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. 2013 Apr 28;17(4):567–577. doi: 10.1111/jcmm.12052

Genetic comparison of mouse lung telocytes with mesenchymal stem cells and fibroblasts

Yonghua Zheng a,b,#, Miaomiao Zhang c,#, Mengjia Qian c,#, Lingyan Wang c,†, V B Cismasiu d,e,†, Chunxue Bai a,b, L M Popescu d,e,*, Xiangdong Wang a,b,c,*
PMCID: PMC3822657  PMID: 23621815

Abstract

Telocytes (TCs) are interstitial cells with telopodes – very long prolongations that establish intercellular contacts with various types of cells. Telocytes have been found in many organs and various species and have been characterized ultrastructurally, immunophenotypically and electrophysiologically (http://www.telocytes.com). Telocytes are distributed through organ stroma forming a three-dimensional network in close contacts with blood vessels, nerve bundles and cells of the local immune system. Moreover, it has been shown that TCs express a broad range of microRNAs, such as pro-angiogenic and stromal-specific miRs. In this study, the gene expression profile of murine lung TCs is compared with other differentiated interstitial cells (fibroblasts) and with stromal stem/progenitor cells. More than 2000 and 4000 genes were found up- or down-regulated, respectively, in TCs as compared with either MSCs or fibroblasts. Several components or regulators of the vascular basement membrane are highly expressed in TCs, such as Nidogen, Collagen type IV and Tissue Inhibitor of Metalloproteinase 3 (TIMP3). Given that TCs locate in close vicinity of small vessels and capillaries, the data suggest the implication of TCs in vascular branching. Telocytes express also matrix metalloproteases Mmp3 and Mmp10, and thus could regulate extracellular matrix during vascular branching and de novo vessel formation. In conclusion, our data show that TCs are not fibroblasts, as the ultrastructure, immunocytochemistry and microRNA assay previously indicated. Gene expression profile demonstrates that TCs are functionally distinct interstitial cells with specific roles in cell signalling, tissue remodelling and angiogenesis.

Keywords: telocytes, mesenchymal stem cells, fibroblasts, gene expression profile, interstitial cells, stroma, connective tissue, lung

Introduction

Recent electron microscopic studies have identified telocytes (TCs), a distinct type of interstitial cells, in many cavitary and non-cavitary organs 1–20. Telocytes are defined by their very long prolongations – called telopodes (Tps; generally, 2–3/cell; length of up to hundreds of μm) – which emerge from a relatively small cellular body. It has been shown that TCs form a 3D network through the organ interstitium surrounding organ-specific structures, blood capillaries, immune cells and nerve endings. As a specific functional property, TCs are key players in intercellular signalling, at both short and long distance. Thus, the long Tps establish direct contacts (junctions) with neighbouring cells and contribute to the (directional) transport of long-range signals driven by TCs 21. Local (paracrine) signalling of TCs is achieved by shedding vesicles 8, 20, 22.

The ultrastructural portrait of TCs was recently complemented with the immunophenotypical and electrophysiological characterization and the specific microRNA expression signature 20, 22, 23. However, the gene expression profile for this type of cells has not been reported yet. Prompted by these studies, we sought to compare murine lung TCs with mesenchymal stem cells (MSCs) and fibroblasts to identify the genes which are specifically regulated in TCs. We choose lung TCs as these are well-characterized ultrastructurally and immunohistochemically in situ and in vitro 4, 5, 11, 16, 17.

Method and Materials

Cell lines and tissue sampling

Mouse colonies were maintained in Animal Research Center of Fudan University, Shanghai, China. Lung samples were obtained from 20 to 25 g male BABL/c mice, 4–6 weeks of age. The mice were killed with an overdose of anaesthetic and the lung tissues were harvested for the isolation of TCs. The animal study was approved by the Ethic Committee for Animal Care and Use, Fudan University. Mesenchymal stem cells and fibroblast cell lines were obtained from Sciencell Research Laboratories (Cat. no. M7500-57, Carlsbad, CA, USA) and from Chinese Academy of Science (Cat. no. GNM28, Shanghai, China) respectively.

