et al. Collaborative interplay between FGF-2 and VEGF-C promotes lymphangiogenesis and metastasis. Proc Natl Acad Sci U S A, 2012, 109(39): 15894-15899.
22.	Saito Y, Nakagami H, Morishita R, et al. Transfection of human hepatocyte growth factor gene ameliorates secondary lymphedema via promotion of lymphangiogenesis. Circulation, 2006, 114(11): 1177-1184.
23.	Dai T, Jiang Z, Cui C, et al. The roles of podoplanin-positive/podoplanin-negative cells from adipose-derived stem cells in lymphatic regeneration. Plast Reconstr Surg, 2020, 145(2): 420-431.
24.	Yoshida S, Hamuy R, Hamada Y, et al. Adipose-derived stem cell transplantation for therapeutic lymphangiogenesis in a mouse secondary lymphedema model. Regen Med, 2015, 10(5): 549-562.
25.	Shimizu Y, Shibata R, Shintani S, et al. Therapeutic lymphangiogenesis with implantation of adipose-derived regenerative cells. J Am Heart Assoc, 2012, 1(4): e000877.
26.	Will PA, Kilian K, Bieback K, et al. Lymphedema-associated fibroblasts are a TGF-β1 activated myofibroblast subpopulation related to fibrosis and stage progression in patients and a murine microsurgical model. Plast Reconstr Surg, 2023.
27.	Wang T, Sharma AK, Wolfrum C. Novel insights into adipose tissue heterogeneity. Rev Endocr Metab Disord, 2022, 23(1): 5-12.
28.	Bucan A, Dhumale P, Jørgensen MG, et al. Comparison between stromal vascular fraction and adipose derived stem cells in a mouse lymphedema model. J Plast Surg Hand Surg, 2020, 54(5): 302-311.
29.	Später T, Tobias AL, Menger MM, et al. Biological coating with platelet-rich plasma and adipose tissue-derived microvascular fragments improves the vascularization, biocompatibility and tissue incorporation of porous polyethylene. Acta Biomater, 2020, 108: 194-206.
30.	Frueh FS, Später T, Körbel C, et al. Prevascularization of dermal substitutes with adipose tissue-derived microvascular fragments enhances early skin grafting. Sci Rep, 2018, 8(1): 10977.
31.	Frueh FS, Später T, Lindenblatt N, et al. Adipose tissue-derived microvascular fragments improve vascularization, lymphangiogenesis, and integration of dermal skin substitutes. J Invest Dermatol, 2017, 137(1): 217-227.
32.	Frueh FS, Gassert L, Scheuer C, et al. Adipose tissue-derived microvascular fragments promote lymphangiogenesis in a murine lymphedema model. J Tissue Eng, 2022, 13: 20417314221109957.
33.	Li ZJ, Yang E, Li YZ, et al. Application and prospect of adipose stem cell transplantation in treating lymphedema. World J Stem Cells, 2020, 12(7): 676-687.
34.	Hwang JH, Kim IG, Lee JY, et al. Therapeutic lymphangiogenesis using stem cell and VEGF-C hydrogel. Biomaterials, 2011, 32(19): 4415-4423.
35.	He M, Chen T, Lv Y, et al. The role of allogeneic platelet-rich plasma in patients with diabetic foot ulcer: Current perspectives and future challenges. Front Bioeng Biotechnol, 2022, 10: 993436.
36.	Ackermann M, Wettstein R, Senaldi C, et al. Impact of platelet rich plasma and adipose stem cells on lymphangiogenesis in a murine tail lymphedema model. Microvasc Res, 2015, 102: 78-85.
37.	Bianchi LMG, Irmici G, Cè M, et al. Diagnosis and treatment of post-prostatectomy lymphedema: What’s new? Curr Oncol, 2023, 30(5): 4512-4526.
38.	Hayashida K, Yoshida S, Yoshimoto H, et al. Adipose-derived stem cells and vascularized lymph node transfers successfully treat mouse hindlimb secondary lymphedema by early reconnection of the lymphatic system and lymphangiogenesis. Plast Reconstr Surg, 2017, 139(3): 639-651.
