Open Access

Global comparison of chromosome X genes of pulmonary telocytes with mesenchymal stem cells, fibroblasts, alveolar type II cells, airway epithelial cells, and lymphocytes

  • Yichun Zhu1,
  • Minghuan Zheng1,
  • Dongli Song1,
  • Ling Ye1 and
  • Xiangdong Wang1Email author
Journal of Translational Medicine201513:318

DOI: 10.1186/s12967-015-0669-8

Received: 5 February 2015

Accepted: 11 September 2015

Published: 28 September 2015

Abstract

Background

Telocytes (TCs) are suggested as a new type of interstitial cells with specific telopodes. Our previous study evidenced that TCs differed from fibroblasts and stem cells at the aspect of gene expression profiles. The present study aims to search the characters and patterns of chromosome X genes of TC-specific or TC-dominated gene profiles and fingerprints, investigate the network of principle genes, and explore potential functional association.

Methods

We compared gene expression profiles in chromosome X of pulmonary TCs with mesenchymal stem cells (MSC), fibroblasts (Fb), alveolar type II cells (ATII), airway basal cells (ABC), proximal airway cells (PAC), CD8+ T cells come from bronchial lymph nodes (T-BL), or CD8+ T cells from lungs (T-L) by global analyses, and selected the genes which were consistently up or down regulated (>1 fold) in TCs compared to other cells as TC-specific genes. The functional and characteristic networks were identified and compared by bioinformatics tools.

Results

We selected 31 chromosome X genes as the TC-specific or dominated genes, among which 8 up-regulated (Flna, Msn, Cfp, Col4a5, Mum1l1, Rnf128, Syn1, and Srpx2) and 23 down-regulated (Abcb7, Atf1, Ddx26b, Drp2, Fam122b, Gyk, Irak1, Lamp2, Mecp2, Ndufb11, Ogt, Pdha1, Pola1, Rab9, Rbmx2, Rhox9, Thoc2, Vbp1, Dkc1, Nkrf, Piga, Tmlhe and Tsr2), as compared with other cells.

Conclusions

Our data suggested that gene expressions of chromosome X in TCs are different with those in other cells in the lung tissue. According to the selected TC-specific genes, we infer that pulmonary TCs function as modulators which may enhance cellular growth and migration, resist senescence, protect cells from external stress, regulate immune responses, participate in tissue remodeling and repair, regulate neural function, and promote vessel formation.

Keywords

Chromosome X Genes Lung Telocytes Mesenchymal stem cells Fibroblasts Alveolar type II cells Airway epithelial cells Lymphocytes

Background

Telocytes (TCs) as a new type of interstitial cells are characterized with extensive telopodes [1], and found in multiple organs/tissues, including heart [2], trachea and lung [3], digestive tract [4, 5], liver [6], skeletal muscle [7], kidney and urinary tract [8, 9], skin [10], mammary gland [11], and others [1218]. TCs were suggested to play a key role in supporting and nutrition of associated cells through the interconnection in forms of a complex three-dimensional network within organs/tissues [12, 1921]. TCs are involved in mechanical support, intercellular signaling, immune surveillance, stem-cell guidance and tissue regeneration [2224].

The electrophysiological properties of TCs were reported in recent studies [25]. Ion channels on the membrane of TCs are found to be related with the different function of TCs and are involved in multiple biological courses, e.g., SK3 channel modulates the contractility of myometrial [26], large conductance Ca2+-activated K+ current and inwardly rectifying K+ current are expressed on TCs in human heart [27], etc.

Our previous studies initially demonstrated that pulmonary TCs were allocated near the basement membrane of the bronchiolar epithelium, between airway smooth muscle cells, or in pulmonary interstitial space [3].Pulmonary TCs were inferred to play significant roles in lung diseases, e.g. involving in the course of repair after injury, contributing to the development of pulmonary infectious diseases and stimulating the proliferation of fibroblasts during the process of fibrosis, etc. [28]

TCs are mainly identified and defined by the structures of telopodes, podoms and podomers through transmission electron microscopy [4, 22]. CD34/PDGFRα double immunohistochemistry can orientate the diagnosis [29]. The identification course of TCs is relatively complicated and the confusion between TCs and other cells is inevitable. Therefore, there is a need to select several specific biomarkers of TCs to differ between pulmonary TCs and other tissue resident cells, e.g. fibroblasts, stem cells, epithelial cells, and inflammatory cells.

Our previous studies focused on TCs in lung and trachea of the mouse [3] provided genetic evidence that pulmonary TCs differ from stem cells and fibroblasts through comparing the variation of gene expression profiles [30]. Other studies suggested specific microRNA expression signatures as TC-specific biomarkers [3133]. Our recent studies identified characters and patterns of TC-specific or TC-dominated gene profiles and fingerprints in chromosome 1, 2, 3, 17 and 18, through global comparison between TCs and other cells in the mouse lung tissue [3436]. The present study aims to search TC-specific or dominated gene profiles and fingerprints of chromosome X, investigate the network of principle genes, and explore potential functional association. We globally compared gene expression profiles of TCs, mesenchymal stem cells (MSCs), fibroblasts (Fbs), alveolar type II cells (ATII), airway basal cells (ABCs), proximal airway cells (PACs), CD8+ T cells from bronchial lymphnodes (T-BL), and CD8+ T cells from lung (T-L), which may interact with TCs in the lung and trachea.

Methods

Isolation and primary culture of TCs from lung tissues

TCs were isolated from mouse lung tissues, cultured in a density of 1 × 105 cells/cm2. TCs usually begin forming telopodes on day 5 and start overlapping and apoptosis on day 10, therefore TCs were harvested on day 5 (TC5) and day 10 (TC10), as described previously [30, 34]. RNAs were isolated and prepared, labeled, and hybridized for DNA microarray (The Mouse 4x44K Gene Expression Array, Agilent, Shanghai, China) with about 39,000+ mouse genes and transcripts represented with public domain annotations, according to the protocol of One-Color Microarray-Based Gene Expression Analysis. The hybridized arrays were washed, fixed and scanned with using the Agilent DNA Microarray Scanner (part number G2505B).

