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IFN-γ and PPARδ influence the efficacy and retention of multipotent adult progenitor cells in graft vs host disease
STEM CELLS Translational Medicine ( IF 6 ) Pub Date : 2021-08-16 , DOI: 10.1002/sctm.21-0008
Fiona Carty 1, 2 , Hazel Dunbar 1, 2 , Ian J Hawthorne 1, 2 , Anthony E Ting 3 , Samantha R Stubblefield 3 , Wouter Van't Hof 3, 4 , Karen English 1, 2
Affiliation  

Cell-based therapy for the treatment of inflammatory disorders has focused on the application of mesenchymal stromal cells (MSCs) and multipotent adult progenitor cells (MAPCs). Despite the recent positive findings in industry-sponsored clinical trials of MSCs and MAPCs for graft vs host disease (GvHD), cell therapy is efficacious in some but not all patients, highlighting the need to identify strategies to enhance cell-based therapeutic efficacy. Here, we demonstrate the capacity for interferon (IFN)-γ licensing to enhance human MAPC efficacy and retention following early administration in a humanized mouse model of acute GvHD (aGvHD). Activation of the nuclear receptor peroxisome proliferator-activated receptor delta (PPARδ) negatively influenced the retention and efficacy of human MAPCs as well as IFN-γ-licensed MAPCs in the aGvHD model. PPARδ antagonism significantly enhanced the efficacy of human MAPCs when administered early in the humanized aGvHD model. COX-2 expression in human MAPC was significantly decreased in IFN-γ licensed MAPCs exposed to a PPARδ agonist. Importantly, MAPC exposure to the PPARδ antagonist in the presence of a COX-2 inhibitor indomethacin before administration significantly reduced the efficacy of PPARδ antagonized MAPCs in the aGvHD humanized mouse model. This is the first study to demonstrate the importance of PPARδ in human MAPC efficacy in vivo and highlights the importance of understanding the disease microenvironment in which cell-based therapies are to be administered. In particular, the presence of PPARδ ligands may negatively influence MAPC or MSC therapeutic efficacy.

中文翻译:

IFN-γ 和 PPARδ 影响多能成体祖细胞在移植物抗宿主病中的功效和保留

用于治疗炎症性疾病的基于细胞的疗法集中在间充质基质细胞 (MSCs) 和多能成体祖细胞 (MAPCs) 的应用上。尽管最近在行业赞助的 MSCs 和 MAPCs 用于移植物抗宿主病 (GvHD) 的临床试验中取得了积极的发现,但细胞疗法在一些但并非所有患者中是有效的,这突出表明需要确定提高基于细胞的治疗效果的策略。在这里,我们展示了干扰素 (IFN)-γ 许可在急性 GvHD (aGvHD) 人源化小鼠模型中早期给药后增强人类 MAPC 功效和保留的能力。核受体过氧化物酶体增殖物激活受体δ (PPARδ) 的激活对 aGvHD 模型中人类 MAPC 以及 IFN-γ 许可的 MAPC 的保留和功效产生负面影响。当在人源化 aGvHD 模型中早期给药时,PPARδ 拮抗作用显着增强了人类 MAPC 的功效。在暴露于 PPARδ 激动剂的 IFN-γ 许可 MAPC 中,人类 MAPC 中的 COX-2 表达显着降低。重要的是,在给药前在 COX-2 抑制剂吲哚美辛存在下 MAPC 暴露于 PPARδ 拮抗剂显着降低了 PPARδ 拮抗 MAPC 在 aGvHD 人源化小鼠模型中的功效。这是第一项证明 PPARδ 在体内人类 MAPC 功效中的重要性的研究,并强调了了解将进行基于细胞的治疗的疾病微环境的重要性。特别是,PPARδ 配体的存在可能会对 MAPC 或 MSC 的治疗效果产生负面影响。
更新日期:2021-08-16
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