39.	Jonas F, Kesa P, Paral P, et al. The effect of vascular endothelial growth factor C and adipose-derived stem cells on lymphatic regeneration in a rat vascularized lymph node transfer model. J Reconstr Microsurg, 2023, 39(4): 311-319.
40.	Conrad C, Niess H, Huss R, et al. Multipotent mesenchymal stem cells acquire a lymphendothelial phenotype and enhance lymphatic regeneration in vivo. Circulation, 2009, 119(2): 281-289.
41.	Beerens M, Aranguren XL, Hendrickx B, et al. Multipotent adult progenitor cells support lymphatic regeneration at multiple anatomical levels during wound healing and lymphedema. Sci Rep, 2018, 8(1): 3852.
42.	Asaad M, Hanson SE. Tissue engineering strategies for cancer-related lymphedema. Tissue Eng Part A, 2021, 27(7-8): 489-499.
43.	Zhou H, Wang M, Hou C, et al. Exogenous VEGF-C augments the efficacy of therapeutic lymphangiogenesis induced by allogenic bone marrow stromal cells in a rabbit model of limb secondary lymphedema. Jpn J Clin Oncol, 2011, 41(7): 841-846.
44.	Michalaki E, Rudd JM, Liebman L, et al. Lentiviral overexpression of VEGFC in transplanted MSCs leads to resolution of swelling in a mouse tail lymphedema model. Microcirculation, 2023, 30(2-3): e12792.
45.	Park HS, Jung IM, Choi GH, et al. Modification of a rodent hindlimb model of secondary lymphedema: surgical radicality versus radiotherapeutic ablation. Biomed Res Int, 2013, 2013: 208912.
46.	Jørgensen MG, Toyserkani NM, Hansen CR, et al. Quantification of chronic lymphedema in a revised mouse model. Ann Plast Surg, 2018, 81(5): 594-603.
47.	Peña Quián Y, Hernández Ramirez P, Batista Cuellar JF, et al. Lymphoscintigraphy for the assessment of autologous stem cell implantation in chronic lymphedema. Clin Nucl Med, 2015, 40(3): 217-219.
48.	Toyserkani NM, Jensen CH, Sheikh SP, et al. Cell-assisted lipotransfer using autologous adipose-derived stromal cells for alleviation of breast cancer-related lymphedema. Stem Cells Transl Med, 2016, 5(7): 857-859.
49.	Jørgensen MG, Toyserkani NM, Jensen CH, et al. Adipose-derived regenerative cells and lipotransfer in alleviating breast cancer-related lymphedema: An open-label phase Ⅰ trial with 4 years of follow-up. Stem Cells Transl Med, 2021, 10(6): 844-854.
50.	Toyserkani NM, Jensen CH, Tabatabaeifar S, et al. Adipose-derived regenerative cells and fat grafting for treating breast cancer-related lymphedema: Lymphoscintigraphic evaluation with 1 year of follow-up. J Plast Reconstr Aesthet Surg, 2019, 72(1): 71-77.
51.	Toyserkani NM, Jensen CH, Andersen DC, et al. Treatment of breast cancer-related lymphedema with adipose-derived regenerative cells and fat grafts: A feasibility and safety study. Stem Cells Transl Med, 2017, 6(8): 1666-1672.
52.	Hou C, Wu X, Jin X. Autologous bone marrow stromal cells transplantation for the treatment of secondary arm lymphedema: a prospective controlled study in patients with breast cancer related lymphedema. Jpn J Clin Oncol, 2008, 38(10): 670-674.
53.	Maldonado GE, Pérez CA, Covarrubias EE, et al. Autologous stem cells for the treatment of post-mastectomy lymphedema: a pilot study. Cytotherapy, 2011, 13(10): 1249-1255.
