Choi, Jung-Kyun Chung, Haeun Oh, Seung Ja Kim, Jong-Wan Kim, Sang-Heon 2024-01-19T09:02:37Z 2024-01-19T09:02:37Z 2023-08-02 2023-08 1742-7061 https://pubs.kist.re.kr/handle/201004/113433 Stem cell therapy has emerged as a promising regenerative medicine strategy but is limited by poor cell survival, leading to low therapeutic outcomes. We developed cell spheroid therapeutics to overcome this limitation. We utilized solid-phase FGF2 to form functionally enhanced cell spheroid-adipose derived (FECS-Ad), a type of cell spheroid that preconditions cells with intrinsic hypoxia to increase the survival of transplanted cells. We demonstrated an increase in hypoxia-inducible factor 1-alpha (HIF-1 & alpha;) levels in FECS-Ad, which led to the upregulation of tissue inhibitor of metalloproteinase 1 (TIMP1). TIMP1 enhanced the survival of FECS-Ad, presumably through the CD63/FAK/Akt/Bcl2 anti-apoptotic signaling pathway. Cell viability of transplanted FECS-Ad was reduced by TIMP1 knockdown in an in vitro collagen gel block and a mouse model of critical limb ischemia (CLI). TIMP1 knockdown in FECS-Ad inhibited angiogenesis and muscle regeneration induced by FECS-Ad transplanted into ischemic mouse tissue. Genetic overexpression of TIMP1 in FECS-Ad further promoted the survival and therapeutic efficacy of transplanted FECS-Ad. Collectively, we suggest that TIMP1 acts as a key survival factor to improve the survival of transplanted stem cell spheroids, which provides scientific evidence for enhanced therapeutic efficacy of stem cell spheroids, and FECS-Ad as a potential therapeutic agent to treat CLI. English Elsevier BV Functionally enhanced cell spheroids for stem cell therapy: Role of TIMP1 in the survival and therapeutic effectiveness of stem cell spheroids Article 10.1016/j.actbio.2023.05.033 1 Acta Biomaterialia, v.166, pp.454 - 469 Acta Biomaterialia 166 454 469 Y scie scopus 001031572300001 2-s2.0-85163348050 Engineering, Biomedical Materials Science, Biomaterials Engineering Materials Science Article BREAST EPITHELIAL-CELLS TISSUE INHIBITOR INFARCTED HEART GROWTH-FACTOR ADHESION DIFFERENTIATION TRANSPLANTATION ACTIVATION DEATH METALLOPROTEINASE-1 Tissue inhibitor matrix metalloproteinase 1 Spheroid Critical limb ischemia Stem cell therapy Survival