Data collection and mining

We obtained gene expression profiles of pulmonary TCs on days 5 and 10, MSCs, Fbs from our previous study [30], ATII, ABCs, PACs, T-BL, and T-LL from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus database (GSE6846 [37], GSE27379 [38], GSE28651). The microarray was composed of 45,101 probes. Our first filter eliminated the probe sets without corresponding official symbol, leaving 39, 417 probes and 21,680 genes.

Our earlier study have made the gene expression profile, composed of 23,861 probes, of mouse lung TCs, Fbs and stromal stem/progenitor cells [30]. After eliminating the probes without corresponding official symbol, there are 13,236 probes and 11,532 genes. Only those genes whose expressions were measured in all cells were considered in our analysis. In total, 11,532 genes were analyzed and 335 genes of chromosome X were focused and furthermore analyzed in the present study.

Identification of differentially expressed genes

The present study compared gene expression profiles in chromosome X of pulmonary TCs with MSCs, Fbs, ATIIs, ABCs, PACs, T-BL, or T-L by global analyses, investigated gene expression profiles of chromosome X in different cells to seek for the TC-specific regulated genes and explored potential association of selected genes.

Hierarchical clustering of genes in chromosomes X was performed by TIGR Multi-experiment Viewer (MeV v4.9) (Fig. 1). Gene expression data were normalized and imported into Agilent GeneSpring GX software (version 11.5.1) for further analysis. Up- or down-regulated folds of TCs genes were calculated by comparing with other cells, after the averages of gene expression in cells were obtained from the raw data of multi-databases. The up-regulated folds were defined as the normalized gene expression values of TC5 or TC10 divide those of other cells, while the down-regulated folds were defined as the expression values of other cells devide those of TC5 or TC10. We selected the genes which were consistently up or down regulated (>1 fold) in both TC5 and TC10 as compared to other cells as TC-specific genes (Additional file 1: Table S1).
Fig. 1

Hierarchical cluster analysis. Hierarchical cluster analysis of the differentially expressed genes on chromosomes X among telocytes (TCs), mesenchymal stem cells (MSCs), fibroblasts (Fbs), lymphocytes from lungs (T-LL) and from bronchial lymph nodes (T-BL), alveolar type II cells (ATII), proximal airway cells (PAC) and airway basal cells (ABC)

Results

Hierarchical clustering of genes in chromosomes X was performed, as shown in Fig. 1. The result of clustering showed a close relationship of TC5 and TC10, and obvious difference between TCs and other kind of cells.

Gene expression array data showed that 8 chromosome X genes (e.g. Flna, Msn, Cfp, Col4a5, Mum1l1, Rnf128, Syn1, and Srpx2) up-regulated in both TC5 and TC10, as compared with those in other cells (Table 1). Of them, Cfp, Col4a5, Mum1l1, Rnf128, and Syn1 up-regulated 2–5 folds, and Srpx2 more than 5 folds as compared with other cells (Table 1B). 23 genes (e.g. Abcb7, Atf1, Ddx26b, Drp2, Fam122b, Gyk, Irak1, Lamp2, Mecp2, Ndufb11, Ogt, Pdha1, Pola1, Rab9, Rbmx2, Rhox9, Thoc2, Vbp1, Dkc1, Nkrf, Piga, Tmlhe and Tsr2) down-regulated in TCs, of which 5 chromosome X genes (Dkc1, Nkrf, Piga, Tmlhe, and Tsr2) in TCs were more than 2 folds lower than in other cells, as compared with other cells (Table 2).
Table 1

Summary of genes up-regulated in TCs, as compared with others

Compaired pairs/fold up-regulated

>1

>2

>5

TC5 vs others

24

9

1

TC10 vs others

12

8

2

TCs vs others

8

6

1

Gene symbol

Folds (TC5 vs others/TC10 vs others)

Fb

MSC

ATII

T_BL

T_LL

ABC

PAC

(A) Genes up-regulated between 1- and 2-folds in TCs as compared with others

 Flna

14.13/8.85

1.82/1.14

16.21/10.15

28.84/18.06

49.80/31.18

26.52/16.60

22.41/14.03

 Msn

5.43/3.93

1.83/1.32

3.45/2.50

2.97/2.15

4.11/2.97

8.02/5.80

7.86/5.69

(B) Genes up-regulated between 2- and 5-folds in TCs as compared with other

 Cfp

6.05/8.22

7.53/10.23

2.15/2.92

113.12/153.60

9.46/12.85

41.52/56.38

36.31/49.30

 Col4a5

11.55/9.00

10.47/8.15

5.20/4.05

313.12/243.83

81.54/63.50

2.89/2.25

7.92/6.16

 Mum1l1

2.67/2.60

3.65/3.56

4.31/4.19

21.36/20.81

35.42/34.50

17.91/17.44

81.21/79.09

 Rnf128

161.75/297.77

13.59/25.01

8.99/16.55

37.62/69.25

11.83/21.77

2.07/3.82

2.52/4.63

 Syn1

34.19/35.13

7.52/7.72

6.66/6.84

9.60/8.86

3.26/3.35

3.36/3.46

2.77/2.85

(C) Genes up-regulated between 5- and 10-folds in TCs as compared with other

 Srpx2

32.62/54.91

20.66/34.78

82.00/138.03

100.82/169.72

55.79/93.92

6.25/10.52

23.63/39.77

Table 2

Summary of genes down-regulated in TCs, as compared with others

Compaired pairs/fold down-regulated

>1

>2

>5

TC5 vs others

41

6

0

TC10 vs others

91

22

1

TCs vs others

23

5

0

Gene symbol

Folds (TC5 vs others/TC10 vs others)