54.	Ismail AM, Abdou SM, Abdelnaby AY, et al. Stem cell therapy using bone marrow-derived mononuclear cells in treatment of lower limb lymphedema: A randomized controlled clinical trial. Lymphat Res Biol, 2018, 16(3): 270-277.
55.	Ehyaeeghodraty V, Molavi B, Nikbakht M, et al. Effects of mobilized peripheral blood stem cells on treatment of primary lower extremity lymphedema. J Vasc Surg Venous Lymphat Disord, 2020, 8(3): 445-451.
56.	Rochlin DH, Inchauste S, Zelones J, et al. The role of adjunct nanofibrillar collagen scaffold implantation in the surgical management of secondary lymphedema: Review of the literature and summary of initial pilot studies. J Surg Oncol, 2020, 121(1): 121-128.
57.	Hadamitzky C, Zaitseva TS, Bazalova-Carter M, et al. Aligned nanofibrillar collagen scaffolds-guiding lymphangiogenesis for treatment of acquired lymphedema. Biomaterials, 2016, 102: 259-267.
58.	Nguyen D, Zaitseva TS, Zhou A, et al. Lymphatic regeneration after implantation of aligned nanofibrillar collagen scaffolds: Preliminary preclinical and clinical results. J Surg Oncol, 2022, 125(2): 113-122.
59.	Jia W, He W, Wang G, et al. Enhancement of lymphangiogenesis by human mesenchymal stem cell sheet. Adv Healthc Mater, 2022, 11(16): e2200464.
60.	Kang HJ, Moon SY, Kim BK, et al. Recellularized lymph node scaffolds with human adipose-derived stem cells enhance lymph node regeneration to improve lymphedema. Sci Rep, 2023, 13(1): 5397.
61.	Lu JH, Hsia K, Su CK, et al. A novel dressing composed of adipose stem cells and decellularized Wharton’s jelly facilitated wound healing and relieved lymphedema by enhancing angiogenesis and lymphangiogenesis in a rat model. J Funct Biomater, 2023, 14(2): 104.

1. Brown S, Dayan JH, Kataru RP, et al. The vicious circle of stasis, inflammation, and fibrosis in lymphedema. Plast Reconstr Surg, 2023, 151(2): 330e-341e.
2. Schulze H, Nacke M, Gutenbrunner C, et al. Worldwide assessment of healthcare personnel dealing with lymphoedema. Health Econ Rev, 2018, 8(1): 10.
3. McLaughlin SA, Brunelle CL, Taghian A. Breast cancer-related lymphedema: Risk factors, screening, management, and the impact of locoregional treatment. J Clin Oncol, 2020, 38(20): 2341-2350.
4. Ogino R, Yokooji T, Hayashida M, et al. Emerging anti-inflammatory pharmacotherapy and cell-based therapy for lymphedema. Int J Mol Sci, 2022, 23(14): 7614.
5. Barufi S, Pereira de Godoy HJ, Pereira de Godoy JM, et al. Exercising and compression mechanism in the treatment of lymphedema. Cureus, 2021, 13(7): e16121.
6. Donahue PMC, MacKenzie A, Filipovic A, et al. Advances in the prevention and treatment of breast cancer-related lymphedema. Breast Cancer Res Treat, 2023, 200(1): 1-14.
7. Nicenboim J, Malkinson G, Lupo T, et al. Lymphatic vessels arise from specialized angioblasts within a venous niche. Nature, 2015, 522(7554): 56-61.
8. Oliver G, Kipnis J, Randolph GJ, et al. The lymphatic vasculature in the 21^st century: Novel functional roles in homeostasis and disease. Cell, 2020, 182(2): 270-296.
9. Baluk P, Fuxe J, Hashizume H, et al. Functionally specialized junctions between endothelial cells of lymphatic vessels. J Exp Med, 2007, 204(10): 2349-2362.
10. Tammela T, Alitalo K. Lymphangiogenesis: Molecular mechanisms and future promise. Cell, 2010, 140(4): 460-476.
11. Rockson SG. Advances in lymphedema. Circ Res, 2021, 128(12): 2003-2016.
12. Ly CL, Nores GDG, Kataru RP, et al. T helper 2 differentiation is necessary for development of lymphedema. Transl Res, 2019, 206: 57-70.
