Mesenchymal stromal cells attenuate alveolar type 2 cells senescence through regulating NAMPT-mediated NAD metabolism.
Mesenchymal stromal cells attenuate alveolar type 2 cells senescence through regulating NAMPT-mediated NAD metabolism.
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DOI：
10.1186/s13287-021-02688-w
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发表时间：
2022-01-10
影响因子：
7.5
通讯作者：
Wang Z
中科院分区：
文献类型：
--
作者：
Lai X;Huang S;Lin S;Pu L;Wang Y;Lin Y;Huang W;Wang Z
特发性肺纤维化（IPF）是一种慢性、进行性、致死性纤维化肺病，在全球范围内具有较高的患病率和死亡率。间充质干细胞（MSCs）具有较强的旁分泌、抗炎、抗凋亡和免疫调节作用，对肺纤维化具有潜在的治疗作用。然而，间充质干细胞在IPF中的治疗作用的潜在机制，特别是在肺泡2型（AT 2）细胞衰老方面，还没有得到很好的理解。本研究的目的是评估MSC在体内外AT 2细胞NAD代谢和衰老中的作用。从人骨髓中分离MSC。通过博莱霉素小鼠模型评估MSC注射对肺纤维化的保护作用。采用SA-β-半乳糖苷酶法、免疫荧光法和Western blotting法检测AT 2细胞与MSCs共培养后的衰老情况。在体外和体内检测MSC对AT 2细胞NAD+水平和NAMPT表达的影响。采用FK 866和NAMPT shRNA载体，观察NAMPT在MSCs抑制AT 2细胞衰老中的作用。我们证明了骨髓间充质干细胞减轻博莱霉素诱导的小鼠肺纤维化。在MSC处理的肺纤维化小鼠中以及与MSC在体外共培养时，AT 2细胞的衰老减轻。机制研究表明，与MSCs共培养的AT 2细胞中NAD+和NAMPT水平得到了拯救，MSCs主要通过抑制溶酶体介导的NAMPT降解来抑制AT 2细胞的衰老。MSC通过上调NAMPT表达和NAD+水平来减轻AT 2细胞的衰老，从而在肺纤维化中发挥保护作用。在线版本包含补充材料，可通过10.1186/s13287-021-02688-w获得。
Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive deadly fibrotic lung disease with high prevalence and mortality worldwide. The therapeutic potential of mesenchymal stem cells (MSCs) in pulmonary fibrosis may be attributed to the strong paracrine, anti-inflammatory, anti-apoptosis and immunoregulatory effects. However, the mechanisms underlying the therapeutic effects of MSCs in IPF, especially in terms of alveolar type 2 (AT2) cells senescence, are not well understood. The purpose of this study was to evaluate the role of MSCs in NAD metabolism and senescence of AT2 cells in vitro and in vivo. MSCs were isolated from human bone marrow. The protective effects of MSCs injection in pulmonary fibrosis were assessed via bleomycin mouse models. The senescence of AT2 cells co-cultured with MSCs was evaluated by SA-β-galactosidase assay, immunofluorescence staining and Western blotting. NAD+ level and NAMPT expression in AT2 cells affected by MSCs were determined in vitro and in vivo. FK866 and NAMPT shRNA vectors were used to determine the role of NAMPT in MSCs inhibiting AT2 cells senescence. We proved that MSCs attenuate bleomycin-induced pulmonary fibrosis in mice. Senescence of AT2 cells was alleviated in MSCs-treated pulmonary fibrosis mice and when co-cultured with MSCs in vitro. Mechanistic studies showed that NAD+ and NAMPT levels were rescued in AT2 cells co-cultured with MSCs and MSCs could suppress AT2 cells senescence mainly via suppressing lysosome-mediated NAMPT degradation. MSCs attenuate AT2 cells senescence by upregulating NAMPT expression and NAD+ levels, thus exerting protective effects in pulmonary fibrosis. The online version contains supplementary material available at 10.1186/s13287-021-02688-w.
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影响因子：
29
作者：
Frederick DW;Loro E;Liu L;Davila A Jr;Chellappa K;Silverman IM;Quinn WJ 3rd;Gosai SJ;Tichy ED;Davis JG;Mourkioti F;Gregory BD;Dellinger RW;Redpath P;Migaud ME;Nakamaru-Ogiso E;Rabinowitz JD;Khurana TS;Baur JA
通讯作者：
Baur JA
影响因子：
7.5
作者：
Takao S;Nakashima T;Masuda T;Namba M;Sakamoto S;Yamaguchi K;Horimasu Y;Miyamoto S;Iwamoto H;Fujitaka K;Hamada H;Takahashi S;Nakashima A;Hattori N
通讯作者：
Hattori N
DOI：
10.1038/s41580-020-00313-x
发表时间：
2021-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Covarrubias AJ;Perrone R;Grozio A;Verdin E
通讯作者：
Verdin E
DOI：
10.1126/science.1171641
发表时间：
2009-05-01
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Ramsey KM;Yoshino J;Brace CS;Abrassart D;Kobayashi Y;Marcheva B;Hong HK;Chong JL;Buhr ED;Lee C;Takahashi JS;Imai S;Bass J
通讯作者：
Bass J
DOI：
10.1164/rccm.201207-1204pp
发表时间：
2013-07-15
影响因子：
24.7
作者：
Toonkel, Rebecca L.;Hare, Joshua M.;Glassberg, Marilyn K.
通讯作者：
Glassberg, Marilyn K.