Fb

MSC

ATII

T_BL

T_LL

ABC

PAC

(A) Genes down-regulated between 1- and 2-folds in TCs as compared with others

 Abcb7

1.37/1.97

1.50/2.15

17.81/25.48

26.27/37.59

15.70/22.47

26.13/37.39

23.93/34.24

 Atf1

1.89/2.00

1.86/1.97

6.57/6.95

11.93/12.62

13.90/14.70

23.09/24.43

17.32/18.32

 Ddx26b

1.32/1.22

4.39/4.06

5.57/5.15

8.24/7.62

14.11/13.05

4.48/4.14

2.93/2.71

 Drp2

1.26/1.79

1.43/2.04

2.58/3.67

2.32/3.30

4.42/6.29

3.67/5.22

2.11/3.01

 Fam122b

5.05/6.22

1.08/1.32

1.52/1.87

4.03/4.96

2.87/3.53

6.53/8.03

1.59/1.96

 Gyk

2.01/1.79

1.59/1.42

24.83/22.14

6.30/5.62

8.25/7.36

5.35/4.77

16.66/14.85

 Irak1

1.31/1.28

1.70/1.66

4.59/4.50

6.03/5.90

5.61/5.49

5.66/5.54

3.52/3.45

 Lamp2

1.23/1.36

2.07/2.30

3.91/4.34

1.02/1.14

1.31/1.45

4.49/4.99

3.49/3.88

 Mecp2

1.59/1.84

2.35/2.72

1.98/2.29

3.26/3.77

2.79/3.23

2.60/3.01

1.48/1.71

 Ndufb11

1.34/1.80

1.05/1.42

4.64/6.26

3.74/5.05

2.71/3.65

5.41/7.30

4.84/6.53

 Ogt

1.48/1.63

5.10/5.64

3.73/4.11

15.00/16.56

14.45/15.96

10.01/11.06

6.00/6.63

 Pdha1

1.08/1.13

1.16/1.21

9.30/9.73

14.59/15.28

12.53/13.11

10.88/11.39

10.18/10.66

 Pola1

1.45/2.04

1.30/1.83

1.31/1.84

1.96/2.76

1.48/2.09

1.69/2.38

2.71/3.82

 Rab9

1.03/1.14

1.53/1.70

5.01/5.56

2.89/3.21

2.83/3.14

2.65/2.95

2.84/3.15

 Rbmx2

1.01/1.54

1.85/2.81

4.23/6.43

14.71/22.35

10.64/16.17

8.91/13.54

9.89/15.03

 Rhox9

1.49/1.53

1.12/1.15

13.98/14.39

13.94/14.35

20.54/21.15

21.07/21.69

8.39/8.64

 Thoc2

1.40/1.66

2.54/3.00

1.83/2.17

10.15/12.00

12.25/14.49

7.73/9.14

6.27/742

 Vbp1

1.04/1.22

1.44/1.70

4.70/5.53

17.42/20.48

16.14/18.98

7.87/9.26

7.10/8.35

(B) Genes down-regulated between 2- and 5-folds in TCs as compared with others

 Dkc1

2.05/2.62

3.58/4.57

8.45/10.78

20.66/26.35

14.18/18.09

28.20/35.98

38.11/48.61

 Nkrf

2.36/2.47

2.38/2.50

10.62/11.12

25.28/26.46

14.63/15.32

10.10/10.57

10.10/10.57

 Piga

3.52/4..74

3.16/4.25

2.05/2.75

3.41/4.59

3.83/5.16

3.24/4.36

13.95/18.76

 Tmlhe

2.62/5.24

3.80/7.61

2.47/4.94

11.75/23.51

8.01/16.03

10.56/21.13

9.27/18.55

 Tsr2

3.65/3.27

3.22/2.89

24.69/22.09

24.70/22.10

23.11/20.69

33.31/29.81

26.16/23.41

A set of genes were found specifically up- or down-regulated in pulmonary TCs, as compared with MSCs, Fbs, ATII, ABCs, PACs, T-BL, or T-L, respectively, as listed in Table 3. A set of genes up- or down-regulated more than one fold in TC5 were 178 or 157, 224 or 111, 101 or 234, 99 or 236, 109 or 226, 68 or 267, or 88 or 247 and in TC10 123 or 212, 180 or 155, 75 or 260, 87 or 248, 86 or 249, 51 or 284, or 71 or 264, as compared with MSCs, Fbs, ATII, T-BL, T-L, ABCs, PACs, respectively. Up- or down-regulated genes in both TC5 and TC10 were 119 or 153, 172 or 103, 72 or 231, 79 or 228, 81 or 221, 43 or 259, or 65 or 241, as compared with MSCs, Fbs, ATII, T-BL, T-L, ABCs, PACs, respectively. Details of up- or down- regulated gene variations of chromosome X were listed in Additional file 2: Table S2, including the number and names of up- or down-regulated genes among different cells.
Table 3

The number of genes specifically up- or down-regulated in pulmonary telocytes, as compared with other cells