Isolation and primary culture of telocytes from lung tissues

Lung tissues were cut into small pieces and harvested under sterile conditions and collected into sterile tubes containing Dulbecco's Modified Eagle's Medium (DMEM, Gibco, NY, USA), supplemented with 100 UI/ml penicillin and 0.1 mg/ml streptomycin (Sigma Chemical, St. Louis, MO, USA), and the samples were brought to the cell culture room immediately. Samples were further rinsed with sterile DMEM and minced into fragments about 1 mm3, which were then incubated at 37°C for 4 hrs on an orbital shaker, with 1 mg/ml type II collagenase (Sigma-Aldrich, St. Louis, MO, USA) in PBS without Ca2+ and Mg2+. Dispersed cells were separated from non-digested tissue by the filtration through a 40-μm-diameter cell strainer (BD Falcon, Franklin, NJ, USA), harvested by centrifugation, and resuspended in DMEM supplemented with 10% foetal calf serum (Gibco, NY, USA), 100 UI/ml penicillin and 0.1 mg/ml streptomycin. Cell density was counted in a haemocytometer and viability was assessed using the Trypan blue. Cells were distributed in 25 cm2 culture flasks at a density of 1 × 105 cells/cm2 and maintained at 37°C in a humidified atmosphere (5% CO2) until becoming semiconfluent (usually 4 days after plating). Culture medium was changed every 48 hrs. Cultured cells were examined by phase contrast microscope, under an inverted Olympus phase contrast microscope (1 × 51).

RNA isolation and preparation

Mouse lung telocytes were isolated after 5 days of culture. Mouse MSCs and fibroblasts were cultured and collected on days 5 and 10 respectively. RNA preparation was performed using TRIzol reagent (Invitrogen Life Technologies, Carlsbad, CA, USA) and the RNeasy kit (Qiagen, Valencia, CA, USA) according to the manufacturer's instructions, including a DNase digestion treatment. The amount and quality of RNA were measured by NanoDrop-1000 spectrophotometer and with the Agilent 2100 Bioanalyzer (Agilent Technologies, Santa Clara, CA, USA).

RNA labelling, array hybridization and DNA microarray

The Mouse 4 × 44K Gene Expression Array (Agilent, Shanghai, China) with about 39,000+ mouse genes and transcripts represented with public domain annotations was applied for the analysis of gene profiles of mouse lung telocytes, MSCs and fibroblasts. Sample labelling and array hybridization were performed according to the protocol of One-Color Microarray-Based Gene Expression Analysis (Agilent Technology). Briefly, 1 μg of total RNA from each sample was linearly amplified and labelled with Cy3-dCTP. The labelled cRNAs were purified by RNAeasy Mini Kit (Qiagen). The concentration and specific activity of the labelled cRNAs (pmol Cy3/μg cRNA) were measured by NanoDrop ND-1000. One microgram of each labelled cRNA was fragmented by adding 11 μl 10 × Blocking Agent and 2.2 μl of 25 × Fragmentation Buffer, and heated at 60°C for 30 min. 55 μl 2 × GE Hybridization buffer was added to dilute the labelled cRNA. Hundred microlitre of hybridization solution was dispensed into the gasket slide and assembled to the gene expression microarray slide. The slides were incubated for 17 hrs at 65°C in an Agilent Hybridization Oven. The hybridized arrays were washed, fixed and scanned with the Agilent DNA Microarray Scanner (part number G2505B).

Data analysis

The acquired array images were analysed with Agilent Feature Extraction software (version 10.7.3.1). Quality normalization and subsequent data processing were performed with the GeneSpring GX v11.5.1 software package. The genes detected in all samples were chosen for further data analysis. Differentially expressed genes were identified through Fold Change filtering and hierarchically clustered by the Agilent GeneSpring GX software (version 11.5.1). Gene ontology and String Network analyses were performed with the standard enrichment computation method to study the relation among variant proteins expressed by variant genes. Fisher's exact test was used to find more overlaps between the descriptive list and the GO annotation list than would be expected by chance. The P-value denoted the significance of GO terms enrichment in the descriptive genes.

Results and discussions

The quality of gene data after filtering and the distribution of data sets were assessed and visualized by Box-Plot. There was no significant difference in distributions of log2 ratios among TCs, MSCs and fibroblasts (Figure S1).

Gene expression analysis

Gene expression array data show that more than 500 genes are at least 10 times higher expressed in TCs comparing with either MSCs or fibroblasts (Table 1). Several genes are found 100 times up-regulated in TCs versus fibroblasts (Cdh2, Cyba, Rnf128, Dpysl3, Fstl1, Rbp1, Gm12892, Cdh2, Aldh1a1, Gm5864) or MSCs (Rbp1 and Glipr1; Table 1A). Additional genes are significantly overexpressed in TCs comparing with MSCs or fibroblasts (Table 1B). Table 2 is a summary of genes found to be down-regulated in TCs. Although many genes are less expressed in TCs comparing with MSCs or fibroblasts, very few are found at least 100 times down-regulated in TCs. Table 2A and B show the genes with known functions that are found at least 30 times down-regulated specifically in TCs comparing with MSCs and fibroblasts.

