ObjectiveTo 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. MethodsThe 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.ResultsVarious 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. ConclusionStem 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.
ObjectiveTo compare the effectiveness of single-stage vascularized lymph node transfer (VLNT) combined with lymphaticovenular anastomosis (LVA) and liposuction (LS) (3L) versus LVA combined with LS (2L) for the treatment of moderate-to-late stage upper limb lymphedema following breast cancer surgery. Methods A retrospective analysis was conducted on the clinical data of 16 patients with moderate-to-late stage upper limb lymphedema after breast cancer surgery, treated between June 2022 and June 2024, who met the selection criteria. Patients were divided into 3L group (n=7) and 2L group (n=9) based on the surgical approach. There was no significant difference (P>0.05) in baseline data between the groups, including age, body mass index, duration of edema, volume of liposuction, International Society of Lymphology (ISL) stage, preoperative affected limb volume, preoperative circumferences of the affected limb at 12 levels (from 4 cm distal to the wrist to 42 cm proximal to the wrist), preoperative Lymphoedema Quality of Life (LYMQoL) score, and frequency of cellulitis episodes. The 2L group underwent LS on the upper arm and proximal forearm and LVA on the middle and distal forearm. The 3L group received additional VLNT in the axilla, with the groin serving as the donor site. Outcomes were assessed included the change in affected limb volume at 12 months postoperatively, and comparisons of limb circumferences, LYMQoL score, and frequency of cellulitis episodes between preoperative and 12-month postoperative. Ultrasound evaluation was performed at 12 months in the 3L group to assess lymph node viability. Results Both groups were followed up 12-20 months, with an average of 15.13 months. There was no significant difference in the follow-up time between the groups (t=–1.115, P=0.284). All surgical incisions healed by first intention. No adverse events, such as flap infection or necrosis, occurred in the 3L group. At 12 months after operation, ultrasound confirmed good viability of the transferred lymph nodes in the 3L group. Palpation revealed significant improvement in skin fibrosis and improved skin softness in both groups. Affected limb volume significantly decreased in both groups postoperatively (P<0.05). The reduction in limb volume significantly greater in the 3L group compared to the 2L group (P<0.05). Circumferences at all 12 measured levels significantly decreased in both groups compared to preoperative values (P<0.05). The reduction in circumference at all 12 levels was better in the 3L group than in the 2L group, with significant differences observed at 7 levels (8, 12, 16, 30, 34, 38, and 42 cm) proximal to the wrist (P<0.05). Both groups showed significant improvement in the frequency of cellulitis episodes and LYMQoL scores postoperatively (P<0.05). While the improvement in LYMQoL scores at 12 months did not differ significantly between groups (P>0.05), the reduction in cellulitis episodes was significantly greater in the 3L group compared to the 2L group (P<0.05). Conclusion The combination of VLNT+LVA+LS provides more durable and comprehensive outcomes for moderate-to-late stage upper limb lymphedema after breast cancer surgery compared to LVA+LS, offering an improved therapeutic solution for patients.