Compared pairs

Up >1

Up >2

Up >5

Down >1

Down >2

Down >5

Down >10

TC5 vs MSC

178

58

21

157

56

9

3

TC10 vs MSC

123

49

18

212

92

14

8

TCs vs MSC

119

36

13

153

45

9

3

TC5 vs Fb

224

100

65

111

28

9

6

TC10 vs Fb

180

81

34

155

65

14

7

TCs vs Fb

172

68

29

103

25

8

5

TC5 vs ATII

101

47

19

234

167

85

42

TC10 vs ATII

75

38

15

260

199

102

56

TCs vs ATII

72

33

12

231

163

73

40

TC5 vs T_BL

99

68

46

236

168

90

54

TC10 vs T_BL

87

59

36

248

201

109

66

TCs vs T_BL

79

54

34

228

166

85

52

TC5 vs T_LL

109

66

35

226

176

103

56

TC10 vs T_LL

86

56

31

249

201

122

75

TCs vs T_LL

81

54

27

221

172

98

55

TC5 vs ABC

68

40

14

267

210

121

67

TC10 vs ABC

51

31

14

284

230

146

90

TCs vs ABC

43

28

11

259

199

116

65

TC5 vs PAC

88

47

22

247

180

89

46

TC10 vs PAC

71

43

20

264

210

111

67

TCs vs PAC

65

37

16

241

174

84

44

We picked out the top 15 % high-expressed genes in chromosome X of TC10, and compared the distribution of such active gene group with other cells, as shown in Fig. 2. The distribution of the high expressed genes in TC10 was similar to those in TC5, while quite different from MSCs, Fbs, ATII, ABCs, PACs, T-BL or T-L. These high expressed genes are mostly involved in gene transcription, energy metabolism, apoptosis and protein degradation, cell migration and intracellular trafficking, and DNA repair. The relationships, including direct (physical) and indirect (functional) associations, of these genes were analyzed by String Network analysis (http://www.string-db.org). The interaction and potential functional links of those genes are also displayed in Fig. 2.
Fig. 2

Expression profiles of the top 15 % up-regulated genes of chomosome X in TCs. Expression profiles of the top 15 % up-regulated genes of chromosome X of TCs isolated and cultured from mouse lungs on days 10 (TC10), as compared with those on days 5 (TC5), MSCs, Fbs, ATII, ABCs, PACs, T-BL, and T-L. The profiles for entire genes are described in Additional file 1. The selected core network and whole mouse network are linked by the documented functional interedractions from various databases (see “Methods”). Genes in each network are indicated in and some of their nearest neighbors are indicated by grey nodes. The top 15 % up-regulated genes within chromosome X of TC10 were selected, and their distribution in each type of cells was compared, and showed the difference between cells

Thirty-one genes were selected as TC-specific or dominated genes, which were up- or down-regulated more than one fold in both TC5 and TC10, as compared with other cells. Among those genes in TCs, 8 were up-regulated, while 23 were down-regulated. Figure 3 demonstrated the distribution of such distinct TC-specific or dominated genes in chromosome X of all cells. The interaction and potential functional links between those genes are also displayed in Fig. 3.
Fig. 3

Expression profiles of TC-specific or dominant genes. Expression profiles of the up- or down-regulated genes (more than one fold) in both TC5 and TC10 as compared with MSCs, Fbs, ATII, ABCs, PACs, T-BL and T-L. The profiles for entire genes are described in Additional file 1. The selected core network and whole mouse network are linked by the documented functional interactions from various databases (see “Methods”). Genes in each network are indicated in red and some of their nearest neighbors are indicated by grey nodes. The 8 up-regulated genes in TCs were shown in the upper right corner, while the 23 down-regulated genes in the lower left and their distribution in each type of cells showed in Fig. 2b. These up- or down-regulated genes were considered as TC-specific or TC-dominant genes. The connections between these genes were analyzed and illustrated

Discussion

Chromosome X is one of the two sex-determining chromosomes, which exists in both gender, with one copy in male and two copies in female, spanning about 156 million base pairs and 1805 genes in human cells. Although chromosome X contains only 4 % of all human genes, a large number of disease condition are related with chromosome X, including X-linked diseases and 10 % of diseases with a mendelian pattern of inheritance [39]. There are 20,000–25,000 genes in mouse, and the similarity of genes between human and mouse is about 85 %. Among 2059 genes in chromosome X of the mouse, 335 were measured by bioinformatics tools in the present study. There were about 8 or 23 up- or down-regulated genes of chromosome X in TCs, as compared with stem cells, lung interstitial cells, pneumocytes, airway cells, or lymphocytes (Fig. 4).
Fig. 4

TC-specific or dominant genes and their main function. Gene expression array data showed that 8 chromosome X genes up-regulated in both TC5 and TC10, and 23 genes down-regulated, as compared with those in other cells. These genes are selected as TC-dominant or specific genes. The up-regulated genes showed in red color while the down-regulated genes in green color. The up-regulated genes are mostly involved in cytoskeleton and cell migration, and regulation of immune responses. The down-regulated genes participates mainly in gene transcription modulation, energy metastasis, material transportation and so on

Srpx2, Cfp, Col4a5, Mum1l1, Rnf128 and Syn1 over-expressed in chromosome X of TCs, as compared with other cells. Srpx2 (sushi-repeat-containing protein, X-linked 2) gene was the only one of chromosome X that expressed more than 5 folds in pulmonary TCs as compared with all the other cells. The Srpx2-encoded protein was found to be the key factor in the development of speech and language centers in the brain [40], the important mediator in endothelial cell migration and tube formation, and the predictor for tumor growth and metastasis [4143]. The enrichment of Srpx2 in pulmonary TCs suggests the potential role of TCs in the regulation of neuron function, promotion of vessel formation, and enhance of cellular growth and migration. Those could be performed through the complicated three-dimensional network constructed by the telopodes with other cells. Cfp, Col4a5, Mum1L1, Rnf128 and Syn1 over-expressed 2–5 folds in TCs within the lung tissue. Cfp (complement factor properdin) encodes a plasma glycoprotein that positively regulates the alternative complement pathway of the innate immune system [44]. TCs were found to be associated with the immune cells including lymphocytes [45], basophiles [46], eosinophils and plasma cells [7]. The high-expressed Cfp suggested that TCs might participate in immune responses and play a potential role in the lung infectious diseases. Col4a5 (collagen, type IV, alpha 5) encodes type IV collagen, which is the major structural component of basement membranes and is critical for tissue remodeling and repair [47]. The Col4a5 gene was also found as a TC-dominant gene as compared with Fbs or MSCs in our previous study [30].

