Table 2 Cell therapy for secondary lymphedema: non-clinical studies
From: Cell therapy as a treatment of secondary lymphedema: a systematic review and meta-analysis
Year | References | Animal model | Groups | Cell type/number | Implantation methods | Follow-up/Assessment | Results | Conclusions |
|---|---|---|---|---|---|---|---|---|
2009 | Conrad et al. [35] | Mouse tail | 2 groups (n = N/A for each group): Control, MSC | Allogeneic up to 3 passages BM-MSC (p53 −/−)/1 × 107 | Subcutaneous | 56 days/Circumference measurements, lymphatic drainage, neolymphangiogenesis (immunohistochemical staining) | (1) In stem cell-treated animals, a marked reduction in the edema was observed (2) Restoration of lymphatic drainage | The administration of BM-MSCs in vivo may contribute to the reduction in lymphatic edema |
2011 | Hwang et al. [36] | Mouse hindlimb | 5 groups (n = 5): Sham, control, hydrogel alone, hADSC, hADSC + hydrogel | PKH-26-labeled hADSC/VEGF-C hydrogel/N/A | Subcutaneous | 28 days/Circumference mesurements, lymphatic vessels (immunohistochemical staining) | (1) Significantly decreased dermal edema depth (2) Significantly greater lymphatic vessel regeneration | Co-administration of hADSCs and VEGF-C hydrogel has a substantial positive effect on lymphangiogenesis |
2011 | Zhou et al. [37] | Rabbit Hindlimb + IR | 4 groups (n = N/A): Control, VEGF-C, BM-MSC, BM-MSC + VEGF-C | Allogeneic 3 passages BM-MSC + VEGF-C/1 × 107 | Intramuscular | 6 months/Limb volume changes, Immunohistochemical staining of lymphatic vessels, western blot analysis for VEGF-C | (1) Reduce limb volume at 6 months (2) Significant greater lymphatic vessel at 28 days | BM-MSC transplantation and VEGF-C administration could enhance the therapeutic effect of each other |
2012 | Shimuzu et al. [38] | Mouse tail | 5 groups (n = 12): Sham, PBS, VEGF-C, BM-MNC, ADSC | Freshly isolated ADSCs/2 × 106 | Subcutaneous | 28 days/Tail diameter, lymphatic vessels diameter (H-E), lymphatic vessels (immunohistochemical staining), bone marrow-derived CD11b + macrophage kinetics assay | (1) Lymphedema was improved significantly by local injection of ADSCs (2) High lymphatic capillary density (3) Enhance recruitment of bone marrow-derived M2 macrophages, which serve as lymphatic endothelial progenitor cells | Implantation of autologous ADSCs could be a useful treatment option for patients with severe lymphedema via enhanced lymphangiogenesis |
2013 | Park et al. [39] | Mouse Hindlimb + IR | 4 groups (n = 8): Control, Surgery, Surgery + IR, Cell therapy | Allogeneic muscle-derived stem cell + hLEC /1 × 107 | N/A | 56 days/Water displacement volumetric analysis, lymphoscintigraphy, lymphatic vessels (immunohistochemical staining), | (1) Attenuation of hindlimb volume (2) High lymphatic vessel density (3) Restore of the lymphatic flow | Stem cell lymphangiogenesis seems to be a promising approach |
2014 | Kawai et al. [40] | Nude rat tail | 4 groups: hLEC (n = 18), hDMEC (n = 8), Control (n = 19), sham (n = 5) | Human dermal microvascular endothelial cells (hDMEC) and human lymphatic endothelial cells (hLEC)/5 × 106 | Wound/on postoperative days 1, 4, 7, 11 and 14 | 36 days/Circumference mesurements, indocyanine green fluorescence lymphography, thickness of epidermis (H-E), lymphatic vessels (immunohistochemical staining) | (1) In hLEC-treated animals, the circumference, lymphatic flow, and thickness of the skin became thinner (2) High lymphatic vessel density (3) hLECs are incorporated into the new vessels | Cell transplantation therapy using human LECs improved secondary lymphedema |
2015 | Ackermann et al. [41] | Mouse tail | 3 groups (n = 10): Control, PRP, ADSC | Allogeneic 3 passages ADSC vs platelet-rich plasma (PRP)/N/A | N/A | 14 days/Wound healing analysis, tail diameter, real-time laser Doppler imaging for perfusion, lymphatic vessels (immunohistochemical staining) | (1) PRP and ADSC show a significantly increased epithelialization (2) High lymphatic vessel density in PRP group (3) Significant enhance perfusion of wounds treated by PRP and ADSC | PRP induces higher lymphangiogenesis than ADSCs |