Table 1.

Summary of genes expressed preferentially in TCs, as compared with mesenchymal stem cells (MSCs) and fibroblasts (Fbs)

Compared pairs/fold up-regulated >2 >10 >30 >100
TCs vs. MSCs 2921 500 174 44
TCs vs. Fbs 3173 661 295 85
(A) Genes up-regulated more than 100-folds in telocytes (TCs) as compared with mesenchymal stem cells (MSCs) and fibroblasts (Fbs)
TCs vs. Fbs TCs vs. MSCs
Gene Folds Gene Folds Gene Folds
Ctgf 6151 Tm4sf1 217 Sprr1a 2971
Sprr1a 2593 Sulf1 212 Cck 1242
Myl9 1668 Chi3l3 204 Wfdc2 551
Tagln 1545 Vopp1 198 Serinc2 527
Cck 1206 Mfhas1 198 Chi3l3 369
Nid1 1143 Myh14 194 Glipr1 355
Sdpr 1004 Ogn 185 Eppk1 284
Crlf1 942 Dsp 182 Trf 259
Anxa8 799 Mmp10 177 Myh14 246
Cd9 718 Khdrbs3 175 Gsta3 244
Wfdc2 660 Atp1b1 174 Gpr56 222
Sox4 501 Papss2 171 Cyb561 210
Dhcr24 496 Gprc5c 168 Gprc5c 204
Timp3 445 Prl2c1 165 Tjp2 202
Trim44 410 Gas6 165 Atp1b1 194
Serpine1 376 Rbp1 161 Lyz1 181
Marcksl1 356 Foxq1 156 Aldh1a2 167
Hs6st2 335 Cblc 149 Gpx2 152
Gpr56 331 Aldh1a2 149 Dsp 150
Nrg1 327 Cdh2 136 Khdrbs3 146
Trf 306 Crct1 133 Acp5 143
Bmp4 298 Mmp3 131 Rbp1 141
Cyba 293 Gpx2 126 Gprc5c 137
Thy1 280 Gprc5c 125 Clu 131
Lrrc32 278 Fstl1 125 Tmc4 128
Rab34 269 Lama2 120 Acp5 114
Dpysl3 263 Tjp2 117 Epb4.1l4b 114
Decr1 256 Igsf9 116 Mfsd6 109
Gsta3 240 Bcr 110 Cblc 107
Evl 237 Lce1i 108 Acta1 105
Tmem45a 233 Rnf128 107 F11r 101
Aldh1a1 225 Klhl13 106
Fzd1 223 Echdc2 103
Cryab 219 Trim16 101
Lyz1 217
(B) Genes up-regulated between 30- and 100-folds in telocytes (TCs) as compared with mesenchymal stem cells (MSCs) and fibroblasts (Fbs)
TCs vs. Fbs TCs vs. MSCs
Gene Folds Gene Folds Gene Folds Gene Folds
Wnt11 100 Letmd1 47 Pdgfb 97 Pcgf5 36
F3 98 Rpgrip1 46 Aldh1a1 93 Fxyd3 36
Pdgfb 97 Trp53i11 46 Itpa 90 Ctsk 35
Fxyd6 94 Hebp2 46 Fxyd6 87 Ctgf 35
Fhl2 94 Dkk3 45 Tns1 79 Ckb 35
Nox4 93 Cryab 45 St14 78 Lama5 35
Ptprf 93 Pvrl3 44 Lce1i 78 Evpl 34
Tgfb1i1 93 P2rx2 44 Crip1 77 Col4a6 34
Ddah1 92 A2bp1 43 S100a16 76 Chst4 34
Cd99 92 Cyba 43 Klhl13 74 Apoe 33
Irx1 87 Cyr61 42 Tnk1 74 Pik3r6 33
Pdlim1 86 Cobl 42 Mmrn2 74 Panx1 33
Epb4.1l3 86 Pdlim3 41 Rpgrip1 72 Rnu1b6 33
Tuft1 86 Map3k9 41 Gsta3 71 Nppb 33
