No abstract

Lysyl oxidase-like 2 (LOXL2) is an extracellular copper-dependent enzyme that plays a central role in fibrosis by catalyzing the crosslinking and deposition of collagen. Therapeutic LOXL2 inhibition has been shown to suppress liver fibrosis progression and promote its reversal. This study investigates the efficacy and underlying mechanisms of human umbilical cord-derived exosomes (MSC-ex) in LOXL2 inhibition of liver fibrosis. MSC-ex, nonselective LOX inhibitor β-aminopropionitrile (BAPN), or PBS were administered into carbon tetrachloride (CCl4)-induced fibrotic livers. Serum LOXL2 and collagen crosslinking were assessed histologically and biochemically. MSC-ex’s mechanisms on LOXL2 regulation were investigated in human hepatic stellate cell line LX-2. We found that systemic administration of MSC-ex significantly reduced LOXL2 expression and collagen crosslinking, delaying the progression of CCl4-induced liver fibrosis. Mechanically, RNA-sequencing and fluorescence in situ hybridization (FISH) indicated that miR-27b-3p was enriched in MSC-ex and exosomal miR-27b-3p repressed Yes-associated protein (YAP) expression by targeting its 3ʹ untranslated region in LX-2. LOXL2 was identified as a novel downstream target gene of YAP, and YAP bound to the LOXL2 promoter to positively regulate transcription. Additionally, the miR-27b-3p inhibitor abrogated the anti-LOXL2 abilities of MSC-ex and diminished the antifibrotic efficacy. miR-27b-3p overexpression promoted MSC-ex mediated YAP/LOXL2 inhibition. Thus, MSC-ex may suppress LOXL2 expression through exosomal miR-27b-3p mediated YAP down-regulation. The findings here may improve our understanding of MSC-ex in liver fibrosis alleviation and provide new opportunities for clinical treatment.

No 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.

Lysyl oxidase-like 2 (LOXL2) is an extracellular copper-dependent enzyme that plays a central role in fibrosis by catalyzing the crosslinking and deposition of collagen. Therapeutic LOXL2 inhibition has been shown to suppress liver fibrosis progression and promote its reversal. This study aims to investigate the efficacy and underlying mechanisms of human umbilical cord-derived exosomes (MSC-ex) in LOXL2 inhibition of liver fibrosis. MSC-ex, nonselective LOX inhibitor β-aminopropionitrile (BAPN), or PBS were administered into carbon tetrachloride (CCl4)-induced fibrotic livers. Serum LOXL2 and collagen crosslinking were assessed histologically and biochemically. MSC-ex’s mechanisms on LOXL2 regulation were investigated in human hepatic stellate cell line LX-2. We found that systemic administration of MSC-ex significantly reduced LOXL2 expression and collagen crosslinking, delaying the progression of CCl4-induced liver fibrosis. Mechanically, RNA-sequencing and fluorescence in situ hybridization (FISH) indicated that miR-27b-3p was enriched in MSC-ex and exosomal miR-27b-3p repressed Yes-associated protein (YAP) expression by targeting its 3' untranslated region in LX-2. LOXL2 was identified as a novel downstream target gene of YAP and YAP bound to the LOXL2 promoter to positively regulate transcription. Additionally, the miR-27b-3p inhibitor abrogated the anti-LOXL2 abilities of MSC-ex and diminished the antifibrotic efficacy. miR-27b-3p overexpression promoted MSC-ex mediated YAP/LOXL2 inhibition. Thus, MSC-ex may suppress LOXL2 expression through exosomal miR-27b-3p mediated YAP down-regulation. The findings here may improve our understanding of MSC-ex in liver fibrosis alleviation and provide new opportunities for clinical treatment.