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The Profile of Gene Expression of Human Marrow Mesenchymal Stem Cells

Center for Cell Therapy and Regional Blood Center, Department of Clinical Medicine, Faculty of Medicine, Ribeirão Preto, Brazil

Key Words. Mesenchymal stem cells • SAGE • Gene expression • Hematopoesis

Correspondence: Marco A. Zago, M.D., Ph.D., Hemocentro, R. Tenente Catao, Roxo, 2501, 14051-140 Ribeirao Preto, Brazil. Telephone: 55-16-3963-9361; Fax: 55-16-3963-9309; e-mail: marazago{at}usp.br

	ABSTRACT

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Mesenchymal stem cells (MSCs) are multipotent precursors present in adult bone marrow, that differentiate into osteoblasts, adipocytes and myoblasts, and play important roles in hematopoiesis. We examined gene expression of these cells by serial analysis of gene expression, and found that collagen I, secreted protein acidic and rich in cysteine (osteonectin), transforming growth factor beta- (TGF-ß) induced, cofilin, galectin-1, laminin-receptor 1, cyclophilin A, and matrix metalloproteinase-2 are among the most abundantly expressed genes. Comparison with a library of CD34⁺ cells revealed that MSCs had a larger number of expressed genes in the categories of cell adhesion molecule, extracellular and development. The two types of cells share abundant transcripts of many genes, some of which are highly expressed in myeloid progenitors (thymosin-ß4 and ß10, fos and jun). Interleukin-11 (IL-11), IL-15, IL-27 and IL-10R, IL-13R and IL-17R were the most expressed genes among the cytokines and their receptors in MSCs, and various interactions can be predicted with the CD34⁺ cells. MSCs express several transcripts for various growth factors and genes suggested to be enriched in stem cells. This study reports the profile of gene expression in MSCs and identifies the important contribution of extracellular protein products, adhesion molecules, cell motility, TGF-ß signaling, growth factor receptors, DNA repair, protein folding, and ubiquination as part of their transcriptome.

	INTRODUCTION

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In addition to hematopoietic cells, bone marrow (BM) comprises a heterogeneous population of cells that plays a key role in hematopoiesis, referred to as marrow stromal cells, including endothelial cells, adipocytes, osteoblasts and fibroblasts. Mesenchymal stem cells (MSCs) are multipotent precursors present in adult BM, capable of differentiating into osteoblasts, adipocytes, and myoblasts [1–3]. Although they represent only about 0.01%-0.001% of the marrow cells, they can be separated from the hematopoietic stem cells (HSC) because they adhere to glass and plastic [4]. Once in culture they proliferate to originate spindle-shaped cells in confluent cultures, but exhibit a variable morphology and differentiation potential under appropriate conditions. These cells are present in adult BM and peripheral blood, and in the fetal BM and liver [5]. Besides their ability to give rise to cells that constitute the BM stroma, they have been reported to originate glial and neuronal cells, whereas protein and mRNA expression have demonstrated epithelial, endothelial, and neuronal markers. A mesoderm progenitor that gives rise to mesenchymal and to endothelial cells has been identified [6]. Although part of these diverse results is probably caused by the fact that the majority of studies have dealt with heterogeneous cell populations that differ because of the preparation protocols or the time in culture, Tremain et al. have demonstrated that markers of various differentiation lineages are concomitantly present in a colony derived from a single MSC [7] providing evidence for their stem-cell (SC) nature.

The wide therapeutic potential of these cells has attracted much attention to them [2, 8], and in vitro and in vivo functional studies and therapeutic trials have been started [9]. However, the transcriptome and broad gene expression profile of a well-defined MSC population has not been described in detail. In addition to the study of Tremain et al. [7], the reports have been limited to analyzing the expression of gene families under particular experimental conditions. We have employed serial analysis of gene expression (SAGE) to examine the gene expression of MSC obtained from normal human BM and compared it with the expression profile of CD34⁺ hematopoietic precursors.

