Anti-senescence ion-delivering nanocarrier for recovering therapeutic properties of long-term-cultured human adipose-derived stem cells

• Published in: Journal of nanobiotechnology Vol. 19; no. 1; p. 352
• Main Authors: Kim, Yeong Hwan, Im, Gwang-Bum, Kim, Sung-Won, Kim, Yu-Jin, Yu, Taekyung, Lee, Ju-Ro, Um, Soong Ho, Joung, Yoon Ki, Bhang, Suk Ho
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 30.10.2021; BioMed Central; BMC
• Subjects: Adipose Tissue; Angiogenesis; Angiogenesis Inducing Agents - pharmacology; Animals; Apoptosis; Biomedical materials; Blood Vessels - pathology; Cell culture; Cell Differentiation; Cell Line; Cell Proliferation; Cells, Cultured; Clinical trials; Cytotoxicity; Design and construction; Drug Carriers; Drug Delivery Systems - methods; Endocytosis; Endosomes; Functionality restoring; Gene expression; Gold; Health aspects; Humans; Intracellular ion delivery; Ions - chemistry; Iron; Ischemic disease; Metal ions; Methods; Mice; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Paracrine signalling; pH effects; Reactive oxygen species; Reactive Oxygen Species - metabolism; Regeneration; Secretion; Senescence; Stem cell therapy; Stem cell transplantation; Stem Cells; Tissue engineering; Transition metals; Transplantation; Vascular endothelial growth factor; South Korea; Angiogenesis; Functionality restoring; Senescence; Stem cell therapy; Intracellular ion delivery; Ischemic disease
• ISSN: 1477-3155; 1477-3155
• DOI: 10.1186/s12951-021-01098-7

Human adipose-derived stem cells (hADSCs) have been used in various fields of tissue engineering because of their promising therapeutic efficacy. However, the stemness of hADSCs cannot be maintained for long durations, and their therapeutic cellular functions, such as paracrine factor secretion decrease during long-term cell culture. To facilitate the use of long-term-cultured hADSCs (L-ADSCs), we designed a novel therapeutic anti-senescence ion-delivering nanocarrier (AIN) that is capable of recovering the therapeutic properties of L-ADSCs. In the present study, we introduced a low-pH-responsive ion nanocarrier capable of delivering transition metal ions that can enhance angiogenic paracrine factor secretion from L-ADSCs. The AINs were delivered to L-ADSCs in an intracellular manner through endocytosis. Low pH conditions within the endosomes induced the release of transition metal ions (Fe) into the L-ADSCs that in turn caused a mild elevation in the levels of reactive oxygen species (ROS). This mild elevation in ROS levels induced a downregulation of senescence-related gene expression and an upregulation of stemness-related gene expression. The angiogenic paracrine factor secretion from L-ADSCs was significantly enhanced, and this was evidenced by the observed therapeutic efficacy in response to treatment of a wound-closing mouse model with conditioned medium obtained from AIN-treated L-ADSCs that was similar to that observed in response to treatment with short-term-cultured adipose-derived stem cells. This study suggests a novel method and strategy for cell-based tissue regeneration that can overcome the limitations of the low stemness and therapeutic efficacy of stem cells that occurs during long-term cell culture.