表达 p16 的间充质基质细胞恢复了慢性肌肉炎症中受损的衰老清除-再生序列。

p16-expressing mesenchymal stromal cells restore the senescence-clearance-regeneration sequence that is impaired in chronic muscle inflammation.

机构信息

Department of Anatomy, Sapporo Medical University School of Medicine, Sapporo, Hokkaido 060-8556, Japan.

出版信息

EBioMedicine. 2019 Jun;44:86-97. doi: 10.1016/j.ebiom.2019.05.012. Epub 2019 May 23.

DOI:10.1016/j.ebiom.2019.05.012

PMID:31129096

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6604166/

Abstract

BACKGROUND

The therapeutic benefits of mesenchymal stromal cells (MSCs) include treatment of chronic inflammation. However, given the short-lived engraftment of these cells in vivo, their therapeutic efficacy remains mysterious. Transient induction of cellular senescence contributes to activation of immune cells, which promotes clearance of damaged cells during tissue remodelling. This may occur in tissue-resident mesenchymal progenitor cells during regeneration. Elucidation of the role of senescence in tissue-resident mesenchymal progenitor cells during regeneration would provide insight into the profile of therapeutic MSCs for treatment of chronic inflammatory disease.

METHODS

We evaluated multipotent mesenchymal progenitor cells, termed fibro/adipogenic progenitors (FAPs), and immune cells in acute muscle injury (AMI) model mice and mice with myosin-induced experimental autoimmune myositis, a model of chronic inflammatory myopathy (CIM). Human bone marrow MSCs were optimised for the treatment of CIM using placental extract.

FINDING

FAPs in AMI transiently expressed p16 on days 1 and 2 after injury and recruited phagocytic immune cells, whereas in CIM, p16 expression in FAPs was low. Cellular senescence occurs during the natural maturation of the placenta. Therefore, we used human placental extract to induce p16 expression in therapeutic human bone marrow MSCs in culture. Treatment of CIM with p16-expressing MSCs promoted tissue remodelling by transiently increasing the abundance of engrafted MSCs, inducing cellular senescence in innate FAPs, and recruiting phagocytic immune cells.

INTERPRETATION

MSCs may exert their effect by remodelling the chronic inflammatory environment via senescence-related regenerative processes.

摘要

背景

间充质基质细胞（MSCs）的治疗益处包括治疗慢性炎症。然而，鉴于这些细胞在体内的短暂植入，其治疗效果仍然是个谜。细胞衰老的短暂诱导有助于激活免疫细胞，这促进了组织重塑过程中受损细胞的清除。这种情况可能发生在组织驻留的间充质祖细胞的再生过程中。阐明衰老在组织驻留的间充质祖细胞在再生过程中的作用，将为治疗慢性炎症性疾病的治疗性 MSC 提供深入了解。

方法

我们在急性肌肉损伤（AMI）模型小鼠和肌球蛋白诱导的实验性自身免疫性肌炎（一种慢性炎症性肌病模型）小鼠中评估了多能间充质祖细胞，称为成纤维/脂肪祖细胞（FAPs）和免疫细胞。使用胎盘提取物优化人骨髓 MSC 治疗慢性炎症性肌病。

发现

AMI 中的 FAPs 在损伤后第 1 天和第 2 天短暂表达 p16，并招募吞噬免疫细胞，而在 CIM 中，FAPs 中的 p16 表达水平较低。细胞衰老发生在胎盘的自然成熟过程中。因此，我们在培养物中用人胎盘提取物诱导治疗性人骨髓 MSC 表达 p16。用表达 p16 的 MSC 治疗 CIM 通过短暂增加植入 MSC 的丰度、诱导先天 FAPs 中的细胞衰老以及招募吞噬免疫细胞来促进组织重塑。