	MATERIALS AND METHODS

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Isolation and Culture of Human MSCs
Human MSCs were obtained by aspiration from the iliac crest of a BM donor who gave consent after full information. The mononuclear cells were separated by ficol gradient (Ficoll-Paque; Amersham Biosciences; Peapack, NJ; http://www.bioprocess.amershambiosciences.com), washed in Hank’s balanced salt solution, and then cultured in a 25 cm² tissue culture flask (Falcon; BD Biosciences; Franklin Lakes, NJ; http://www.bdbiosciences.com) in alpha-minimal essential medium supplemented with 100 µg/ml penicillin, 100 µg/ml streptomycin, 2 mM L-glutamine, and 20% fetal calf serum (Atlanta Biological; Norcross, GA; http://www.atlantabio.com) [10, 11]. After 24 hours the nonadherent cells were removed and the adherent layer cultured until it reached 50%-70% confluence. Cells were then harvested by incubation with 0.2% trypsin-EDTA. Cells collected after the fourth culture passage were stimulated to osteoblast and to adipocyte differentiation as described [2, 10] and used for RNA extraction for SAGE analysis.

Flow Cytometry Analysis
The cells harvested were washed in phosphate-buffered saline, counted pelleted by centrifugation, and resuspended in 100 µl of the appropriate monoclonal antibody and corresponding isotype controls (Pharmingen; San Diego, CA; http://www.bdbiosciences.com/pharmingen). The labeled cells were analyzed on a FACSort by collecting 10,000 events with the Cell Quest software program (Becton Dickinson; San Jose, CA; http://www.bd.com). The antibodies used were CD90-PE, CD51/61-PE, CD29-PE, CD49e-PE, CD49d-PE, CD44-FITC, CD45-FITC, CD13-FITC, HLADR-FITC, HLAclassI-FITC.

SAGE Procedure
Total RNA was prepared from 4 x 10⁷ cells obtained from a fresh cell culture using TRIzol^®LS Reagent (Cat No. 10296010; Invitrogen Corporation; Carlsbad, CA; http://www.invitrogen.com) and treated with RQ1 RNase-Free Dnase (Cat. No. M6101; Promega Corporation; Madison, WI; http://www.promega.com) according to manufacturer’s instructions. Absence of DNA contamination was ascertained by Southern blot analysis with a mitochondrial DNA marker (D-loop) as a probe, using the treated RNA as template in a polymerase chain reaction (PCR). Thirty µg of total RNA were then used for the SAGE procedure. SAGE was carried out using the I-SAGE^TM Kit (Cat. No. T5001-01; Invitrogen) based on the original SAGE [12]. Amplified inserts were sequenced with forward M13 primer in a MegaBACE^TM1000 sequencer and the DYEnamic ET Dye Terminator Sequencing Kit (Cat. No. US81090; Amersham Biosciences; Piscataway, NJ; http://www.amershambiosciences.com).

SAGE Analysis
Tag frequency tables were obtained from sequences by the SAGE^TM analysis software, with minimum tag count set to one, maximum ditag length set to 28 bp, and other parameters set as default. The annotation was based on two specific tools, SAGEmap (http://www.ncbi.nlm.nih.gov/SAGE/) and CGAP SAGE Genie (http://cgap.nci.nih.gov/SAGE). We downloaded a SAGE library of CD34⁺ HSCs purified from BM [13] available as supplemental material in the Proceedings of the National Academy of Science (PNAS) website http://www.pnas.org. When the two libraries were compared, the number of tags was normalized to a total count of 200,000 tags.

Semiquantitative Evalution by Real Time-PCR (RT-PCR)
Total RNA was obtained from seven human tissues. The transcription reaction was performed with 2 µg of total RNA, 0.5 µg of Oligo (dT) primer and 200 U of Superscript II Rnase H Reverse Transcriptase (Invitrogen) in a total volume of 20 µl, and one-tenth of the volume of the cDNA was used in the semiquantitative PCR. The specific primers used are listed in Table 1. When the reaction was positive in the undiluted samples, the cDNA was serially diluted (1:2 to 1:128) before performing the PCR. Secreted protein acidic and rich in cysteine (SPARC) expression was measured by RT-PCR with the Taqman approach (Applied Biosystems; Foster City, CA; http://www.appliedbiosystems.com).

	RESULTS

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Gene Expression of MSC
A total of 102,796 tags were obtained by sequencing. Excluding redundancy, these results correspond to 34,649 unique tags, 22,343 of which matched known genes or expressed sequence tags (ESTs) in the CGAP SAGE Genie mapping (84,364 total tags corresponding to 15,167 UniGene clusters), whereas 12,306 unique tags were no matches (18,432 total tags). The 50 most abundant transcripts are listed in Table 2. Some are known to be highly expressed genes in this type of cell, whereas others are recognized here for the first time.

