AUTHOR=Hu Liru , Zhang Nian , Zhao Chengzhi , Pan Jian 

TITLE=Engineering ADSCs by manipulating YAP for lymphedema treatment in a mouse tail model

JOURNAL=Experimental Biology and Medicine

VOLUME=Volume 249 - 2024

YEAR=2024

URL=https://www.ebm-journal.org/journals/experimental-biology-and-medicine/articles/10.3389/ebm.2024.10295

DOI=10.3389/ebm.2024.10295

ISSN=1535-3699

ABSTRACT=Secondary lymphedema is a chronic disease associated with deformity of limbs and dysfunction; however, conventional therapies are not curative. Adipose-derived stem cells (ADSCs) based therapy is a promising way, but a single transplantation of ADSCs has limited efficacy. In this study, ADSCs were engineered in vitro and then transplanted into the site of lymphedema. Yes-associated protein (YAP), a crucial regulator of Hippo pathway, plays an important role in regulating stem cell functions. We examined the YAP expression in a mouse tail lymphedema model, and found that transplanted ADSCs exhibited high expression level of YAP and a large number of YAP positive cells existed in lymphedema environment. In vitro, the downregulation of YAP in ADSCs resulted in higher expression levels of genes related to lymphangiogenesis such as Lyve-1, VEGFR-3 and Prox-1. In vivo, YAPengineered ADSCs generated abundant VEGFR-3-positive lymphatic vessels and significantly improved subcutaneous fibrosis. These results indicated that the transplantation of pre-engineered ADSCs by manipulating YAP is a promising strategy for lymphatic reconstruction.Millions of patients suffer from secondary lymphedema; however, conventional therapies are not curative. Promoting the growth of lymphatic vessels and reconstructing the lymphatic system are the key to ameliorate lymphedema. This study aimed to explore the role of Hippo pathway in regulating adipose-derived stem cell (ADSC) fate during the process of lymphangiogenesis and investigated the efficacy of engineered ADSC based therapy in lymphedema. The study showed that lymphedema-associated ADSCs exhibited high expression level of YAP and a large number of YAP positive cells existed in lymphedema environment. In vitro, the downregulation of YAP in ADSCs resulted in higher expression levels of genes related to lymphangiogenesis such as Lyve-1, VEGFR-3 and Prox-1. In vivo, YAP-engineered ADSCs generated abundant VEGFR-3-positive lymphatic vessels and significantly improved subcutaneous fibrosis. This work provided new scientific evidences for revealing the mechanism of promoting lymphangiogenesis and YAP-engineered ADSC based therapy for patients suffering from lymphedema.