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发表于 2009-3-5 10:35 |只看该作者 |倒序浏览 |打印

a Center for Cell Therapy and Regional Blood Center, Department of Clinical Medicine, and

b Department of Pathology, Faculty of Medicine, Ribeir?o Preto, Brazil;- T4 x& \9 Q2 j5 v2 O! {" @  b

c Bone Marrow Transplant Unit, H?pital Saint Louis, Paris, France
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Key Words. Mesenchymal stem cells ? Gene expression ? Umbilical cord ? Angiogenesis7 \# [% [  A7 y7 R+ i1 R
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Correspondence: Marco A. Zago, M.D., Ph.D., Hemocentro, R. Tenente Cat?o Roxo 2501, 14051-140 Ribeir?o Preto, Brazil. Telephone: 55-16-3963-9361; Fax: 55-16-3963-9309; e-mail: marazago@usp.br

ABSTRACT8 a7 j/ Z/ z$ A

Mesenchymal stem cells (MSCs) of the bone marrow (BM) give origin to the stromal environment that supports the hematopoiesis maintained by the hematopoietic stem cells (HSCs). They are multipotent precursors that are capable of differentiating into various cell types of mesodermal origin, including condrocytes, osteocytes, adipocytes, and stromal cells , and they probably have a key role in hematopoiesis, both by cell–cell contacts and by secreted proteins.
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Although the differentiation potential of adult stem cells was initially believed to be restricted to its tissue of origin, a great deal of work accumulated recently on the issue of stem cell plasticity. There are many reports on the ability of these precursor cells to originate differentiated cells of other organs and tissues, such as hepatic, renal, neural, and cardiac cells , although the interpretation is often controversial. Moreover, a matched-pair analysis showed that the co-infusion of HLA-identical BM donor–derived MSCs with the HSC graft in the allogeneic transplant setting increased the speed of myeloid engraftment, decreased graft-versus-host disease, and showed improvement of survival, compared with the patients who did not receive the co-infusion of MSCs . Thus, the therapeutic potential of these cells is the focus of considerable interest. In addition to BM, MSCs can be obtained from other sites in the adult, fetus , amniotic fluid , or cord blood cells . MSCs are also enriched in preterm cord blood, decreasing in number with gestational age . Recently, many groups succeeded in isolating MSCs from umbilical cord (UC) blood , whereas controversial results were obtained by others who suggested that cord blood is not a source for MSCs ., q/ l# a0 H* P, L6 L" P
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Instead of using the cord blood, Romanov et al.  and Covas et al.  obtain MSCs starting from cells detached from the UC vein, in a manner similar to that for initiating human umbilical vein endothelial cell (HUVEC) cultures. In vitro and in vivo observations indicate a complex relationship between MSCs of different origins with HSCs and endothelial cells . One means of evaluating the functional relationship between these different cells is by comparing their gene expression profiles. We have recently described the global pattern of gene expression of BM-derived MSCs (obtained by serial analysis of gene expression ) and pointed out similarities and differences with the CD34 hematopoietic precursors .( M. B$ T( B8 b$ H( k8 i4 y

To extend the characterization of the MSCs derived from UC veins and to drive hypotheses concerning the presence of these cells in the UC, we compared the expression profiles obtained by SAGE of these cells to that of cultured BM MSCs. Their functional relationships with HSCs, endothelial cells, and other cells related and unrelated to hematopoiesis were evaluated by cluster analysis of the gene expression profiles.

MATERIALS AND METHODS3 z/ i! Z; {" |) z6 W9 U

Characteristics of the Umbilical Cord MSC Population4 l4 U/ p! z# b% X$ p& J# j

With this approach, we have regularly obtained a cell population that assumes a spindle-shaped morphology in confluent wave-like layers in culture and can be replated several (20 or more) times. The cells harvested are negative for hematopoietic lineage markers (CD34, CD45, and CD133); for monocytic markers (CD14); and for endothelial markers such as KDR, cadherin-5, CD31, and CD133. As observed with other MSCs, the majority of cells were positive for CD13, CD29, CD44, CD54, CD90, and HLA class I, but negative for HLA class II (Table 1). Additionally, the sample used for SAGE was CD49e , CD56/61–, and CD49d–. When cultured with dexamethasone and ascorbic acid they undergo osteogenic differentiation, as demonstrated by alkaline phosphatase expression and positive calcium staining by the von Kossa reaction; in contrast, in culture with insulin, dexamethasone, and indomethacin, they originate adipocytes, which are identified by numerous vacuoles that stain positively with Sudan III. When cultured as a pellet in the bottom of the tube, they originate a mass of cells with condrocyte or condroblast features such as rounded shape with a large vacuolated and basophilic cytoplasm on hematoxylin and eosin stains. The cells are disposed in nests intermingled by an extracellular matrix rich in type II and IV collagen (Fig. 1). Also, these cells stain positively for vimentin and S-100 protein. Thus, they exhibit distinguishing characteristics of the MSCs .
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Table 1. Immunophenotypic findings in three separate samples of mesenchymal stem cells obtained from the umbilical cord wall& w% X9 v' q  E0 K' I