Msln 83 Tlr13 41 Endod1 71 Sema6a 33
Panx1 83 Tjp3 41 Scnn1a 69 Serpinb6b 33
Clic5 83 Grhl2 41 Tacstd2 69 Apoc2 32
Ggh 83 Sdcbp2 41 Mboat1 68 Vill 32
Bst1 79 Cd14 41 Gas6 67 Irx1 31
Mansc1 79 Krt17 41 Dapk2 66 Isyna1 30
Slco3a1 78 Loxl2 40 Cpsf3l 65 Map3k9 30
Tnfsf15 78 Cald1 40 Plac9 64
Il6 78 Brsk1 40 Krtcap3 63
Saa3 77 Ppp1r9a 40 Mapkapk3 62
Fgd3 77 Stxbp2 39 Tbc1d2 62
Echdc2 77 Rab25 39 Tbc1d2 61
Mapk13 75 Stfa3 39 Cytip 60
Tnfrsf11b 75 Cald1 39 Spint1 60
Basp1 70 Brsk1 39 Lcp1 60
Slc4a11 70 Lmo7 38 Grhl2 59
Bst1 69 Timp1 38 Wnt11 59
F3 69 Slc35f5 38 Rarb 57
Ubqln2 69 Id1 38 Ctsh 57
Adam8 68 Rnf130 37 Mansc1 56
Parp8 67 Serping1 37 Mmp10 56
Sox4 67 Csf2rb 37 Ephx1 55
Egfl7 66 Olfr1383 37 Coro1a 55
Gsta3 64 Sulf2 37 Rpgrip1 53
Tnk1 64 Nhsl1 37 Cd36 53
Fzd2 64 Itm2a 37 Klf6 52
Gpm6b 63 Slamf9 37 Heph 52
Cgn 62 Cacnb3 36 Nipsnap1 50
Unc13b 61 Spint1 36 Arhgef16 50
Celsr1 61 Tuba1a 36 Atp9a 50
Mmrn2 61 Rgs17 36 Bst1 49
Dok2 61 Col4a6 36 Adm 49
Tpm2 60 Tpm1 36 Elovl7 49
Ppfibp2 60 Scnn1a 35 Fcgr2b 49
Npr3 60 Sirpb1a 35 Tjp3 48
Cpsf3l 59 Clic3 35 Hic1 48
Peg13 59 Klf13 35 Rab25 47
Arhgef16 59 Lrrc33 35 Serpine1 47
Lass3 58 Gprc5a 35 Abcc3 47
Dapk2 58 Sgk1 35 Psmg2 47
Plac9 58 Ankrd1 34 Col4a4 46
Msrb2 58 Mid1ip1 34 Csf2rb2 45
Ckb 57 Coro1a 34 Tmem88 45
Fam83h 57 Cd248 34 Cd97 45
Vcan 56 Acta1 34 Ppl 45
Acp5 56 Inadl 33 P2rx2 44
Csf1r 56 Sesn3 33 A2bp1 43
Ap1s3 56 Evpl 33 Akr1c13 43
Pbx3 56 C3 33 St6gal1 42
Tmc4 56 Tpm2 33 Efnb1 41
Rpgrip1 55 Pilra 33 Dok2 41
Ctsw 55 H19 33 Adam8 41
Wwc1 54 Pfkfb3 32 Clic5 41
Glipr1 54 Zfhx3 32 Sh3bgr 40
Hes6 54 Fcer1g 32 Fgd3 39
Tacstd2 54 Stab 1 32 Csf2rb 39
Nsd1 54 Col1a2 32 Olfr1383 39
Cyb561 53 Igfbp2 31 H19 39
Fcgr2b 53 Vcam1 31 Sirpb1a 39
Cdc42ep5 53 Chpf2 31 Fcer1g 38
Mdfi 52 Nppb 31 Slc39a4 38
Galntl4 52 Ccl27a 31 Fcgr4 38
Anxa8 52 Ccl2 31 Sh3bgr 38
Plcg2 52 Tnfaip3 31 Slc22a18 38
Col4a4 51 Fnbp1l 31 Alcam 38
Acp5 50 Marveld3 31 Stfa3 38
Btg3 49 Spint2 30 Ppfibp2 37
Ltbp2 48 Sh3bgr 30 Clic3 37
Cd93 47 Adamts9 30 Csf1r 37
Gadd45b 47 Abcc3 30 Spint2 36
Afap1l2 47 Lcp1 30 Lamc2 36
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Table 2.