Rnf128 (ring finger protein 128, E3 ubiquitin protein ligase) is associated with cellular apoptosis and cytokine regulation, of which over-expression inhibits the production of activation-induced IL2 and IL4 cytokine, and may converse T cells to the anergic phenotype [48, 49]. This implies that TCs may be involved in inflammation, immune surveillance, or tissue repair after injury by regulating immune function and inflammatory cell. Syn1 (synapsin I) encodes neuronal phosphoproteins associated with the cytoplasmic surface of synaptic vesicles, by which TCs may establish synapses as a special type of heterocellular junctions with other neighbouring cells, including lymphocytes, macrophages, or mast cells [46, 50, 51]. Through those connections to immune cells, TCs could integrate signals, and behave as an immune system modulator. Mum1l1 (melanoma associated antigen (mutated) 1-like 1) is a gene related with melanoma or some other tumors, its function in TCs is not quite clear yet.

Genes down-regulated in chromosome X of pulmonary TCs mainly contribute to gene transcription, protein synthesis and energy metabolism. Nkrf (NFKB repressing factor) encodes a transcriptional repressor of nuclear factor kappa B (NF-κB) and is activated for cell survival, proliferation and immune responses. It indicates that TCs per se have relatively high capacities of proliferation and involvements of immune reactions in physiological conditions, although there are needs of direct evidences to show roles and changes of TCs in cancers, infection, autoimmune diseases, or injury [5255]. Tsr2 [TSR2, 20S rRNA accumulation, homolog (S. cerevisiae)] is another inhibitor of NF-κB, and induces cell apoptosis [56]. Pulmonary TCs may be more involved in activities and processes dominanted by NF-κB such as the production of inflammatory mediators, due to the down-regulation of NF-κB inhibitors in TCs. Dkc1 (dyskeratosis congenita 1, dyskerin) plays an important role in telomerase stabilization and DNA damage response, regulation of a subset of microRNAs, nucleo-cytoplasmic shuttling, and cell adhesion [57]. It suggested that TCs have better abilities to resist senescence and external stresses. Piga (phosphatidylinositol glycan anchor biosynthesis, class A) is a gene related with paroxysmal nocturnal hemoglobinuria and encodes a protein required for synthesis of N-acetylglucosaminyl phosphatidylinositol, the first intermediate in the biosynthetic pathway of a glycolipid on blood cells and to anchor proteins to the cell surface [58]. Tmlhe (trimethyllysine hydroxylase, epsilon) encodes the first enzyme in the carnitine biosynthesis pathway related with the transport of activated fatty acids across the inner mitochondrial membrane [59]. The significance of those two down-regulated genes in TCs still remains unclear. Based on the level of gene expression, the limitation of the study is inevitable, since gene expression level cannot equally reflect the protein level or the function change in the cells. Fold changes of gene expression may not be in direct proportion to the functional significance. More studies will be conducted in the future to detect the relationships among TC-specific genes, TC-specific proteins and the function of TCs.

Conclusions

In conclusion, the present study initially compared genetic variations of chromosome X of pulmonary TCs with MSCs, Fbs, ATIIs, ABCs, PACs, or bronchial and lung lymphocytes by global analyses. Our data demonstrated that 8 or 23 genes of TC chromosome X up- or down-regulated, respectively, indicating that biological functions of TCs may be mainly fulfilled through the network constructed by the telopodes with connecting cells and act as an integrated modulator to regulate neural function and immune responses, promote vessel formation and cellular growth and migration, and participate in tissue remodeling and repair. TCs may have the potential function to support cell survival, anti-senescence, and protection from stresses. Pulmonary TCs with stronger NF-kB-dominant activities may play the important and critical roles in pathogeneses of lung diseases, although further studies on those chromosome X genes of pulmonary TC are needed.

Abbreviations

TC: 

telocyte

TC10: 

telocytes isolated and cultured from mouse lungs on days 10

TC5: 

telocytes isolated and cultured from mouse lungs on days 5

MSC: 

mesenchymal stem cell

Fb: 

fibroblast

ATII: 

alveolar type II cell

ABC: 

airway basal cell

PAC: 

proximal airway cell

T-BL: 

CD8+ T cells come from bronchial lymph node

T-L: 

CD8+ T cells from lungs

Declarations

Authors' contributions

YCZ planned and performed studies, analyzed data and wrote the manuscript; and XDW made study plans, overviewed data, and prepare the manuscript. MHZ, DLS, and LY analysed data and performed data mining. All authors read and approved the final manuscript.

Acknowledgements

The work was supported by Shanghai Leading Academic Discipline Project (B115), Zhongshan Distinguished Professor Grant (XDW), The National Nature Science Foundation of China (91230204, 81270099, 81320108001, 81270131), The Shanghai Committee of Science and Technology (12JC1402200, 12431900207, 11410708600).