Figure 1. (A): A culture of MSCs obtained from the umbilical vein. (B): Sudan III staining of adipocytes derived from the MSCs. (C, D): Osteogenic differentiation of MSCs, shown by (C) positive staining for alkaline phosphatase and (D) calcium deposits demonstrated by the von Kossa reaction. (E, F): Chondrocyte differentiation of MSCs cultured as a pellet in the bottom of a 15-ml Falcon tube. Hematoxylin eosin–stained sections of the firm mass of cells recovered after 30 days showed cells with characteristic features of condrocytes or chondroblasts (E); there are abundant collagen bundles in the extracellular matrix that stain with anti-collagen II (F), anti-collagen IV, and vimentin (not shown). Abbreviation: MSC, mesenchymal stem cell.! I0 `$ ]+ l# s5 w+ U
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Gene Expression of Umbilical Cord MSCs5 }' ^6 p9 Y6 A

A total of 100,922 tags were obtained by sequencing. Excluding redundancy, these results correspond to 29,407 unique tags, of which 18,689 matched known genes or expressed sequence tags in the CGAP SAGE Genie mapping (85,080 total tags corresponding to 11,965 UniGene clusters); in contrast, 10,718 unique tags had no matches (15,842 total tags). The 50 most abundant transcripts of UC-MSCs are listed in Table 2. All the tags that appear in this list are found in the MSCs derived from BM , and 36 of those are also among the 50 most expressed tags in BM-MSCs, whereas all but three of the remaining are among the 100 most abundant in BM-MSCs.3 ~8 r9 x- J7 p* o9 D) ^; z
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Table 2. First 50 most frequent tags in UC-MSCs: the numbers of tags (normalized for 200,000) in UC-MSCs are compared with BM-MSCs, and the CGAP (SAGEgenie) and NCBI SAGEMap mapping for each tag are shown6 E; F: k0 i8 Y) C* {. h8 x2 k+ m9 h9 N
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A list of all the tags found in UC-MSC is at our Website: htpp://bit.fmrp.usp.br/uc-msc_tags/.

Corroboration of SAGE Results  ]0 I& q1 z2 ~9 K9 w- ^
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Gene expression was measured semiquantitatively by RT-PCR or by real-time PCR in different tissues to validate SAGE results. The expressions of the transcripts COL1A1, COL1A2, TPT1, SPARC, LGALS1, TAGLN2, VIM, MMP2, TAGLN, and ANXA2, common to UC vein and BM-derived MSCs were all confirmed (Fig. 2). The higher levels of CXCL6 and CXCL8 in UC-MSC were also confirmed (Fig. 3). CXCL6 was detected only in UC-MSCs up to 1/32 dilution: It showed 226 tags in UC-MSCs and was absent in BM-MSCs. There were 24 tags for CXCL8 in UC-MSCs and none in BM-MSCs; the transcript was detected up to a dilution of 1/32 in UC vein MSCs and up to 1/4 dilution in BM-MSCs. The expression of the gene SPARC was measured by real-time PCR, and its level was at least 10 times higher in MSCs of both sources, as compared with the other tissues tested, which included bulk BM, CD34  HSCs, peripheral blood leukocytes (PBLs), liver, brain, and skeletal muscle. The expression level of LGALS1, VIM, TPT1, TAGLN, TAGLN2, MMP2, COL1A1, COL1A2, and ANXA2 was also measured in the additional tissues mentioned above. The TPT1 gene was detected in all the tissues tested, whereas the TAGLN2 gene expression was observed only in the hematopoiesis-related tissues and was absent in muscle, brain, and liver. All the other genes (COL1A1, COL1A2, LGALS1, VIM, TAGLN, MMP2, and ANXA2) were positive mainly in the two MSC cell types, thus agreeing with the tag counts observed in the SAGE libraries of the different tissues (Fig. 2).( {$ Q( T, j/ T/ v& l
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Figure 2. Comparison of gene expression by reverse transcription polymerase chain reaction for nine genes in the MSCs obtained from two different sources and in six additional tissues. Underneath each band, the normalized number of tags obtained by us BM-MSCs and UCV-MSCs or from the literature is indicated. The expression of GAPDH was used as reference for evaluating the quality of mRNA. Abbreviations: BM, bone marrow; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HSC, hematopoietic stem cell; MSC, mesenchymal stem cell; PBL, peripheral blood leukocytes; UCV, umbilical cord vein.8 h& l/ S$ N% X. z4 n! m# j8 S