Summary of genes less expressed in TCs, as compared with mesenchymal stem cells (MSCs) and fibroblasts (Fbs)

Compared pairs/fold down-regulated >2 >10 >30 >100
TCs vs. MSCs 4365 175 32 5
TCs vs. Fbs 5451 326 63 16
(A) Genes down-regulated more than 100-folds in telocytes (TCs) as compared with mesenchymal stem cells (MSCs) and fibroblasts (Fbs)
TCs vs. Fbs TCs vs. MSCs
Gene Folds Gene Folds
Car6 323 Ccl5 282
Odz4 275 Hoxc6 146
Tenm4 269 Cdsn 159
Pla2g2e 253 Ifi203 63
Cdsn 229 Gdpd2 85
Glod5 209
Rarres2 180
Hoxc6 152
Ndufa4l2 150
Hoxc10 133
Rhd 122
Plin4 113
Gm2022 105
Car9 102
(B) Genes down-regulated between 30- and 100-folds in telocytes (TCs) as compared with mesenchymal stem cells (MSCs) and fibroblasts (Fbs)
TCs vs. Fbs TCs vs. MSCs
Gene Folds Gene Folds Gene Folds
Serpinb9f 95 Tbx15 44 Tbx15 93
Foxg1 94 Dmrtc1c2 42 Hoxc10 92
Mst1 88 Igf2bp3 41 Nkx2-5 84
Ifi203 82 Itk 41 Gbp3 72
Avil 75 Paip1 38 Lpar4 67
Hsd17b14 69 Rps3a 38 Hoxb9 66
Acacb 68 Slx 37 Odz4 58
Angpt1 67 Gchfr 35 Eif2s1 58
Csprs 67 Hc 35 Pde8b 54
Gm4951 67 Ptgir 33 Ebf3 46
Mtap1b 65 Accn2 32 Angpt1 46
Serpinb9e 59 Masp2 32 Rsad2 45
Cox6a2 59 Cbr2 31 Ifi202b 45
Matn2 57 Col5a3 30 Fbln1 37
Pla2g2e 54 Ifi204 35
Nrxn3 49 Thbs2 35
Cbr2 49 Mx2 34
Ebf3 48 Ndufa4l2 34
Cldn15 47 Tgfbr3 31
Ppargc1a 45 Car6 31
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Hierarchical cluster and gene ontology analyses

The hierarchical cluster of the genes with more than twofold changes among telocytes, MSCs and fibroblasts is shown in Figure 1. Remarkably, the MCSs and fibroblast gene expression profiles relate each other to higher extent than to TCs supporting the view that TCs have a distinct gene expression pattern. In fact this is an important additional proof that TCs and fibroblasts are different cells. The GO analysis indicates that the genes differentially expressed in TCs are mainly involved in development, in tissue and organ morphogenesis and in transport and maintenance of a biological compound to a specific location (Fig. 2A). In addition, many of the differentially expressed genes likely function in extracellular compartments (Fig. 2B) and may play roles in cell survival, growth and differentiation through autocrine and paracrine activity (Fig. 2C). The relationships, including direct (physical) and indirect (functional) associations, of those genes were analysed by String Network analysis (http://www.string-db.org). Among the 156 co-expressed genes, 46 genes were found to have certain interactions (Fig. 3).

Fig. 1.

Fig. 1

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Hierarchical cluster analysis of the differentially expressed genes among telocytes (TCs), mesenchymal stem cells (MSCs) and fibroblasts (Fbs).

Fig. 2.

Fig. 2

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Gene ontology of the genes with at least twofolds difference among telocytes (TCs), mesenchymal stem cells (MSCs) and fibroblast (Fbs), analysed under following categories: Biological Processes (A), Cellular Components (B) and Molecular Function (C). (P ≤ 0.01).

Fig. 3.

Fig. 3

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String Network of the proteins that are differentially expressed among telocytes (TCs), mesenchymal stem cells (MSCs) and fibroblast (Fbs). A group of 46 genes are found connected functionally. Strong associations are represented by thick lines.