Compliance with ethical guidelines

Competing interests The authors declare that they have no competing interests.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Zhongshan Hospital, Shanghai Institute of Clinical Bioinformatics, Fudan University Center for Bioinformatics, Fudan University

References

  1. Popescu L, Faussone-Pellegrini MS. TELOCYTES–a case of serendipity: the winding way from Interstitial Cells of Cajal (ICC), via Interstitial Cajal-Like Cells (ICLC) to TELOCYTES. J Cell Mol Med. 2010;14:729–40.PubMed CentralView ArticlePubMedGoogle Scholar
  2. Gherghiceanu M, Popescu L. Cardiomyocyte precursors and telocytes in epicardial stem cell niche: electron microscope images. J Cell Mol Med. 2010;14:871–7.PubMed CentralView ArticlePubMedGoogle Scholar
  3. Zheng Y, Li H, Manole CG, Sun A, Ge J, Wang X. Telocytes in trachea and lungs. J Cell Mol Med. 2011;15:2262–8. doi:10.1111/j.1582-4934.2011.01404.x.PubMed CentralView ArticlePubMedGoogle Scholar
  4. Cantarero Carmona I, Luesma Bartolomé MJ, Junquera Escribano C. Identification of telocytes in the lamina propria of rat duodenum: transmission electron microscopy. J Cell Mol Med. 2011;15:26–30. doi:10.1111/j.1582-4934.2010.01207.x.View ArticlePubMedGoogle Scholar
  5. Rusu MC, Nicolescu MI, Jianu AM, Lighezan R, Manoiu VS, Paduraru D. Esophageal telocytes and hybrid morphologies. Cell Biol Int. 2012;36:1079–88. doi:10.1042/cbi20120007.View ArticlePubMedGoogle Scholar
  6. Xiao J, Wang F, Liu Z, Yang C. Telocytes in liver: electron microscopic and immunofluorescent evidence. J Cell Mol Med. 2013;17:1537–42. doi:10.1111/jcmm.12195.PubMed CentralView ArticlePubMedGoogle Scholar
  7. Popescu LM, Manole E, Serboiu CS, Manole CG, Suciu LC, Gherghiceanu M, et al. Identification of telocytes in skeletal muscle interstitium: implication for muscle regeneration. J Cell Mol Med. 2011;15:1379–92. doi:10.1111/j.1582-4934.2011.01330.x.PubMed CentralView ArticlePubMedGoogle Scholar
  8. Gevaert T, De Vos R, Van Der Aa F, Joniau S, van den Oord J, Roskams T, et al. Identification of telocytes in the upper lamina propria of the human urinary tract. J Cell Mol Med. 2012;16:2085–93. doi:10.1111/j.1582-4934.2011.01504.x.PubMed CentralView ArticlePubMedGoogle Scholar
  9. Qi G, Lin M, Xu M, Manole CG, Wang X, Zhu T. Telocytes in the human kidney cortex. J Cell Mol Med. 2012;16:3116–22. doi:10.1111/j.1582-4934.2012.01582.x.PubMed CentralView ArticlePubMedGoogle Scholar
  10. Rusu MC, Mirancea N, Manoiu VS, Valcu M, Nicolescu MI, Paduraru D. Skin telocytes. Ann Anat. 2012;194:359–67. doi:10.1016/j.aanat.2011.11.007.View ArticlePubMedGoogle Scholar
  11. Mou Y, Wang Y, Li J, Lu S, Duan C, Du Z, et al. Immunohistochemical characterization and functional identification of mammary gland telocytes in the self-assembly of reconstituted breast cancer tissue in vitro. J Cell Mol Med. 2013;17:65–75. doi:10.1111/j.1582-4934.2012.01646.x.PubMed CentralView ArticlePubMedGoogle Scholar
  12. Nicolescu MI, Popescu LM. Telocytes in the interstitium of human exocrine pancreas: ultrastructural evidence. Pancreas. 2012;41:949–56. doi:10.1097/MPA.0b013e31823fbded.View ArticlePubMedGoogle Scholar
  13. Popescu BO, Gherghiceanu M, Kostin S, Ceafalan L, Popescu LM. Telocytes in meninges and choroid plexus. Neurosci Lett. 2012;516:265–9. doi:10.1016/j.neulet.2012.04.006.View ArticlePubMedGoogle Scholar
  14. Hatta K, Huang ML, Weisel RD, Li RK. Culture of rat endometrial telocytes. J Cell Mol Med. 2012;16:1392–6. doi:10.1111/j.1582-4934.2012.01583.x.PubMed CentralView ArticlePubMedGoogle Scholar
  15. Suciu L, Popescu LM, Gherghiceanu M, Regalia T, Nicolescu MI, Hinescu ME, et al. Telocytes in human term placenta: morphology and phenotype. Cells Tissues Organs. 2010;192:325–39. doi:10.1159/000319467.View ArticlePubMedGoogle Scholar
  16. Nicolescu MI, Bucur A, Dinca O, Rusu MC, Popescu LM. Telocytes in parotid glands. Anat Rec Hoboken. 2012;295:378–85. doi:10.1002/ar.21540.View ArticlePubMedGoogle Scholar
  17. Corradi LS, Jesus MM, Fochi RA, Vilamaior PS, Justulin LA Jr, Goes RM, et al. Structural and ultrastructural evidence for telocytes in prostate stroma. J Cell Mol Med. 2013;17:398–406. doi:10.1111/jcmm.12021.PubMed CentralView ArticlePubMedGoogle Scholar
  18. Luesma MJ, Gherghiceanu M, Popescu LM. Telocytes and stem cells in limbus and uvea of mouse eye. J Cell Mol Med. 2013;17:1016–24. doi:10.1111/jcmm.12111.PubMed CentralView ArticlePubMedGoogle Scholar
  19. Gherghiceanu M, Popescu LM. Cardiac telocytes—their junctions and functional implications. Cell Tissue Res. 2012;348:265–79.PubMed CentralView ArticlePubMedGoogle Scholar
  20. Creţoiu SM, Creţoiu D, Popescu LM. Human myometrium—the ultrastructural 3D network of telocytes. J Cell Mol Med. 2012;16:2844–9.PubMed CentralView ArticlePubMedGoogle Scholar