Figure 3. Semiquantitative evaluation of mRNA abundance by reverse transcription PCR. Total RNA was reverse transcribed into cDNA and diluted 1/1 to 1/32, followed by a 30-cycle PCR with specific primers located in different exons. At the left is shown the reaction for chemokine CXCL6, at the center the reaction for IL-8, and at the right the control for GAPDH (only the 1/64 and 1/128 reactions are shown). The expression of the two genes is more abundant for UCV-MSCs than for BM-MSCs, in agreement with the results of serial analysis of gene expression. Abbreviations: BM, bone marrow; CXCL6, C-X-C motif ligand 6; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; IL-8, interleukin-8; MSC, mesenchymal stem cell; PCR, polymerase chain reaction; UCV, umbilical cord vein.. `- b, w& {0 g+ n7 K6 u9 L
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Comparison of Umbilical Cord and Bone Marrow MSCs

Similarities ? When the first thousand more abundant transcripts of each library are compared with the whole set of transcripts from the other library, only 8 tags found in UC veins are not found in BM (0.8 %), whereas 29 tags found in BM are not found in the UC (2.9 %). In addition, the Pearson’s correlation coefficient, calculated on the basis of the normalized expression values of the first 1,000 transcripts of the two sources of MSCs (excluding the 37 exclusive tags) was .93. A comparison of the gene ontologies of the first thousand most abundant transcripts from each of the two libraries revealed differences in only two categories: response to external stimulus (19.30% in BM versus 8.86% in UC) and cell growth and/or maintenance (28.07% in BM versus 37.34% in UC). The expressions of COL1A1, COL1A2, TPT1, SPARC, LGALS1 (all 5 among the top 50 in UC; Table 2), VIM, MMP2, TAGLN (among the top 50 in BM), TAGLN2, and ANXA2 were validated by RT-PCR.2 y6 ?* N+ B$ E: U" Y! I

Differences ? A set of 45 transcripts had at least 10-fold more abundant tags in BM-MSCs than in UC-MSCs (p * N3 H6 R# ~& O1 S9 A- g9 S
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Table 3. Differentially expressed transcripts in BM-MSCs and UC-MSCs
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Clustering ? With a few exceptions, for all three sets of tags (top 100, 500, or 1,000) and metrics used for the hierarchical analysis, cultured endothelial cells, CD34  HSCs, MSCs, and bulk BM clustered together, separated from the hematopoiesis-unrelated tissues. PBLs also clustered together with the hematopoiesis-related tissues with all three tag sets, except for Euclidean metrics. K-median clustering corroborated this structure as in general, cultured endothelial cells, CD34  HSCs, and MSCs clustered together. The dendrogram obtained by uncentered Pearson’s correlation with the top 500 tag set (Fig. 4) illustrates the overall relationship between hematopoiesis-related tissues.

Figure 4. Dendrogram generated by hierarchical clustering (uncentered Pearson’s correlation, average linkage). Clustering was carried out with the first 500 most frequent tags of each of 14 libraries obtained from normal human tissues. Abbreviations: BM, bone marrow; HMVEC, microvascular endothelial cell; HSC, hematopoietic stem cell; HUVEC, human umbilical vein endothelial cell; MSC, mesenchymal stem cell; UCV, umbilical cord vein.
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Discrimination Analysis ? The software CIT identified a set of 350 tags that best differentiate the clusters of hematopoiesis-related from the hematopoiesis-unrelated cells. There were 39 unique tags (Table 4) that were at least 4-fold more abundant in hematopoiesis-related cells, present with counts of at least 10 tags. Those tags represent genes with higher expression among the hematopoietic-related tissues as compared with nonrelated. Their gene ontology categories include genes associated with cell motility, communication, cell death, cell growth and/or maintenance, morphogenesis, and response to external stimulus, among others. The higher or exclusive expression of VIM, SPARC, LGALS1, ANXA2, and TAGLN2 in hematopoiesis-related tissues or in MSCs was confirmed by RT-PCR (Fig. 2). The lower or absent expression of albumin, actin -1, desmin, and clusterin in hematopoiesis-related cells (including MSCs) was confirmed by RT-PCR, in comparison with high expression in other tissues: liver (ALB), muscle (ACTA1 and DES), and brain (CLU) (data not shown).5 B) @3 M* M. l3 }' ?, ]" S# R

Table 4. Transcripts expressed at higher levels in the cluster of hematopoiesis-related cells

DISCUSSION
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This work was supported by Funda??o de Amparo 角 Pesquisa do Estado de S?o Paulo (FAPESP), Conselho Nacional de Desenvolvimento Cient赤fico e Tecnol車gico (CNPq), and Financiadora de Estudos e Projetos (FINEP), Brazil. The authors thank Amelia G. Araujo, Marli H. Tavela, Cristiane A. Ferreira, Fernanda G. Barbuzano, Anemari R. D. Santos, 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.4 p* B* A* X  C- |: b( u6 f/ L/ g

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