Bone marrow mesenchymal stem cells prevent pulmonary fibrosis through inhibiting myeloid-derived suppressor cells_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

YIN Yanfeng ¹ , YANG Liu ¹ , YU Lu ² , WANG Yiyin ¹ , CHEN Rui ¹ ,  ZHOU Kaihua ³ ,  SU Xiaosan ¹

1. Biomedical Research Center, The Affiliated Calmette Hospital of Kunming Medical University, Kunming, Yunnan 650011, P. R. China;
2. Department of Pathology, The Affiliated Calmette Hospital of Kunming Medical University, Kunming, Yunan 650011, P. R. China;
3. Department of Respiratory Medicine, The Affiliated Calmette Hospital of Kunming Medical University, Kunming 650011, P. R. China;

Corresponding author：

ZHOU Kaihua, Email: zkh51033528@sina.com; SU Xiaosan, Email: suxs163@163.com

Keywords：

Pulmonary fibrosis; Mesenchymal stem cell; Myeloid-derived suppressor cell; Bleomycin

DOI：

10.7507/1671-6205.201906010

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Objective To investigate the role of myeloid-derived suppressor cell (MDSC) in bleomycin (BLM)-induced pulmonary fibrosis and the possible mechanism of bone marrow mesenchymal stem cell (MSC) in therapy of BLM-induced pulmonary fibrosis.Methods Bone marrow mesenchymal stem cells (MSC) were harvested from 6-week old male BALB/c mice. One hundred and four female BALB/c mice were randomly divided into 3 groups. Mice in control (n=32) and BLM group were instilled with normal saline (NS) or BLM via trachea and NS were injected via tail vein on the 1st, 2nd and 3rd day after NS administration. Mice in MSC group (n=40) were instilled with BLM via trachea and MSC (total cell number=1.5×10⁶) were injected via tail vein. On the 1st, 3rd, 5th, 8th, 11th, 14th, 18th, 21st, 25th and 32nd day after BLM administration, the percentage of Gr-1⁺CD11b⁺ cells in peripheral blood mononuclear cell (PBMC) was detected by flow cytometry. Eight mice from each group were killed on the 3rd, 8th, 18th and 32nd day after BLM administration, the percentage of Gr-1⁺CD11b⁺ cells in the lung tissue was detected by flow cytometry. Meanwhile, the lung tissue specimens were stained with Masson. The sry gene of Y chromosome was detected by polymerase chain reaction (PCR).Results Compared with BLM group, MSC transplantation significantly reduced pulmonary inflammation in MSC group [(1.32±0.25) vs. (2.53±0.56); and (1.06±0.42) vs. (2.27±0.82), respectively, P<0.01)]. Likewise, MSC transplantation significantly reduced pulmonary fibrosis and deposition of collagen as compared with BLM group [(1.02±0.44) vs. (1.81±0.74), and (1.51±0.73) vs. (2.72±0.54), respectively, P<0.05)]. The percentage of Gr-1⁺CD11b⁺ cells in the BLM group was significantly increased as compared with control group. Compared with BLM group, MSC transplantation significantly reduced Gr-1⁺CD11b⁺ cells in MSC group (P<0.05). The sry gene (201 bp) was detected in the lungs of female mice within 96 hours after MSC administration.Conclusions MDSC participates in the procedure of BLM-induced pulmonary fibrosis. Syngeneic MSC inhibits the generation of MDSC and further suppresses BLM-induced pulmonary fibrosis.

Citation： YIN Yanfeng, YANG Liu, YU Lu, WANG Yiyin, CHEN Rui, ZHOU Kaihua, SU Xiaosan. Bone marrow mesenchymal stem cells prevent pulmonary fibrosis through inhibiting myeloid-derived suppressor cells. Chinese Journal of Respiratory and Critical Care Medicine, 2021, 20(5): 339-344. doi: 10.7507/1671-6205.201906010 Copy