Objective To isolate extracellular vesicles (EVs) from the wound-edge skin tissue of type 2 diabetic foot ulcers and to investigate their effect on wound healing in mice. Methods Twenty 8-week-old male db/db mice were used to establish a full-thickness skin defect wound with a diameter of 1.0 cm on the back, and divided into GW4869 (hydrochloride hydrate) group and DMSO group (control group), with 10 mice in each group. The wound healing rate was calculated on days 3, 6, 9, and 12 after injection. HE staining was used to observe epithelialization and inflammatory cell infiltration on days 7 and 12 after injection. Masson staining was used to observe collagen fiber formation. Immunofluorescence staining was used to detect CD206 and interleukin 1β (IL-1β) expressions in wound tissues. Skin tissues from the wound edge of 30 patients with type 2 diabetic foot ulcer were collected for tissue cutting, enzyme dissociation, gradient size exclusion, differential centrifugation combined with ultra-high speed centrifugation to extract tissue EVs (Dia-EVs), which were identified by transmission electron microscopy and particle size analysis. Twenty 8-week-old male C57BL/6 mice were used to establish a full-thickness skin defect wound with a diameter of 1.0 cm on the back, and divided into Dia-EVs group and PBS group, with 10 mice in each group. The wound healing rate was calculated on days 3, 5, 7, 9, and 12 after injection. HE staining was used to observe epithelialization and inflammatory cell infiltration on days 7 and 12 after injection. Masson staining was used to observe collagen fiber formation. Immunofluorescence staining was used to detect CD206 and IL-1β expressions in wound tissues. In vitro experiments were conducted using RAW264.7 cells, which were divided into three groups: the control group [cultured in PRMI 1640 medium containing 10% fetal bovine serum (FBS)], the M1 group [induced with PRMI 1640 medium containing 10%FBS, 200 ng/mL lipopolysaccharide, and 20 ng/mL interferon γ (IFN-γ) for 48 hours], and the Dia-EVs group (treated with PRMI 1640 medium containing 10%FBS and 40 μg/mL Dia-EVs for 48 hours). The expression levels of CD206 and IL-1β in each group of cells were observed. Results In db/db mice experiment, on days 3, 6, 9, and 12 after injection, the wound healing rate of the GW4869 group was significantly faster than that of the DMSO group (P<0.05). On day 7 after injection, inflammatory cell infiltration in the DMSO group was obvious, and the number of inflammatory cells was significantly higher than that in the GW4869 group (P<0.05). Masson staining showed no obvious new collagen formation in either group. On day 12 after injection, HE staining showed that the GW4869 injection group had completed epithelialization without obvious inflammatory cell infiltration, while the DMSO injection group still had a large number of inflammatory cells infiltrating (P<0.05). Moreover, a large amount of new collagen was formed in the GW4869 group, and the collagen volume ratio was significantly greater than that of the DMSO group (P<0.05). On 7 days after injection, no significant CD206 positive expression was observed in either group, but a large amount of IL-1β positive expression was seen. Moreover, the IL-1β relative expression in the DMSO group was significantly more than that in the GW4869 group (P<0.05). On 12 days after injection, CD206 positive expression was observed in the GW4869 group, while no significant expression was seen in the DMSO group (P<0.05); no obvious IL-1β positive expression was found in the GW4869 group, while the DMSO group still had a large amount of IL-1β positive expression (P<0.05). In C57BL/6 mice experiment, on days 3, 5, 7, 9, and 12 after injection, the wound healing rate of the Dia-EVs group was significantly slower than that of the PBS group (P<0.05). On day 7 after injection, inflammatory cell infiltration in the Dia-EVs group was obvious, and the number of inflammatory cells was significantly higher than that in the PBS group (P<0.05). Masson staining showed no obvious new collagen formation in either group. On day 12 after injection, wound defects still existed in both the Dia-EVs group and the PBS group, but the wound area in the PBS group was narrower. The number of inflammatory cells showed no significant difference (P>0.05), while a large amount of new collagen formation was observed in the PBS group, significantly more than that in the Dia-EVs group (P<0.05). Immunofluorescence results showed that on days 7 and 12 after injection, the number of IL-1β-positive cells in the Dia-EVs group was significantly higher than that in the PBS group (P<0.05), while no significant CD206 positive expression was observed in either group (P>0.05). In vitro experimental results showed that there was no significant difference in the relative expression of CD206 among the three groups (P>0.05). The relative expressions of IL-1β in M1 group and Dia-EVs group were significantly higher than that in the control group (P<0.05), but there was no significant difference between the two groups (P>0.05).Conclusion Dia-EVs delay wound healing in mice by inducing M1 polarization of macrophages, inhibiting M2 transformation, and reducing collagen deposition.