13. Henderson NC, Rieder F, Wynn TA. Fibrosis: from mechanisms to medicines. Nature, 2020, 587(7835): 555-566.
14. Zhao W, Zhang H, Liu R, et al. Advances in immunomodulatory mechanisms of mesenchymal stem cells-derived exosome on immune cells in scar formation. Int J Nanomedicine, 2023, 18: 3643-3662.
15. Ogino R, Hayashida K, Yamakawa S, et al. Adipose-derived stem cells promote intussusceptive lymphangiogenesis by restricting dermal fibrosis in irradiated tissue of mice. Int J Mol Sci, 2020, 21(11): 3885.
16. Baik JE, Park HJ, Kataru RP, et al. TGF-β₁ mediates pathologic changes of secondary lymphedema by promoting fibrosis and inflammation. Clin Transl Med, 2022, 12(6): e758.
17. Yoon SH, Kim KY, Wang Z, et al. EW-7197, a transforming growth factor-beta type Ⅰ receptor kinase inhibitor, ameliorates acquired lymphedema in a mouse tail model. Lymphat Res Biol, 2020, 18(5): 433-438.
18. Levy D, Abadchi SN, Shababi N, et al. Induced pluripotent stem cell-derived extracellular vesicles promote wound repair in a diabetic mouse model via an anti-inflammatory immunomodulatory mechanism. Adv Healthc Mater, 2023, 12(26): e2300879.
19. Huethorst E, Krebber MM, Fledderus JO, et al. Lymphatic vascular regeneration: The next step in tissue engineering. Tissue Eng Part B Rev, 2016, 22(1): 1-14.
20. Saijo H, Suzuki K, Yoshimoto H, et al. Paracrine effects of adipose-derived stem cells promote lymphangiogenesis in irradiated lymphatic endothelial cells. Plast Reconstr Surg, 2019, 143(6): 1189e-1200e.
21. Cao R, Ji H, Feng N, et al. Collaborative interplay between FGF-2 and VEGF-C promotes lymphangiogenesis and metastasis. Proc Natl Acad Sci U S A, 2012, 109(39): 15894-15899.
22. Saito Y, Nakagami H, Morishita R, et al. Transfection of human hepatocyte growth factor gene ameliorates secondary lymphedema via promotion of lymphangiogenesis. Circulation, 2006, 114(11): 1177-1184.
23. Dai T, Jiang Z, Cui C, et al. The roles of podoplanin-positive/podoplanin-negative cells from adipose-derived stem cells in lymphatic regeneration. Plast Reconstr Surg, 2020, 145(2): 420-431.
24. Yoshida S, Hamuy R, Hamada Y, et al. Adipose-derived stem cell transplantation for therapeutic lymphangiogenesis in a mouse secondary lymphedema model. Regen Med, 2015, 10(5): 549-562.
25. Shimizu Y, Shibata R, Shintani S, et al. Therapeutic lymphangiogenesis with implantation of adipose-derived regenerative cells. J Am Heart Assoc, 2012, 1(4): e000877.
26. Will PA, Kilian K, Bieback K, et al. Lymphedema-associated fibroblasts are a TGF-β1 activated myofibroblast subpopulation related to fibrosis and stage progression in patients and a murine microsurgical model. Plast Reconstr Surg, 2023.
27. Wang T, Sharma AK, Wolfrum C. Novel insights into adipose tissue heterogeneity. Rev Endocr Metab Disord, 2022, 23(1): 5-12.
28. Bucan A, Dhumale P, Jørgensen MG, et al. Comparison between stromal vascular fraction and adipose derived stem cells in a mouse lymphedema model. J Plast Surg Hand Surg, 2020, 54(5): 302-311.
29. Später T, Tobias AL, Menger MM, et al. Biological coating with platelet-rich plasma and adipose tissue-derived microvascular fragments improves the vascularization, biocompatibility and tissue incorporation of porous polyethylene. Acta Biomater, 2020, 108: 194-206.
