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. 2012 Feb;16(2):376-85.
doi: 10.1111/j.1582-4934.2011.01326.x.

A therapeutic role for mesenchymal stem cells in acute lung injury independent of hypoxia-induced mitogenic factor

Lin Song  1 , Jinfu Xu, Jieming Qu, Yin Sai, Chunmei Chen, Long Yu, Dechun Li, Xuejun Guo
Affiliations

A therapeutic role for mesenchymal stem cells in acute lung injury independent of hypoxia-induced mitogenic factor

Lin Song et al. J Cell Mol Med. 2012 Feb.

Abstract

Bone marrow mesenchymal stem cells (BM-MSCs) have therapeutic potential in acute lung injury (ALI). Hypoxia-induced mitogenic factor (HIMF) is a lung-specific growth factor that participates in a variety of lung diseases. In this study, we evaluated the therapeutic role of BM-MSC transplantation in lipopolysaccharide (LPS)- induced ALI and assessed the importance of HIMF in MSC transplantation. MSCs were isolated and identified, and untransduced MSCs, MSCs transduced with null vector or MSCs transduced with a vector encoding HIMF were transplanted into mice with LPS-induced ALI. Histopathological changes, cytokine expression and indices of lung inflammation and lung injury were assessed in the various experimental groups. Lentiviral transduction did not influence the biological features of MSCs. In addition, transplantation of BM-MSCs alone had significant therapeutic effects on LPS-induced ALI, although BM-MSCs expressing HIMF failed to improve the histopathological changes observed with lung injury. Unexpectedly, tumour necrosis factor α levels in lung tissues, lung oedema and leucocyte infiltration into lungs were even higher after the transplantation of MSCs expressing HIMF, followed by a significant increase in lung hydroxyproline content and α-smooth muscle actin expression on day 14, as compared to treatment with untransduced MSCs. BM-MSC transplantation improved LPS-induced lung injury independent of HIMF.

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Figures

Fig 1
Fig 1
Mice were treated with LPS to induce lung injury, followed by intravenous injection simultaneously with PBS, cultured MSCs, MSCs-null vector or MSCs-HIMF. Mice were then sacrificed on days 0, 3, 7 and 14 to evaluate the therapeutic efficacy.
Fig 2
Fig 2
In vitro identification of MSCs. FACS analysis of MSCs expressing CD105, CD73, CD29 and CD44, but not the typical haematopoietic or endothelial markers CD45, CD34, CD14, CD19 and MHC-II. The multipotent potential of MSCs was assessed via (A) oil red staining for adipocytes, (B, C) alizarin staining and alkaline phosphatase staining for osteoblasts and (D) toluidine blue staining for chondrocytes.
Fig 3
Fig 3
Transduction of MSCs with HIMF-eGFP or eGFP and identification five days after transduction. Fluorescence (left) and phase contrast microscopy (right) showing the expression of eGFP in MSCs-HIMF (A and B) and MSCs-null vector (C and D) five days after lentiviral transduction at a MOI = 5 × 200. MSCs without eGFP transduction (E and F) are shown as a negative control for autofluorescence. RT-PCR (G) and Western blot (H) indicating HIMF expression in MSCs-HIMF.
Fig 4
Fig 4
The histopathology score of lung injury was evaluated after LPS challenge (A, B). Transplantation of MSCs prevented LPS-induced increase in lung injury score on day 7 compared to treatment with PBS (*P < 0.05), but treatment with MSCs-HIMF had no effect. The scores increased significantly seven days after transplantation of MSCs-HIMF compared with MSCs-null vector (*P < 0.05). Intra-alveolar septal thickness in lung sections of various treatment groups was evaluated (C, D). In animals treated with MSCs, intra-alveolar septal thickness was significantly reduced compared with controls on day 7 (*P < 0.05), whereas transplantation of MSCs-HIMF resulted in an increase in intra-alveolar septal thickness on day 7 and 14 compared with MSCs-null vector (*P < 0.05). Data are expressed as mean ± S.D.
Fig 5
Fig 5
Histopathology of injured lungs on day 7 (A–H) and day 14 (a–f). Lung tissue sections were stained with haematoxylin and eosin. Histopathological changes in the lungs are shown at low (×100) and high (×400) magnification. (A, a) MSCs-HIMF transplantation; (C, c) MSC transplantation; (E, e) controls; (G) MSC-null vector transplantation.
Fig 6
Fig 6
Biochemical indices of lung injury were examined after LPS challenge. (A, B) Lung W/D ratio was significantly decreased after transplantation of MSCs compared with controls (*P < 0.05), but not after MSCs-HIMF transplantation. (C, D) MPO activity was significantly reduced in the MSC treated group compared with controls on day 3 (*P < 0.05). In animals transplanted with MSCs-HIMF, MPO activity increased significantly seven and 14 days after LPS (*P < 0.05). (E, F) Total protein levels in BAL fluid were significantly decreased with MSC transplantation on day 3 (*P < 0.05), whereas TP levels remained high in animals transplanted with MSCs-HIMF. Data are expressed as mean ± S.D.
Fig 7
Fig 7
Pro- and anti-inflammatory factor expression in different groups. (A, B) Compared to controls, TNF-α mRNA expression was significantly decreased in lung homogenates on days 3 and 7 after MSC transplantation (*P < 0.05), whereas in animals transplanted with MSCs-HIMF, TNF-α mRNA levels increased significantly seven and 14 days after LPS (*P < 0.05). (C, D) Similar results were observed for TNF-α levels in lung homogenates. (E, F) Lung levels of IL-10 mRNA in animals treated with MSCs or MSCs-null vector were significantly increased seven days after LPS treatment compared with those treated with PBS (*P < 0.05), but not in animals treated with MSCs-HIMF. (G, H) Similar results were obtained for IL-10 levels in lung homogenates. Data are expressed as mean ± S.D.
Fig 8
Fig 8
α-SMA expression and hydroxyproline content on day 14. In lungs of control-treated animals (A), those treated with MSCs (B) and those treated with MSCs-null vector (C), α-SMA+ cells were distributed in a scattered pattern. In the MSCs-HIMF-treated group (D), α-SMA+ cells had significantly increased with collagen deposition. (E, F) Transplantation of MSCs and MSCs-null vector resulted in significantly decreased hydroxyproline levels compared with controls (*P < 0.05). This was not the case for MSCs-HIMF-treated animals. Data are expressed as mean ± S.D.
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