Adipose-Derived Stem Cells and Vascularized Lymph Node Transfers Successfully Treat Mouse Hindlimb Secondary Lymphedema by Early Reconnection of the Lymphatic System and Lymphangiogenesis

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We read with respect the recent article entitled “Adipose-Derived Stem Cells and Vascularized Lymph Node Transfers Successfully Treat Mouse Hindlimb Secondary Lymphedema by Early Reconnection of the Lymphatic System and Lymphangiogenesis” by Kenji Hayashida et al.1 in Plastic and Reconstructive Surgery. In this article, the authors did a good job of finding that combined adipose-derived stem cell and vascularized lymph node transfer may effectively decrease edema volume and restore lymphatic function in a mouse hindlimb secondary lymphedema model. In this communication, we would like to propose some protocols that we hope are conducive in the authors’ future studies.
First, in this article, the authors transferred the abdominal cutaneous flap or injected the adipose-derived stem cells after simultaneously establishing a lymphedema mouse model. In other words, no observable swelling occurred when the authors gave the interventional therapy. Thus, if the word “treat” in the title can be modified as “prevent,” from our perspective, that would be more suitable.
Second, as to the secondary lymphedema mouse model in this article, a 5-mm-wide skin gap was left open, which differs from the development of human lymphedema, because the skin is intact in humans regardless of the cause of secondary lymphedema. In addition, the skin structure of mice is different from that of humans. The subcutaneous tissue of mice lacks adipose tissue, which contains the majority of the superficial lymphatic collectors in humans.2 Thus, if the experiment can be conducted using an animal model that can simulate clinical lymphedema to the greatest extent, the outcome would be more reliable.
Third, the authors stated that the degree of edema peaks at day 2 and the degree decreases gradually by day 14, where the edema reaches a plateau. However, as we know, the site of lymphatic obstruction has a remarkable regenerative capacity of the lymphatics and the formation of collateral pathways.3 Thus, the possibility may exist that the left hindlimb volume in all the four groups returns to the presurgery state after a long period. Based on the above possibility, the vascularized lymph node transfer combined with adipose-derived stem cells may play just an auxiliary rather than a therapeutic role in the treatment of lymphedema.
Moreover, in this article, the result of lymphatic transport capacity and function revealed that mice in the vascularized lymph node transfer–positive/adipose-derived stem cell–positive group developed lymph node metastases more quickly than those in the vascularized lymph node transfer–positive/adipose-derived stem cell–negative group. That may be explained by the effect of adipose-derived stem cells on lymphangiogenesis. However, recent studies have shown that mesenchymal stem cells derived from adipose tissue can promote tumor progression.4,5 Thus, the lymphangiogenetic role of adipose-derived stem cells may be mixed through transplanting melanoma cells.

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