  21. Popescu L, Gherghiceanu M, Cretoiu D, Radu E. The connective connection: interstitial cells of Cajal (ICC) and ICC-like cells establish synapses with immunoreactive cells: electron microscope study in sity. J Cell Mol Med. 2005;9:714–30.View ArticlePubMedGoogle Scholar
  22. Popescu LM, Gherghiceanu M, Suciu LC, Manole CG, Hinescu ME. Telocytes and putative stem cells in the lungs: electron microscopy, electron tomography and laser scanning microscopy. Cell Tissue Res. 2011;345:391–403.PubMed CentralView ArticlePubMedGoogle Scholar
  23. Hinescu ME, Gherghiceanu M, Suciu L, Popescu LM. Telocytes in pleura: two- and three-dimensional imaging by transmission electron microscopy. Cell Tissue Res. 2011;343:389–97. doi:10.1007/s00441-010-1095-0.PubMed CentralView ArticlePubMedGoogle Scholar
  24. Vannucchi MG, Bani D, Faussone-Pellegrini MS. Telocytes contribute as cell progenitors and differentiation inductors in tissue regeneration. Curr Stem cell Res Ther 2015 [Epub ahead of print].Google Scholar
  25. Cretoiu SM, Popescu LM. Telocytes revisited. Biomol Concept. 2014;5:353–69.View ArticleGoogle Scholar
  26. Rosenbaum ST, Svalø J, Nielsen K, Larsen T, Jørgensen JC, Bouchelouche P. Immunolocalization and expression of small-conductance calcium-activated potassium channels in human myometrium. J Cell Mol Med. 2012;16:3001–8.PubMed CentralView ArticlePubMedGoogle Scholar
  27. Sheng J, Shim W, Lu J, Lim SY, Ong BH, Lim TS, et al. Electrophysiology of human cardiac atrial and ventricular telocytes. J Cell Mol Med. 2014;18:355–62.PubMed CentralView ArticlePubMedGoogle Scholar
  28. Zheng Y, Bai C, Wang XD. Potential significance of telocytes in the pathogenesis of lung diseases. Expert Rev Respir Med. 2012;6(1):45–9. doi:10.1586/ers.11.91.
  29. Vannucchi MG, Traini C, Manetti M, Ibba-Manneschi L, Faussone-Pellegrini MS. Telocytes express PDGFRα in the human gastrointestinal tract. J Cell Mol Med. 2013;17:1099–108.PubMed CentralView ArticlePubMedGoogle Scholar
  30. Zheng Y, Zhang M, Qian M, Wang L, Cismasiu VB, Bai C, et al. Genetic comparison of mouse lung telocytes with mesenchymal stem cells and fibroblasts. J Cell Mol Med. 2013;17:567–77. doi:10.1111/jcmm.12052.PubMed CentralView ArticlePubMedGoogle Scholar
  31. Cismasiu VB, Radu E, Popescu LM. miR-193 expression differentiates telocytes from other stromal cells. J Cell Mol Med. 2011;15:1071–4. doi:10.1111/j.1582-4934.2011.01325.x.PubMed CentralView ArticlePubMedGoogle Scholar
  32. Gherghiceanu M, Popescu LM. Cardiac telocytes—their junctions and functional implications. Cell Tissue Res. 2012;348:265–79. doi:10.1007/s00441-012-1333-8.PubMed CentralView ArticlePubMedGoogle Scholar
  33. Manole CG, Cismasiu V, Gherghiceanu M, Popescu LM. Experimental acute myocardial infarction: telocytes involvement in neo-angiogenesis. J Cell Mol Med. 2011;15:2284–96. doi:10.1111/j.1582-4934.2011.01449.x.PubMed CentralView ArticlePubMedGoogle Scholar
  34. Sun X, Zheng M, Zhang M, Qian M, Zheng Y, Li M, et al. Differences in the expression of chromosome 1 genes between lung telocytes and other cells: mesenchymal stem cells, fibroblasts, alveolar type II cells, airway epithelial cells and lymphocytes. J Cell Mol Med. 2014;18:801–10.PubMed CentralView ArticlePubMedGoogle Scholar
  35. Zheng M, Sun X, Zhang M, Qian M, Zheng Y, Li M, et al. Variations of chromosomes 2 and 3 gene expression profiles among pulmonary telocytes, pneumocytes, airway cells, mesenchymal stem cells and lymphocytes. J Cell Mol Med. 2014;18:2044–60.PubMed CentralView ArticlePubMedGoogle Scholar
  36. Wang J, Ye L, Jin M, Wang X. Global analyses of Chromosome 17 and 18 genes of lung telocytes compared with mesenchymal stem cells, fibroblasts, alveolar type II cells, airway epithelial cells, and lymphocytes. Biol Direct. 2015;10:9.PubMed CentralView ArticlePubMedGoogle Scholar
  37. Xu Y, Ikegami M, Wang Y, Matsuzaki Y, Whitsett JA. Gene expression and biological processes influenced by deletion of Stat3 in pulmonary type II epithelial cells. BMC Genom. 2007;8:455. doi:10.1186/1471-2164-8-455.View ArticleGoogle Scholar
  38. Chen W, Ware LB. Prognostic factors in the acute respiratory distress syndrome. Clin Transl Med. 2015;4(1):65. doi:10.1186/s40169-015-0065-2.PubMedGoogle Scholar
  39. Ross MT, Grafham DV, Coffey AJ, Scherer S, McLay K, Muzny D, et al. The DNA sequence of the human X chromosome. Nature. 2005;434:325–37.PubMed CentralView ArticlePubMedGoogle Scholar
  40. Sia GM, Clem RL, Huganir RL. The human language-associated gene SRPX2 regulates synapse formation and vocalization in mice. Science. 2013;342:987–91. doi:10.1126/science.1245079.PubMed CentralView ArticlePubMedGoogle Scholar
  41. Yamada T, Oshima T, Yoshihara K, Sato T, Nozaki A, Shiozawa M, et al. Impact of overexpression of Sushi repeat-containing protein X-linked 2 gene on outcomes of gastric cancer. J Surg Oncol. 2014;109:836–40. doi:10.1002/jso.23602.View ArticlePubMedGoogle Scholar