30. Frueh FS, Später T, Körbel C, et al. Prevascularization of dermal substitutes with adipose tissue-derived microvascular fragments enhances early skin grafting. Sci Rep, 2018, 8(1): 10977.
31. Frueh FS, Später T, Lindenblatt N, et al. Adipose tissue-derived microvascular fragments improve vascularization, lymphangiogenesis, and integration of dermal skin substitutes. J Invest Dermatol, 2017, 137(1): 217-227.
32. Frueh FS, Gassert L, Scheuer C, et al. Adipose tissue-derived microvascular fragments promote lymphangiogenesis in a murine lymphedema model. J Tissue Eng, 2022, 13: 20417314221109957.
33. Li ZJ, Yang E, Li YZ, et al. Application and prospect of adipose stem cell transplantation in treating lymphedema. World J Stem Cells, 2020, 12(7): 676-687.
34. Hwang JH, Kim IG, Lee JY, et al. Therapeutic lymphangiogenesis using stem cell and VEGF-C hydrogel. Biomaterials, 2011, 32(19): 4415-4423.
35. He M, Chen T, Lv Y, et al. The role of allogeneic platelet-rich plasma in patients with diabetic foot ulcer: Current perspectives and future challenges. Front Bioeng Biotechnol, 2022, 10: 993436.
36. Ackermann M, Wettstein R, Senaldi C, et al. Impact of platelet rich plasma and adipose stem cells on lymphangiogenesis in a murine tail lymphedema model. Microvasc Res, 2015, 102: 78-85.
37. Bianchi LMG, Irmici G, Cè M, et al. Diagnosis and treatment of post-prostatectomy lymphedema: What’s new? Curr Oncol, 2023, 30(5): 4512-4526.
38. Hayashida K, Yoshida S, Yoshimoto H, et al. Adipose-derived stem cells and vascularized lymph node transfers successfully treat mouse hindlimb secondary lymphedema by early reconnection of the lymphatic system and lymphangiogenesis. Plast Reconstr Surg, 2017, 139(3): 639-651.
39. Jonas F, Kesa P, Paral P, et al. The effect of vascular endothelial growth factor C and adipose-derived stem cells on lymphatic regeneration in a rat vascularized lymph node transfer model. J Reconstr Microsurg, 2023, 39(4): 311-319.
40. Conrad C, Niess H, Huss R, et al. Multipotent mesenchymal stem cells acquire a lymphendothelial phenotype and enhance lymphatic regeneration in vivo. Circulation, 2009, 119(2): 281-289.
41. Beerens M, Aranguren XL, Hendrickx B, et al. Multipotent adult progenitor cells support lymphatic regeneration at multiple anatomical levels during wound healing and lymphedema. Sci Rep, 2018, 8(1): 3852.
42. Asaad M, Hanson SE. Tissue engineering strategies for cancer-related lymphedema. Tissue Eng Part A, 2021, 27(7-8): 489-499.
43. Zhou H, Wang M, Hou C, et al. Exogenous VEGF-C augments the efficacy of therapeutic lymphangiogenesis induced by allogenic bone marrow stromal cells in a rabbit model of limb secondary lymphedema. Jpn J Clin Oncol, 2011, 41(7): 841-846.
44. Michalaki E, Rudd JM, Liebman L, et al. Lentiviral overexpression of VEGFC in transplanted MSCs leads to resolution of swelling in a mouse tail lymphedema model. Microcirculation, 2023, 30(2-3): e12792.
45. Park HS, Jung IM, Choi GH, et al. Modification of a rodent hindlimb model of secondary lymphedema: surgical radicality versus radiotherapeutic ablation. Biomed Res Int, 2013, 2013: 208912.
46. Jørgensen MG, Toyserkani NM, Hansen CR, et al. Quantification of chronic lymphedema in a revised mouse model. Ann Plast Surg, 2018, 81(5): 594-603.
