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Identification of Differential Genes Expression Profiles and Pathways of Bone Marrow Mesenchymal Stem Cells of Adolescent Idiopa

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Identification of Differential Genes Expression Profiles and Pathways of Bone Marrow Mesenchymal Stem Cells of Adolescent Idiopa SPINE Volume 41, Number 10, pp 840–855 ß 2016 Wolters Kluwer Health, Inc. All rights reserved BASIC SCIENCE Identification of Differential Genes Expression Profiles and Pathways of Bone Marrow Mesenchymal Stem Cells of Adolescent Idiopathic Scoliosis Patients by Microarray and Integrated Gene Network Analysis Qianyu Zhuang, MD,Ã Wenzhe Mao, PhD,y Pengchao Xu, PhD,y Hongling Li, PhD,y Zhao Sun, PhD,y Shugang Li, PhD,Ã Guixing Qiu, MD,Ã Jing Li, PhD,y and Jianguo Zhang, MDÃ transduction network analysis of DEGs contained in significant Study Design. Microarray approach and integrated gene net- pathways, 24 potential crucial genes were selected for validation work analysis. by reverse transcription polymerase chain reaction. Objective. To explore the differential genetic expression pro- Results. There are 1027 previously unrecognized DEGs in BM- file, gene ontology terms, and Kyoto Encyclopedia of Genes and MSCs from AIS patients. Pathway analysis revealed dysregulated Genomes pathways in bone marrow mesenchymal stem cells mitogen-activated protein kinase (MAPK) signaling pathway, PI3K- (BM-MSCs) of idiopathic scoliosis (AIS) and non-AIS controls. Akt signaling pathway, calcium signaling pathway, peroxisome Summary of Background Data. The pathogenesis of adoles- proliferator-activated receptor (PPAR) signaling pathway, ubiquitin- cent AIS and the accompanying generalized osteopenia remain mediated proteolysis, and Notch signaling pathway, all of which unclear. Our previous study suggested increased proliferation have been reported to play an important role in regulating the ability and decreased osteogenic differentiation ability of BM- osteogenic or adipogenic differentiation of MSCs. Furthermore, MSCs of AIS. Therefore, we hypothesized that MSCs may play a gene signal transduction networks analysis indicated that mitogen- significant role in the etiology and pathogenesis of AIS. Methods. In this study, microarray analysis was used to identify activated protein kinase kinase 1 (MAP2K1), SMAD family member differentially expressed genes (DEGs) of BM-MSCs from AIS 3 (SMAD3), homeobox C6 (HOXC6), heat shock 70kDa protein 6 patients compared with those from healthy individuals. Compre- (HSPA6), general transcription factor IIi (GTF2I), CREB binding hensive bioinformatics analyses were then used to enrich datasets protein (CREBBP), phosphoinositide-3-kinase, regulatory subunit 2 for gene ontology and pathway. Based on the gene signal (PIK3R2), and dual specificity phosphatase 2 (DUSP2) may play essential roles in AIS pathogenesis and accompanied osteopenia. Conclusion. This study reports the differential genes expres- From the ÃDepartment of Orthopedics, Peking Union Medical College sion profiles of BM-MSCs from AIS patients and related potential y Hospital, Beijing, P.R. China; and Center of Excellence in Tissue Engin- pathways for the first time. These previously unrecognized genes eering, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, and molecular pathways might play a significant role in not only Beijing, P.R. China. the causal mechanism of osteopenia in AIS, but also the AIS Acknowledgment date: June 30, 2015. First revision date: October 16, initiation and development. The identification of these candidate 2015. Acceptance date: November 2, 2015. genes provides novel insight into the underlying etiological Qianyu Zhuang and Wenzhe Mao contributed equally to this paper as the mechanisms of AIS. first authors. Key words: adolescent idiopathic scoliosis, bone marrow Jing Li and Jianguo Zhang contributed equally to this paper as the corre- mesenchymal stem cells, differentially expressed gene, gene sponding authors. expression profiles, microarray, osteopenia. The manuscript submitted does not contain information about medical Level of Evidence: N/A. device(s)/drug(s). Spine 2016;41:840–855 The National Natural Science Foundation of China (81272054, 81171673) funds were received to support this work. Relevant financial activities outside the submitted work: board membership, consultancy. Address correspondence and reprint requests to Jianguo Zhang, MD and tiology of adolescent idiopathic scoliosis (AIS) Professor, Peking Union Medical College Hospital, 1 Shuai Fu Yuan Beijing remains unclear.1–3 Low bone mineral density in 100730 P. R. China; E-mail: [email protected] E AIS reported by many authors suggests the possibility DOI: 10.1097/BRS.0000000000001394 of bone metabolism disturbance as an underlying 840 www.spinejournal.com May 2016 Copyright © 2016 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. BASIC