Exosomes derived from human umbilical cord Wharton's jelly mesenchymal stem cells ameliorate experimental lymphedema

Abstract

Dear Editor, Acquired lymphedema is a complex disease caused by cancer treatment or parasitic infection and few effective treatments are available for lymphedema. [1][2][3] It is urgently needed to develop new experimental approaches and therapeutic strategies. 3 In this study, we address a new role and mechanism of MSC-ex (human umbilical cord Wharton's jelly mesenchymal stem cells derived exosome) in lymphedema treatment. We found that MSC-ex delivered Ang-2 (angiopoietin-2) promoted lymphangiogenesis by upregulating Prox1 (Prospero Homeobox 1) mediated Akt signaling. MSC-ex can improve lymphatic function and ameliorate edema in a mouse model of acquired lymphedema.MSC-ex were isolated from the conditional medium of WJ-MSC, which were negative for CD206 and positive for CD29, CD44 (Figure 1A,D). Exosomal markers CD9, CD63, CD81, and TSG101 were expressed in MSC-ex, whereas Calnexin was not detected (Figure 1B,C). MSC-ex showed a spheroid shape, and the size was about 130 nm (Figure 1E-G). To investigate the effect of MSC-ex on edema, we developed an acquired lymphedema model via surgical dissection of lymphatic vessels in the mouse tail (Figure 1H). As shown in Figure 1I, subcutaneously administered Dir labeled MSC-ex localized in the injured tail at 24 h after treatment. MSC-ex treatment promoted lymphatic drainage in lymphedema mice as injected methylene blue across the site of incision at week 6, which was not found in PBS treated mice (Figure 1J). The edema determined by tail diameter was persisted in mice treated by PBS. However, the edema was markedly reduced at week 2 in mice treated by MSC-ex (Figure 1K). As lymphangiogenesis is crucial in lymphedema development after lymphatic ablation, 4,5 we analyzed the lymphatic anatomy and lymphangiogenesis in MSC-ex treated animals. Relative to PBS-treated animals, a relatively thinner dermis and epidermis was found in MSC-ex treated mice (Figure 1L). Number of LYVE-1 + (lymphatic endothelial hyluronan receptor-1) lymphaticsThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Wharton’s jelly mesenchymal stem cells: a concise review of their secretome and prospective clinical applications

“…Moreover, WJ-MSCs can modify T cell receptor-mediated T cell activation via EVs enriched with programmed death-ligand 1 (PD-L1) which reduces T cell activation in acute graft versus host disease ( Li et al, 2021 ). WJ-MSCs’ exosomes also proved to be beneficial for treating lymphedema by increasing the expression of lymphangiogenic factors including angiopoietin-2 (Ang2), prospero-homeobox protein 1 (Prox1), and phospho-Akt ( Ting et al, 2021 ). Moreover, based on their immunomodulatory effects, whether through cell-to-cell contact or soluble factors, WJ-MSCs and their secretome have been used to successfully treat morbid conditions, such as graft versus host disease ( Newell et al, 2014 ; Soder et al, 2020 ; Pochon et al, 2022 ), diabetes ( Katuchova et al, 2015 ; Moreira et al, 2017 ; Gao et al, 2018 ; Qi et al, 2019 ), and cancer ( Hendijani et al, 2015 ).…”

Therapeutic Lymphangiogenesis Is a Promising Strategy for Secondary Lymphedema

“…Energetic studies for exploring therapeutic lymphangiogenesis for lymphedema by the administration of proteins or other therapeutic applications targeting specific molecules are also under investigation [129]. Adiponectin, one of the cytoprotective adipokines [76], hydrogen sulfide (H 2 S), which is emerging as one of the gas transmitters [77], and exosomes [130] have been attracting attention as they can act on lymphatic endothelial cells and enhance lymphangiogenesis. In addition, their effects on improving lymphedema have been demonstrated in animal models.…”