Department of Biology, Maynooth University, Maynooth, Co. Kildare, Ireland.
Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Co. Kildare, Ireland.
Stem Cells Transl Med. 2021 Nov;10(11):1561-1574. doi: 10.1002/sctm.21-0008. Epub 2021 Aug 16.
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.
细胞疗法治疗炎症性疾病的重点在于间充质基质细胞（MSCs）和多能成体祖细胞（MAPCs）的应用。尽管最近在行业赞助的 MSC 和 MAPC 治疗移植物抗宿主病（GvHD）的临床试验中取得了积极的发现，但细胞疗法在一些患者中有效，但并非所有患者都有效，这突出表明需要确定增强细胞治疗功效的策略。在这里，我们证明了干扰素（IFN）-γ许可在人类 GvHD（aGvHD）的人源化小鼠模型中早期给药后增强人 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）的激活对人 MAPC 的保留和功效以及 IFN-γ许可的 MAPC 在 aGvHD 模型中的功效产生负面影响。在人源化 aGvHD 模型中早期给予 PPARδ 拮抗剂时，显著增强了人 MAPC 的功效。IFN-γ 许可的 MAPC 暴露于 PPARδ 激动剂时，COX-2 在人 MAPC 中的表达明显降低。重要的是，在给予 COX-2 抑制剂吲哚美辛之前，MAPC 暴露于 PPARδ 拮抗剂中，可显著降低 aGvHD 人源化小鼠模型中 PPARδ 拮抗的 MAPC 的功效。这是第一项证明 PPARδ 在体内人 MAPC 功效中的重要性的研究，并强调了了解细胞治疗要给药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 治疗功效产生负面影响。