47. Peña Quián Y, Hernández Ramirez P, Batista Cuellar JF, et al. Lymphoscintigraphy for the assessment of autologous stem cell implantation in chronic lymphedema. Clin Nucl Med, 2015, 40(3): 217-219.
48. Toyserkani NM, Jensen CH, Sheikh SP, et al. Cell-assisted lipotransfer using autologous adipose-derived stromal cells for alleviation of breast cancer-related lymphedema. Stem Cells Transl Med, 2016, 5(7): 857-859.
49. Jørgensen MG, Toyserkani NM, Jensen CH, et al. Adipose-derived regenerative cells and lipotransfer in alleviating breast cancer-related lymphedema: An open-label phase Ⅰ trial with 4 years of follow-up. Stem Cells Transl Med, 2021, 10(6): 844-854.
50. Toyserkani NM, Jensen CH, Tabatabaeifar S, et al. Adipose-derived regenerative cells and fat grafting for treating breast cancer-related lymphedema: Lymphoscintigraphic evaluation with 1 year of follow-up. J Plast Reconstr Aesthet Surg, 2019, 72(1): 71-77.
51. Toyserkani NM, Jensen CH, Andersen DC, et al. Treatment of breast cancer-related lymphedema with adipose-derived regenerative cells and fat grafts: A feasibility and safety study. Stem Cells Transl Med, 2017, 6(8): 1666-1672.
52. Hou C, Wu X, Jin X. Autologous bone marrow stromal cells transplantation for the treatment of secondary arm lymphedema: a prospective controlled study in patients with breast cancer related lymphedema. Jpn J Clin Oncol, 2008, 38(10): 670-674.
53. Maldonado GE, Pérez CA, Covarrubias EE, et al. Autologous stem cells for the treatment of post-mastectomy lymphedema: a pilot study. Cytotherapy, 2011, 13(10): 1249-1255.
54. Ismail AM, Abdou SM, Abdelnaby AY, et al. Stem cell therapy using bone marrow-derived mononuclear cells in treatment of lower limb lymphedema: A randomized controlled clinical trial. Lymphat Res Biol, 2018, 16(3): 270-277.
55. Ehyaeeghodraty V, Molavi B, Nikbakht M, et al. Effects of mobilized peripheral blood stem cells on treatment of primary lower extremity lymphedema. J Vasc Surg Venous Lymphat Disord, 2020, 8(3): 445-451.
56. Rochlin DH, Inchauste S, Zelones J, et al. The role of adjunct nanofibrillar collagen scaffold implantation in the surgical management of secondary lymphedema: Review of the literature and summary of initial pilot studies. J Surg Oncol, 2020, 121(1): 121-128.
57. Hadamitzky C, Zaitseva TS, Bazalova-Carter M, et al. Aligned nanofibrillar collagen scaffolds-guiding lymphangiogenesis for treatment of acquired lymphedema. Biomaterials, 2016, 102: 259-267.
58. Nguyen D, Zaitseva TS, Zhou A, et al. Lymphatic regeneration after implantation of aligned nanofibrillar collagen scaffolds: Preliminary preclinical and clinical results. J Surg Oncol, 2022, 125(2): 113-122.
59. Jia W, He W, Wang G, et al. Enhancement of lymphangiogenesis by human mesenchymal stem cell sheet. Adv Healthc Mater, 2022, 11(16): e2200464.
60. Kang HJ, Moon SY, Kim BK, et al. Recellularized lymph node scaffolds with human adipose-derived stem cells enhance lymph node regeneration to improve lymphedema. Sci Rep, 2023, 13(1): 5397.
61. Lu JH, Hsia K, Su CK, et al. A novel dressing composed of adipose stem cells and decellularized Wharton’s jelly facilitated wound healing and relieved lymphedema by enhancing angiogenesis and lymphangiogenesis in a rat model. J Funct Biomater, 2023, 14(2): 104.

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Research advances on stem cell-based treatments in animal studies and clinical trials of lymphedema

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