1.	郑林鑫, 陈灿, 麦玉梅, 等. 两种表皮生长因子抑制剂下调肿瘤抑制素 M 抑制博来霉素诱导的小鼠肺纤维化. 中国呼吸与危重监护杂志, 2018, 17(4): 400-406.
2.	李玉坤, 王华, 姜纯国, 等. 脐带间充质干细胞对博来霉素诱导小鼠肺纤维化的干预机制初探. 中华结核和呼吸杂志, 2013, 36: 808-813.
3.	Srour N, Thébaud B. Mesenchymal stromal cells in animal bleomycin pulmonary fibrosis models: a systematic review. Stem Cells Transl Med, 2015, 4(12): 1500-1510.
4.	Szapiel SV, Elson NA, Fulmer JD, et al. Bleomycin-induced interstitial pulmonary disease in the nude, athymic mouse. Am Rev Respir Dis, 1979, 120(4): 893-899.
5.	Toonkel RL, Hare JM, Matthay MA, et al. Mesenchymal stem cells and idiopathic pulmonary fibrosis. Potential for clinical testing. Am J Respir Crit Care Med, 2013, 188(2): 133-140.
6.	King Jr TE, Pardo A, Selman M. Idiopathic pulmonary fibrosis. Lancet, 2011, 378: 1949-1961.
7.	万璇, 代华平. 间充质干细胞治疗间质性肺疾病的研究进展. 中华结核和呼吸杂志, 2013, 36(11): 848-851.
8.	Parker KH, Beury DW, Ostrand-Rosenberg S. Myeloid-derived suppressor cells: critical cells driving immune suppression in the tumor microenvironment. Adv Cancer Res, 2015, 128: 95-139.
9.	Hashimoto N, Jin H, Liu T, et al. Bone marrow-derived progenitor cells in pulmonary fibrosis. J Clin Invest, 2004, 113(2): 243-252.
10.	Ortiz ML, Lu L, Ramachandran I, et al. Myeloid-derived suppressor cells in the development of lung cancer. Cancer Immunol Res, 2014, 2(1): 50-58.
11.	Anjos-Afonso F, Siapati EK, Bonnet D. In vivo contribution of murine mesenchymal stem cells into multiple cell-types under minimal damage conditions. J Cell Sci, 2004, 117(Pt 23): 5655-5664.
12.	崔瑷, 代华平, 戴建武, 等. 骨髓间充质干细胞对博来霉素致大鼠肺纤维化形成的影响. 中华结核和呼吸杂志, 2007, 30(9): 677-682.
13.	Ortiz LA, Gambelli F, McBride C, et al. Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc Natl Acad Sci U S A, 2003, 100(14): 8407-8711.
14.	Wang J, Su XS, Yang L, et al. The influence of myeloid derived suppressor cells on angiogenesis and tumor growth after cancer surgery. Int J Cancer, 2016, 138(11): 2688-2699.

1. 郑林鑫, 陈灿, 麦玉梅, 等. 两种表皮生长因子抑制剂下调肿瘤抑制素 M 抑制博来霉素诱导的小鼠肺纤维化. 中国呼吸与危重监护杂志, 2018, 17(4): 400-406.
2. 李玉坤, 王华, 姜纯国, 等. 脐带间充质干细胞对博来霉素诱导小鼠肺纤维化的干预机制初探. 中华结核和呼吸杂志, 2013, 36: 808-813.
3. Srour N, Thébaud B. Mesenchymal stromal cells in animal bleomycin pulmonary fibrosis models: a systematic review. Stem Cells Transl Med, 2015, 4(12): 1500-1510.
4. Szapiel SV, Elson NA, Fulmer JD, et al. Bleomycin-induced interstitial pulmonary disease in the nude, athymic mouse. Am Rev Respir Dis, 1979, 120(4): 893-899.
5. Toonkel RL, Hare JM, Matthay MA, et al. Mesenchymal stem cells and idiopathic pulmonary fibrosis. Potential for clinical testing. Am J Respir Crit Care Med, 2013, 188(2): 133-140.
6. King Jr TE, Pardo A, Selman M. Idiopathic pulmonary fibrosis. Lancet, 2011, 378: 1949-1961.
7. 万璇, 代华平. 间充质干细胞治疗间质性肺疾病的研究进展. 中华结核和呼吸杂志, 2013, 36(11): 848-851.
8. Parker KH, Beury DW, Ostrand-Rosenberg S. Myeloid-derived suppressor cells: critical cells driving immune suppression in the tumor microenvironment. Adv Cancer Res, 2015, 128: 95-139.
9. Hashimoto N, Jin H, Liu T, et al. Bone marrow-derived progenitor cells in pulmonary fibrosis. J Clin Invest, 2004, 113(2): 243-252.
10. Ortiz ML, Lu L, Ramachandran I, et al. Myeloid-derived suppressor cells in the development of lung cancer. Cancer Immunol Res, 2014, 2(1): 50-58.
11. Anjos-Afonso F, Siapati EK, Bonnet D. In vivo contribution of murine mesenchymal stem cells into multiple cell-types under minimal damage conditions. J Cell Sci, 2004, 117(Pt 23): 5655-5664.
12. 崔瑷, 代华平, 戴建武, 等. 骨髓间充质干细胞对博来霉素致大鼠肺纤维化形成的影响. 中华结核和呼吸杂志, 2007, 30(9): 677-682.
13. Ortiz LA, Gambelli F, McBride C, et al. Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc Natl Acad Sci U S A, 2003, 100(14): 8407-8711.
14. Wang J, Su XS, Yang L, et al. The influence of myeloid derived suppressor cells on angiogenesis and tumor growth after cancer surgery. Int J Cancer, 2016, 138(11): 2688-2699.

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Bone marrow mesenchymal stem cells prevent pulmonary fibrosis through inhibiting myeloid-derived suppressor cells

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