Cahill Emer F, Kennelly Helen, Carty Fiona, Mahon Bernard P, English Karen
Institute of Immunology, Department of Biology, Maynooth University, Maynooth, County Kildare, Ireland.
Institute of Immunology, Department of Biology, Maynooth University, Maynooth, County Kildare, Ireland
Stem Cells Transl Med. 2016 Oct;5(10):1307-1318. doi: 10.5966/sctm.2015-0337. Epub 2016 Jul 7.
: The incidence of idiopathic pulmonary fibrosis is on the rise and existing treatments have failed to halt or reverse disease progression. Mesenchymal stromal cells (MSCs) have potent cytoprotective effects, can promote tissue repair, and have demonstrated efficacy in a range of fibrotic lung diseases; however, the exact mechanisms of action remain to be elucidated. Chemical antagonists and short hairpin RNA knockdown were used to identify the mechanisms of action used by MSCs in promoting wound healing, proliferation, and inhibiting apoptosis. Using the bleomycin induced fibrosis model, the protective effects of early or late MSC administration were examined. The role for hepatocyte growth factor (HGF) in MSC protection against bleomycin lung injury was examined using HGF knockdown MSC. Terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling assay was performed on ex vivo lung sections to examine the effects of MSC on apoptosis. MSC conditioned media (CM) enhanced wound closure and inhibited apoptosis of pulmonary cells in vitro. HGF was required for MSC CM enhancement of epithelial cell proliferation and inhibition of apoptosis. In contrast, MSC required COX-2 for CM to inhibit fibroblast proliferation. In a murine model, early administration of MSC protected against bleomycin induced lung fibrosis and correlated with reduced levels of the proinflammatory cytokine interleukin-1β, reduced levels of apoptosis, and significantly increased levels of HGF. These protective effects were in part mediated by MSC derived HGF as HGF knockdown MSC were unable to protect against fibrosis in vivo. These findings delineate the mechanisms of MSC protection in a preclinical model of fibrotic lung disease.
The mechanisms used by mesenchymal stromal cells (MSCs) in mediating protective effects in chronic models of lung disease are not understood and remain to be elucidated. These findings from in vitro studies highlight an important role for the MSC-derived soluble factors hepatocyte growth factor (HGF) and prostaglandin E in promoting wound healing and inhibiting apoptosis. Furthermore, this study translates these findings demonstrating an important role for HGF in the protective effects mediated by MSC in vivo in the bleomycin model. These findings support a targeted approach to enhancing MSC therapy for fibrotic disease and highlight the importance of timing of MSC therapy.
特发性肺纤维化的发病率正在上升，现有治疗方法未能阻止或逆转疾病进展。间充质基质细胞（MSC）具有强大的细胞保护作用，可促进组织修复，并已在一系列纤维化肺病中显示出疗效；然而，确切的作用机制仍有待阐明。使用化学拮抗剂和短发夹RNA敲低来确定MSC促进伤口愈合、增殖和抑制细胞凋亡的作用机制。利用博来霉素诱导的纤维化模型，研究了早期或晚期给予MSC的保护作用。使用HGF敲低的MSC研究了肝细胞生长因子（HGF）在MSC对博来霉素肺损伤的保护作用中的作用。对离体肺切片进行末端脱氧核苷酸转移酶（TdT）dUTP缺口末端标记分析，以研究MSC对细胞凋亡的影响。MSC条件培养基（CM）在体外增强了伤口闭合并抑制了肺细胞的凋亡。HGF是MSC CM增强上皮细胞增殖和抑制凋亡所必需的。相比之下，MSC需要COX-2才能使CM抑制成纤维细胞增殖。在小鼠模型中，早期给予MSC可预防博来霉素诱导的肺纤维化，并与促炎细胞因子白细胞介素-1β水平降低、凋亡水平降低以及HGF水平显著升高相关。这些保护作用部分由MSC衍生的HGF介导，因为HGF敲低的MSC在体内无法预防纤维化。这些发现阐明了纤维化肺病临床前模型中MSC保护的机制。
间充质基质细胞（MSC）在慢性肺病模型中介导保护作用的机制尚不清楚，仍有待阐明。这些体外研究结果突出了MSC衍生的可溶性因子肝细胞生长因子（HGF）和前列腺素E在促进伤口愈合和抑制细胞凋亡中的重要作用。此外，本研究转化了这些发现，证明了HGF在博来霉素模型中MSC体内介导保护作用中的重要作用。这些发现支持了一种有针对性的方法来增强MSC治疗纤维化疾病的效果，并突出了MSC治疗时机的重要性。