TCs are potentially involved in tissue remodelling and basement membrane homeostasis

A set of genes are specifically up- or down-regulated in TCs comparing with both fibroblasts and MSC (Table 3). As last two cell types are developmentally and functionally quite different, one being progenitors and the other differentiated, specialized cells, this set of genes should connect to the specific biological activities of TCs among the other stromal cells. Thus, we have found that several genes with roles in tissue remodelling and repair are significantly up-regulated in TCs (Tables 1A and 3): connective tissue growth factor (CTGF) 24, 25, Transgelin (Tagln) 26, Nidogen 1 (Nid1) 27, 28, tissue inhibitor of metalloproteinase 3 (TIMP3) 29, collagen type IV, alpha (Col4a4, Col4a6, Col4a5) 28, 30, Matrix Metallopeptidase 10 (Mmp10) 31–33, Matrix Metallopeptidase 3 (Mmp3) 31–33 and Retinol-binding protein 1 (RBP1). RBP1 (also known as CRABP-I, CRBP, CRBP1, CRBPI, RBPC) is required in tissue remodelling 34. Regarding the molecular mechanisms, RBP1 delivers vitamin A to other cells through the plasma membrane protein STRA6 involved in JAK/STAT signalling and the intracellular metabolism of the vitamin 35. Remarkably, two main components of basement membrane, Collagen type IV and Nidogen 1 are up-regulated in the cultured TCs comparing with both MSCs and fibroblasts. Moreover, TIMP3 is an extracellular matrix-anchored metalloproteinase inhibitor that acts specifically to increase vascular (endothelial) basement membrane stability 36, 37. As TCs express Matrix Metalloproteases Mmp3 and Mmp10 also, it is likely that TCs are involved in both basement membrane assembly (stability) and surrounding extracellular matrix remodelling.

Table 3.

Genes up- or down-regulated in telocytes (TCs) relative to both mesenchymal stem cells (MSCs) and fibroblasts (Fbs)

TCs vs. Fbs TCs vs. MSCs
Gene name Fold change Reg Fold change Reg
Ctgf 6150 Up 35 Up
Mmp10 177 Up 56 Up
Mmp3 131 Up 25 Up
Col4a4 46 Up 51 Up
Col4a6 34 Up 36 Up
Col4a5 8 Up 32 Up
Unc13b 61 Up 7 Up
Mapk13 75 Up 13 Up
Igsf9 115 Up 3 Up
Glipr1 54 Up 355 Up
Clic5 83 Up 41 Up
Myh14 194 Up 245 Up
Aldh1a1 225 Up 92 Up
Aldh1a2 148 Up 167 Up
Rbp1 161 Up 141 Up
Gprc5c 125 Up 136 Up
Gsta3 64 Up 70 Up
Plac9 57 Up 63 Up
Fgd3 77 Up 39 Up
Dok2 60 Up 41 Up
Scnn1a 35 Up 68 Up
Car6 323 Down 31 Down
Odz4 275 Down 59 Down
Oz/ten-m 269 Down 56 Down
Cdsn 229 Down 153 Down
Hoxc6 152 Down 207 Down
Ifi203 82 Down 150 Down
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Concluding remarks

Overall, the data indicate that TCs are clearly distinct from both MSCs and fibroblasts, and the gene signature of TCs suggests specific biological functions in (a) development and tissue morphogenesis, (b) biological compound transport and (c) extracellular matrix remodelling. It has been proposed that TCs play essential roles in angiogenesis given that TCs are frequently found in close vicinity of small vessels and express angiogenesis-related factors (VEGF, NO) and pro-angiogenic microRNAs 22. The data presented here bring additional support to this view suggesting that TCs may also regulate vascular basement membrane remodelling as key step in vascular branching and de novo vessel formation.

Acknowledgments

The authors would like to thank Hongjian Gao, Department of Electronic Microscopy, Shanghai Medical College, Fudan University, for the technical assistance in TEM; Biomedical Research Center of Fudan University Zhongshan Hospital for technical supports and facility supplies. The work was supported by Shanghai Leading Academic Discipline Project (Project Number: B115), Fudan University (Distinguished Professor Grant), Shanghai Science & Technology Committee Grants for International Collaboration (11410708600), Project of Science and Technology Innovation Plan in Biomedicine, National Natural Science foundation of China (H0108) and National Natural Key Science foundation of China: ‘Lung injury of ischemic reperfusion’ (30930090). This study is partially supported by the Sectorial Operational Programme Human Resources Development (SOPHRD), financed from the European Social Fund and by the Romanian Government under the contract number POSDRU/89/1.5/S/64153 (to V.B.C) and by grant 350/2012 PN-II-ID-PCE-2011-3-0134 of the Romanian National Authority for Scientific Research, CNCS – UEFISCDI (to L.M.P).

Conflict of interest

The authors confirm that there are no conflicts of interest.

Supporting information

Additional Supporting Information may be found in the online version of this article:

Figure S1 Box-Plot of Quality assessment of gene data after filtering. After normalization, the distributions of log2 ratios among all samples are nearly the same.

jcmm0017-0567-SD1.pptx (104.1KB, pptx)

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