2015 | Yoshida et al. [42] | Mouse Hindlimb + IR | 5 groups (n = 20): Sham, control, ADSC 104, ADSC 105, ADSC 106 | Allogeneic up to 5 passages ADSC/1 × 104, 1 × 105, 1 × 106 | N/A | 16 days/Circumferential measurement, lymphatic flow assessment, quantification of lymphatic vessels (immunohistochemical staining and EGFP) | (1) The numbers of lymphatic vessels were significantly increased (2) ADSCs are not detected in lymphangiogenesis | ADSCs can restore the lymphatic vascular network in secondary lymphedema with increased collecting vessels |
2016 | Gousopoulos et al. [43] | Transgenic mice tail | 2 groups (n = 5) Control, Treg | Regulatory T Cells (Treg)/0.8–0.9 × 106 | Intravenous | 14 or 42 days/Tail volume, lymphatic vessels (immunohistochemical staining), RT-PCR, flow cytometry | (1) Reverse all of the major hallmarks of lymphedema, including edema, inflammation, and fibrosis (2) Promote lymphatic drainage function | Treg application constitutes a potential new curative treatment modality for lymphedema |
2017 | Hayasida et al. [44] | Mouse Hindlimb + IR | 4 groups (n = 5): Control, VLNT, ADSC, ADSC + VLNT | Allogeneic 1–3 passages ADSC and vascularized lymph node transfers/1 × 104 | Subcutaneous | 14 days/Volumetric analysis of edema, near-infrared video camera system for lymphatic flow assessment, B16 mouse melanoma cells for lymphatic vessel and lymph node function, lymphatic vessels (immunohistochemical staining) | (1) ADSC + VLNT reduce the edema at 14 days (2) Increase the number of lymphatic vessels (3) Accelerate the lymphatic drainage to the venous systems | Combined ADSC and vascularized lymph node transfer treatment in secondary lymphedema may effectively decrease edema volume and restore lymphatic function |
2018 | Beerens et al. [45] | Nude mouse Skin flap model/Nude mouse Lymph node transplantation model | (1) Skin flaps groups (PBS n = 10/mMAPCs n = 6/hMAPCs n = 6) (2) Lymph node transplantation groups (PBS n = 10/hMAPCs 1n = 10/hMAPCs2 n = 6) | Allogeneic MAPCs/0.5 × 106 in lymph node transplantation model; 1 × 106 in skin flap model | Subcutaneous | 16 weeks/lymphography, lymphatic vessels (immunohistochemical staining) | (1) Restored lymph drainage across skin flaps (2) Reconnected transplanted lymph nodes to the host lymphatic vessel | MAPC transplantation represents a promising remedy for lymphatic system restoration at different anatomical levels and hence an appealing treatment for lymphedema |
2020 | Bucan et al. [46] | Mouse Hindlimb + IR | 3 groups (n = 15): Control, SVF, ADSC | Freshly isolated ADSCs vs stromal vascular fraction/1 × 106 | Subcutaneous | 8 weeks/CT and SPECT lymphoscintigraphy for volumetric measures, lymph vessel morphometry | (1) Treatment with ADSC did not reduce the edema at 8 weeks (2) lymph vessel lumen decreased when treated with ADSC | ADSC did not improve secondary lymphedema in this animal model |
2020 | Dai et al. [47] | Mouse Hindlimb | 4 groups (n = 5): Control, ADSC unsorted, ADSC Pod+, ADSC Pod− | Freshly isolated ADSCs (Pod+, Pod−) / 2 × 106 | Subcutaneous | 10 weeks/Limb volume change, lymphatic vessels (immunohistochemical staining) | (1) More attenuation of hindlimb volume in Pod + cells (2) High lymphatic vessel density | The podoplanin-positive cells possessed lymphatic paracrine and differentiation abilities and may represent LEPCs |
2020 | Ogino et al. [48] | Mouse Hindlimb + IR | 3 groups (n = 6): Control without IR, Control with IR, ADSC | Allogeneic 2–4 passages ADSCs/7.5 × 105 | Subcutaneous | 14 days/lymphatic vessels (immunohistochemical staining), picrosirius red staining for fibrosis | (1) ADSC transplantation accelerated LEC proliferation and increased lymphatic vessel numbers (2) ADSC mitigated fibrosis | ADSC transplantation contributes to lymphedema reduction by promoting LEC proliferation, improving fibrosis and increasing the number of lymphatic vessels |