Aims: Microarray data were analyzed using bioinformatic tools to screen marker genes of human mesenchymal stem cells (hMSC) in response to bone morphogenetic protein 6 (BMP6). Results: A total of 190 differentially expressed genes were identified. The interaction network was divided into three functional modules. These genes were connected with BMP signaling pathways and regulation of cell processes, while NOG and BMPR2 participated in the transforming growth factor-beta signal pathway. Besides, several related small molecules were acquired. Conclusion: Marker genes in osteogenic responses to BMP6 treatment for hMSC were screened with microarray data along with elaborate function analysis by bioinformatics. NOG and BMPR2 showed potential to become indicators to monitor the directed differentiation of hMSC into osteoblasts, which can be used for bone disease treatment. Moreover, small molecules such as W-13 were retrieved and provided directions for future drug design.
BaeS, ShimSH, ParkCWet al.2011. Combined omics analysis identifies transmembrane 4 L6 family member 1 as a surface protein marker specific to human mesenchymal stem cells. Stem Cells Dev, 20:197-203.
3.
BernsteinBE, BirneyE, DunhamIet al.2012. An integrated encyclopedia of DNA elements in the human genome. Nature, 489:57-74.
4.
BerrizGF, BeaverJE, CenikCet al.2009. Next generation software for functional trend analysis. Bioinformatics, 25:3043-3044.
5.
ChenG, DengC, LiYP. 2012. TGF-beta and BMP signaling in osteoblast differentiation and bone formation. Int J Biol Sci, 8:272-288.
6.
ChenJL, HuntP, McElvainMet al.1997. Osteoblast precursor cells are found in CD34+ cells from human bone marrow. Stem Cells, 15:368-377.
7.
ChielliniC, GrenninglohG, CochetOet al.2008. Stathmin-like 2, a developmentally-associated neuronal marker, is expressed and modulated during osteogenesis of human mesenchymal stem cells. Biochem Biophys Res Commun, 374:64-68.
8.
DuncanD, ProdduturiN, ZhangB. 2010. WebGestalt2: an updated and expanded version of the Web-based Gene Set Analysis Toolkit. BMC Bioinformatics, 11:P10.
9.
FriedensteinAJ, ChailakhyanRK, GerasimovUV. 1987. Bone marrow osteogenic stem cells: in vitro cultivation and transplantation in diffusion chambers. Cell Tissue Kinet, 20:263-272.
10.
FuLJ, ZhouAQ, HuangMRet al.2008. A novel mutation in the BMPR2 gene in familial pulmonary arterial hypertension. Chin Med J (Engl), 121:399-404.
11.
FujitaA, SatoJR, Rodrigues LdeOet al.2006. Evaluating different methods of microarray data normalization. BMC Bioinformatics, 7:469.
12.
GazzerroE, GangjiV, CanalisE. 1998. Bone morphogenetic proteins induce the expression of noggin, which limits their activity in cultured rat osteoblasts. J Clin Invest, 102:2106-2114.
13.
GerhartJ, ScheinfeldVL, MilitoTet al.2011. Myo/Nog cell regulation of bone morphogenetic protein signaling in the blastocyst is essential for normal morphogenesis and striated muscle lineage specification. Dev Biol, 359:12-25.
GonzalezR, MakiCB, PacchiarottiJet al.2007. Pluripotent marker expression and differentiation of human second trimester Mesenchymal Stem Cells. Biochem Biophys Res Commun, 362:491-497.
KassemM, KristiansenM, AbdallahBM. 2004. Mesenchymal stem cells: cell biology and potential use in therapy. Basic Clin Pharmacol Toxicol, 95:209-214.
18.
LambJ. 2007. The Connectivity Map: a new tool for biomedical research. Nat Rev Cancer, 7:54-60.
19.
LambJ, CrawfordED, PeckDet al.2006. The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Science, 313:1929-1935.
20.
LoriesRJ, DaansM, DereseIet al.2006. Noggin haploinsufficiency differentially affects tissue responses in destructive and remodeling arthritis. Arthritis Rheum, 54:1736-1746.
21.
LuoW, FriedmanMS, SheddenKet al.2009. GAGE: generally applicable gene set enrichment for pathway analysis. BMC Bioinformatics, 10:161.
22.
MarieP. 1997. Growth factors and bone formation in osteoporosis: roles for IGF-I and TGF-beta. Rev Rhum Engl Ed, 64:44-53.
23.
MasudaH, AnwarSS, BuhringHJet al.2012. A novel marker of human endometrial mesenchymal stem-like cells. Cell Transplant, 21:2201-2214.
24.
OkamotoM, MuraiJ, YoshikawaHet al.2006. Bone morphogenetic proteins in bone stimulate osteoclasts and osteoblasts during bone development. J Bone Miner Res, 21:1022-1033.
25.
OriguchiN, IshidouY, NagamineTet al.1998. The spatial and temporal immunolocalization of TGF-beta 1 and bone morphogenetic protein-2/-4 in phallic bone formation in inbred Sprague Dawley male rats. In Vivo, 12:473-480.
26.
PatilA, NakaiK, NakamuraH. 2011. HitPredict: a database of quality assessed protein-protein interactions in nine species. Nucleic Acids Res, 39:D744-D749.
27.
PatilA, NakamuraH. 2005. Filtering high-throughput protein-protein interaction data using a combination of genomic features. BMC Bioinformatics, 6:100.
28.
RiekstinaU, CakstinaI, ParfejevsVet al.2009. Embryonic stem cell marker expression pattern in human mesenchymal stem cells derived from bone marrow, adipose tissue, heart and dermis. Stem Cell Rev, 5:378-386.
29.
RubinLJ. 2008. BMPR2 mutation and outcome in pulmonary arterial hypertension: clinical relevance to physicians and patients. Am J Respir Crit Care Med, 177:1300-1301.
30.
SawantA, ChandaD, IsayevaTet al.2012. Noggin is novel inducer of mesenchymal stem cell adipogenesis: implications for bone health and obesity. J Biol Chem, 287:12241-12249.
31.
SmythGK. 2005. Limma: linear models for microarray data. GentlemanR, CareyV, DudoitSet al.Bioinformatics and Computational Biology Solutions Using R and Bioconductor. Springer: New York, 397-420.
32.
StroblJS, PetersonVA. 1992. Tamoxifen-resistant human breast cancer cell growth: inhibition by thioridazine, pimozide and the calmodulin antagonist, W-13. J Pharmacol Exp Ther, 263:186-193.
33.
TroyanskayaO, CantorM, SherlockGet al.2001. Missing value estimation methods for DNA microarrays. Bioinformatics, 17:520-525.
34.
WeiJW, HickieRA, KlaassenDJ. 1983. Inhibition of human breast cancer colony formation by anticalmodulin agents: trifluoperazine, W-7, and W-13. Cancer Chemother Pharmacol, 11:86-90.
35.
WenZ, WangZ, WangSet al.2011. Discovery of molecular mechanisms of traditional Chinese medicinal formula Si-Wu-Tang using gene expression microarray and connectivity map. PLoS One, 6:e18278.
36.
YoonBS, OvchinnikovDA, YoshiiIet al.2005. Bmpr1a and Bmpr1b have overlapping functions and are essential for chondrogenesis in vivo. Proc Natl Acad Sci U S A, 102:5062-5067.
37.
ZengY, QuX, LiHet al.2012. MicroRNA-100 regulates osteogenic differentiation of human adipose-derived mesenchymal stem cells by targeting BMPR2. FEBS Lett, 586:2375-2381.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