Comparison of MSC with CD34⁺ Cells
The 1,000 most abundant tags of each of the two types of progenitor cells (our MSC library and the downloaded library obtained from CD34⁺ cells) were compared directly with the complete list of tags of the other cell type. This comparison revealed 607 tags exclusively expressed in CD34⁺ hematopoietic precursors, 602 exclusively expressed in MSCs and 791 tags common to both, 393 of which were more expressed in CD34⁺ cells and 398 more expressed in MSCs (Table 3). A search of gene ontology (GO) terms was performed for 549 and 489 unique tags among the 1,000 more expressed respectively in MSCs and CD34 cells. The search revealed that MSCs, as compared with CD34⁺ cells, had a higher percentage of genes in the categories of "cell adhesion" (6.1% x 1.6%), "extracellular" (11.1% x 2.9%) and "development" (11.4 x 7.3%) (p < 0.05). When compared with the number of the gene products annotated under a specific term for the whole GO, MSCs had a higher percentage of genes in "cell adhesion" (0.4% x 6.1%), "extracellular" (6.5% x 11.1%), "cell motility" (1.97% x 4.0%), and "metabolism" (48.7% x 65.0%). A comparison of the two types of cells concerning genes expressed for cell adhesion, extracellular, and motility is shown in Table 4.

View larger version (53K): [in this window] [in a new window]   Figure 1. Semiquantitative evaluation of mRNA abundance by RT-PCR. Total RNA was diluted 1/2 to 1/128 (only 1/8 to 1/64 dilutions are shown), reverse transcribed into cDNA and then a 30-cycle PCR with specific primers located in different exons was performed. At the left is shown the reaction for vimentin (VIM) and at the right the reaction for galectin 1 (LGAL1S). MSC: mesenchymal stem cells; CD34: CD34+ hematopoietic progenitor cells; Liver: adult human liver; PBL: peripheral blood leukocytes; Brain: control human normal brain (temporal); Muscle: skeletal muscle; BM: normal human unfractioned bone marrow. A control with GAPDH primers was carried out and gave positive results up to 1/128 dilution for all samples (last two columns).

	DISCUSSION

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The transcriptome of MSC reveals both significant differences and similarities with the CD34⁺ hematopoietic precursor. One-third of the most abundant gene products of one cell type is also detected in the other, while about two-thirds are exclusively or significantly overexpressed in one type of cell. Most of the highly expressed genes in MSC are related to extracellular components, receptors to matrix components, and cell adhesion molecules (CAMs), such as collagens, SPARC, galectin-1, laminin receptor, fibronectin and MMP2. SPARC is also found in fibroblasts, in cells derived from the MSC (osteoblasts and condrocytes) [21], and in cells derived from hematopoietic precursor (megakaryoblast and platelet). Galectin-1 (ß-galactoside binding protein) is involved in regulation of cell adhesion, cell proliferation, and cell death of T-cells [22], B-cells [23], and the muscular differentiation of dermal fibroblasts [24]. Transforming growth factor beta (TGF-ß)-induced is the third most abundant transcript, thus confirming the important role of the TGF-ß signaling pathway in this cell population [25, 26], although only two tags specific for endoglin have been detected. The finding that activin A (a cytokine of the TGF-ß superfamily) and its receptors are expressed moderately in the MSC agrees with the suggestion that it may influence the growth of stromal cells in an autocrine fashion, whereas only activin receptors were found in CD34 cells [27].

A comparison of Gene Ontology^TM (GO) [28] terms between the two libraries and with all gene products in GO revealed that the number of genes expressed in the categories of CAMs and metabolism are over-represented both in MSCs and CD34. Those in the categories of extracellular, cell motility, and cell proliferation are over-represented in MSCs, and genes in the categories of extracellular and development are under-represented in CD34 cells. The most expressed adhesion molecule in the two types of cells is laminin-1 receptor, suggesting that it may contribute to colocalization of the cells in postnatal BM, in addition to other adhesion molecules that may have a homing function, such as CD44 (H-CAM), CD47, and integrins alpha 4 and alpha E. Also highly expressed in MSCs are the genes for integrin (alpha V component of vitronectin receptor and alpha 2 component of VLA or glycoprotein I/II), CD151 antigen TGF-ß-induced, osteoblast specific factor 2, milk fat globule-epidermal growth factor (EGF) 8 protein (also known as medin and lactadherin), and activated leukocyte cell adhesion molecule (ALCAM). Some of these molecules, such as laminin receptor and integrins, participate also in cell surface signaling. The most striking difference between the top expressed genes of the two types of SCs is the number of genes related to cell adhesion and extracellular component.