SCIENCE Identification of DEGs of BM-MSCs of AIS Patients Zhuang et al mechanism.4–8 In spite of the controversy engendered by for the following experiments. Primary antibodies against extensive hypotheses,9–12 there is a growing consensus that human CD29, CD31, CD34, CD44, CD45, CD73, and anomalies of bone growth and development are strongly CD105 (BD Biosciences) were used for immunophenotype related to the onset and progression of scoliosis.13-17 analysis of BM-MSCs. Mesenchymal stem cells (MSCs) act as progenitors of To identify the MSC capacity for multilineage differen- osteoblasts and regulate osteoclastogenesis via Receptor Acti- tiation, MSCs were cultured under differentiation con- vator for Nuclear Factor-k B Ligand and osteoprotegerin ditions. As previously described,21 cells were stained with expression.18–20 In addition, MSCs are indispensable in both the ALP staining kit (Beyotime, China) to reveal osteogenic intramembranous and endochondral bone formation.20 differentiation and stained with fresh Oil Red O solution Given the functional characteristics of MSCs in bone for- (Sigma, St.Louis, MO, USA) to show lipid droplets in mation and resorption, we hypothesized that MSCs play a induced cells. significant role in the etiology and pathogenesis of AIS. Our previous study21 identified 25 differentially Total RNA Extraction and Microarray Assay expressed proteins in MSCs from AIS patients using two- RNA was extracted from MSCs using TRIzol Reagent dimensional differential gel electrophoresis (2D-DIGE) and (Invitrogen, Carlsbad, CA, USA). Following purification MS-based proteomic approaches, and the function analysis with an RNeasy kit (Qiagen, Valencia, CA), cDNA was of these proteins suggested increased proliferation ability of generated using One-Cycle Target Labeling and Control MSCs and decreased osteogenic differentiation ability in Reagents (Affymetrix, Santa Clara, CA), and cRNA was AIS. These results were further supported by Park et al’s created with a GeneChip IVT Labeling Kit (Affymetrix, study,22 which revealed lower osteogenic differentiation Santa Clara, CA). Biotin-labeled, fragmented (200 nt) abilities and alkaline phosphatase (ALP) activities of MSCs cRNA was then hybridized for 16 hours at 458C to Affy- from AIS patients, indicating that the decreased osteogenic metrix GeneChip HumanTranscript 2.0 arrays (Affyme- differentiation ability of MSCs might be a possible mech- trix). GeneChips were washed and stained in the anism leading to low bone mass in AIS. In addition, a recent Affymetrix Fluidics Station 450. GeneChips were scanned study disclosed that the adipogenic ability of MSCs from by using Affymetrix GeneChip Command Console (AGCC) AIS girls was lower than controls.23 which installed in GeneChip Scanner 3000 7G. The data Based on these findings, we used a microarray approach were analyzed with robust multichip analysis algorithm in this study to further investigate specific alterations in the using Affymetrix default analysis settings and global scaling genetic expression profile of MSCs from AIS patients. as normalization method. Values presented are log2 robust Furthermore, the gene expression data were processed by multichip analysis signal intensity. gene ontology (GO), Kyoto Encyclopedia of Genes and Differentially expressed genes (DEGs) were identified Genomes (KEGG) orthology, and Signal network, which based on random-variance model t test and false discovery are effective bioinformatics analytical methods. rate (FDR) analysis. P < 0.05 and FDR < 0.05 was set as a threshold. Cluster 3.0 and TreeView analysis (Stanford MATERIALS AND METHODS University, California, USA) were performed to generate a dendrogram for each cluster of genes based on their Patients and Specimens expression profiling similarities. Bone marrow (BM) aspirates were obtained from 10 AIS patients (mean age 14.3 yr, range 12–17) and five non-AIS GO and Pathway Analysis patients with lower-leg fracture (mean age 14.6 yr, range Functional analysis of DEGs was carried out by the GO 12–17) (Table 1). In the AIS group, all of the patients under- project (http://www.geneontology.org) on the basis of bio- went full clinical and radiological examinations to rule out logical process [31], while pathway analysis was used to find other causes of scoliosis and to ascertain the diagnosis of out the significant pathway of the differential genes accord- AIS.24,25 In the control group, each of the five age- and sex- ing to KEGG (http://www.genome.jp/kegg/). The Fisher matched subjects had a straight spine and a normal forward exact test and x2 test were used to classify the GO category bending test on the physical examination. They were con- and pathway, and the FDR was calculated to correct the P firmed to be free of any associated medical diseases or spinal value. P < 0.05 and FDR < 0.1 were
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