  42. Tanaka K, Arao T, Tamura D, Aomatsu K, Furuta K, Matsumoto K, et al. SRPX2 is a novel chondroitin sulfate proteoglycan that is overexpressed in gastrointestinal cancer. PLoS One. 2012;7:e27922. doi:10.1371/journal.pone.0027922.PubMed CentralView ArticlePubMedGoogle Scholar
  43. Tanaka K, Arao T, Maegawa M, Matsumoto K, Kaneda H, Kudo K, et al. SRPX2 is overexpressed in gastric cancer and promotes cellular migration and adhesion. Int J Cancer. 2009;124:1072–80. doi:10.1002/ijc.24065.View ArticlePubMedGoogle Scholar
  44. Saggu G, Cortes C, Emch HN, Ramirez G, Worth RG, Ferreira VP. Identification of a novel mode of complement activation on stimulated platelets mediated by properdin and C3(H2O). J Immunol. 2013;190:6457–67. doi:10.4049/jimmunol.1300610.PubMed CentralView ArticlePubMedGoogle Scholar
  45. Wang XY, Berezin I, Mikkelsen HB, Der T, Bercik P, Collins SM, et al. Pathology of interstitial cells of Cajal in relation to inflammation revealed by ultrastructure but not immunohistochemistry. Am J Pathol. 2002;160:1529–40.PubMed CentralView ArticlePubMedGoogle Scholar
  46. Popescu LM, Gherghiceanu M, Cretoiu D, Radu E. The connective connection: interstitial cells of Cajal (ICC) and ICC-like cells establish synapses with immunoreactive cells. Electron microscope study in situ. J Cell Mol Med. 2005;9:714–30.View ArticlePubMedGoogle Scholar
  47. Massella L, Muda AO, Faraggiana T, Bette C, Renieri A, Rizzoni G. Epidermal basement membrane alpha 5(IV) expression in females with Alport syndrome and severity of renal disease. Kidney Int. 2003;64:1787–91. doi:10.1046/j.1523-1755.2003.00251.x.View ArticlePubMedGoogle Scholar
  48. Su LL, Iwai H, Lin JT, Fathman CG. The transmembrane E3 ligase GRAIL ubiquitinates and degrades CD83 on CD4 T cells. J Immunol. 2009;183:438–44. doi:10.4049/jimmunol.0900204.PubMed CentralView ArticlePubMedGoogle Scholar
  49. MacKenzie DA, Schartner J, Lin J, Timmel A, Jennens-Clough M, Fathman CG, et al. GRAIL is up-regulated in CD4 + CD25 + T regulatory cells and is sufficient for conversion of T cells to a regulatory phenotype. J Biol Chem. 2007;282:9696–702. doi:10.1074/jbc.M604192200.View ArticlePubMedGoogle Scholar
  50. Rusu MC, Jianu AM, Mirancea N, Didilescu AC, Manoiu VS, Paduraru D. Tracheal telocytes. J Cell Mol Med. 2012;16:401–5. doi:10.1111/j.1582-4934.2011.01465.x.PubMed CentralView ArticlePubMedGoogle Scholar
  51. Chen X, Zheng Y, Manole CG, Wang X, Wang Q. Telocytes in human oesophagus. J Cell Mol Med. 2013;17:1506–12. doi:10.1111/jcmm.12149.PubMed CentralView ArticlePubMedGoogle Scholar
  52. King PT. Inflammation in chronic obstructive pulmonary disease and its role in cardiovascular disease and lung cancer. Clin Transl Med. 2015;4:26.PubMed CentralView ArticleGoogle Scholar
  53. Ho SC, Lee KY, Chan YF, Kuo LW, Ito K, Adcock IM, et al. Neutrophil elastase represses IL-8/CXCL8 synthesis in human airway smooth muscle cells through induction of NF-kappa B repressing factor. J Immunol. 2009;183:411–20. doi:10.4049/jimmunol.0803729.View ArticlePubMedGoogle Scholar
  54. Swindell WR, Sarkar MK, Stuart PE, Voorhees JJ, Elder JT, Johnston A, Gudjonsson JE. Psoriasis drug development and GWAS interpretation through in silico analysis of transcription factor bindingsites. Clin Transl Med. 2015;4:13. doi:10.1186/s40169-015-0054-5.PubMed CentralView ArticlePubMedGoogle Scholar
  55. López E, Muñoz S, Pascual J, Madero L. Relevant phosphoproteomic and mass spectrometry: approaches useful in clinical research. Clin Transl Med. 2012;1:2.PubMed CentralView ArticlePubMedGoogle Scholar
  56. Graves CA, Abboodi FF, Tomar S, Wells J, Pirisi L. The translational significance of epithelial-mesenchymal transition in head and neck cancer. Clin Transl Med. 2014;3:39.View ArticleGoogle Scholar
  57. Gu BW, Bessler M, Mason PJ. A pathogenic dyskerin mutation impairs proliferation and activates a DNA damage response independent of telomere length in mice. Proc Natl Acad Sci U S A. 2008;105:10173–8. doi:10.1073/pnas.0803559105.PubMed CentralView ArticlePubMedGoogle Scholar
  58. Johnston JJ, Gropman AL, Sapp JC, Teer JK, Martin JM, Liu CF, et al. The phenotype of a germline mutation in PIGA: the gene somatically mutated in paroxysmal nocturnal hemoglobinuria. Am J Hum Genet. 2012;90:295–300. doi:10.1016/j.ajhg.2011.11.031.PubMed CentralView ArticlePubMedGoogle Scholar
  59. Nava C, Lamari F, Heron D, Mignot C, Rastetter A, Keren B, et al. Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE. Transl Psychiatry. 2012;2:e179. doi:10.1038/tp.2012.102.PubMed CentralView ArticlePubMedGoogle Scholar

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© Zhu et al. 2015

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