There are also various similarities between MSCs and CD34⁺ cells, which include specialized genes such as filamin, calpactin, calcyclin, cofilin, insulin-like growth factor-binding protein 7, VIM, prosaposin, lysozyme and macrophage migration inhibitory factor. Abundant transcripts were found in the two cell types for genes that are highly expressed in myeloid progenitors (CD15⁺) [29], such as thymosin-ß4 and thymosin-ß10, which are involved in the differentiation of granulocytes, monocytes and lymphocytes. Recently Tsai and McKay associated nucleostemin with cell-cycle progression in stem and cancer cells [30]. This protein is present in nucleoli of nervous and embryonic stem cells, in several cancer cell lines, and is preferentially expressed in other SC-enriched populations We found transcripts for its gene in the two cell types (18 tags in MSC and 10 tags in CD34⁺ cells).

Cytokine and growth factor signaling is an important determinant of the functional state of these cells and of the relationship between MSC and CD34⁺ progenitors. We found 30 unique tags for ILs, their receptors, and related proteins that were enriched in the two progenitors cells: 10 were shared by the two types of cells, whereas 10 were exclusive of MSC and 10 were exclusive of CD34. The most abundant transcript in this category was that for the IL-10 receptor both in CD34⁺ and MSCs. IL-1 is produced by the CD34⁺ cells, whereas MSCs have moderate expression of genes for IL-1 receptor and IL-1 receptor-associated kinase 1. Three IL genes were actively expressed in MSC—IL-11, IL-15 and IL-27—whereas CD34 cells have receptors for IL-11. Other IL receptors detected in MSCs are those for IL-9, IL-13 and for IL-17, which was found also in CD34 and plays a role in hematopoietic regulation. There were also 669 tags for various growth factors, such as stem cell growth factor, TGF-ß1, CTGF, hepatoma-derived growth factor, midkine (neurite growth-promoting factor 2), fibroblast growth factor 2, platelet derived growth factor C, and endothelial cell growth factor 1.

Finally, we found at least 6,300 tags related to genes from six of the seven categories indicated by Ramalho-Santos et al. [26] as basic characteristics of "stemness": A) Notch, Yes, JAK/STAT and TGF-ß pathways; B) seven genes related to interaction with the extracellular matrix; C) ubiquination pathways, protein folding, and DNA repair; D) cell cycle and cell cycle control; E) DNA helicases and histone deacetylases, and F) RNA helicases. The strategy of comparing unfractionated BM cells with the mesenchymal and hematopoietic progenitor cells (results not shown) did not reveal a common set of transcripts enriched in the more primitive cells. These findings seem to strengthen the suggestion that although some similar genes may be active in more than one SC type, there is not a rigid pattern that can be associated with the signature of "stemness" for all the SCs, since related but not identical genes may perform the same function in different SCs, and "stem" or progenitor cells of different tissues probably do not have an equivalent collection of expressed genes.

Thus we report the profile of gene expression in MSC from adult BM in culture and find both similarities and differences with CD34⁺ progenitors. Although the majority of the results probably reflect the gene expression inherent to this particular cell type, we cannot rule out the possible effect of culture-induced changes on gene expression. The study identifies the important contribution of extracellular protein products, adhesion molecules, cell motility, growth factor receptors, DNA repair, protein folding, and ubiquination as part of the transcriptome of these cells. However, when extrapolating these results to MSCs of other origins, it is necessary to take into consideration possible differences that depend on the anatomical site of the cell [31]. Our results must be viewed from the perspective that large-scale gene expression profiles are more adequate to propose the rationale for future hypothesis-driven studies than to provide a direct explanation for the cell functioning and behavior [32].

	ACKNOWLEDGMENT

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The authors would like to thank Maristela Orellana, Amelia G. Araujo, Marli H. Tavela, Cristiane A. Ferreira, Fernanda G. Barbuzano, and Adriana A. Marques for their assistance with the laboratory techniques, and Israel T. Silva, Marco V. Cunha, and Daniel G. Pinheiro for their help with the bioinformatic analysis.

This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), and Financiadora de Estudos e Projetos (FINEP), Brazil.

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