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Functional differences among human postnatal stem cells of different origin are reflected by their transcriptome

ABSTRACT: GENES ASSOCIATED WITH THE CELL CYCLE, LINEAGE COMMITMENT AND IMMUNOMODULATORY POTENTIAL DISCRIMINATE HUMAN POSTNATAL STEM CELLS OF DIFFERENT ORIGIN. Stem cells hold great promise for future clinical use. Their intrinsic biological properties are, however, not fully understood and many of their therapeutic benefits still unclear. Better understanding of their genetic and biological properties is essential for the development of clinically relevant stem cell applications. The neonatal unrestricted somatic stem cell (USSC) from cord blood has the capacity to differentiate into cells from all three germ layers. Here we investigate the gene expression profile of USSC using the Affymetrix Exon Array platform and compare it with those of bone-marrow derived mesenchymal adult stem cells (BM-MSC) and adipose tissue-derived adult stem cells (AdAS). Extensive data analysis revealed limited variation in the expression profile of the different cell lines from the same origin, while stem cells from different origins showed distinct profiles, with the BM-MSC and AdAS being more closely related to each other than to USSC. Interestingly, USSC expressed genes involved in the cell cycle at much higher levels, indicative of their relatively higher cycling rate (~ 24 hrs as opposed to more than 2 days for BM-MSC and AdAS). They also show higher expression of genes involved in neurogenesis, consistent with their reported neuronal differentiation capacity. The BM-MSC signature indicates that they are primed towards developmental processes of tissues and organs derived from the mesoderm and endoderm. Remarkably, AdAS appear to be highly enriched in immune-related genes. Together, the data suggest that the different mesenchymal stem cell types have distinct gene expression profiles,that reflect their origin and differentiation potential. Keywords: Adult stem cells, developmental biology, gene expression, genomics, human cord blood, mesenchymal stem cells, cell type comparison

ORGANISM(S): Homo sapiens

PROVIDER: GSE18698 | GEO | 2009/10/22

SECONDARY ACCESSION(S): PRJNA121483

REPOSITORIES: GEO

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Project description:Ewing sarcoma family of tumors (ESFT) are aggressive bone and soft tissue tumors of unknown cellular origin. Most ESFT express EWS-FLI1, a chimeric protein which functions as a growth-promoting oncogene in ESFT but is toxic to most normal cells. A major difficulty in understanding EWS-FLI1 function has been the lack of an adequate model in which to study EWS-FLI1-induced transformation. Although the cell of origin of ESFT remains elusive, both mesenchymal (MSC) and neural crest (NCSC) have been implicated. We recently developed the tools to generate NCSC from human embryonic stem cells (hNCSC). In the current study we used this model to test the hypothesis that neural crest-derived stem cells are the cells of origin of ESFT and to evaluate the consequences of EWS-FLI1 expression on human neural crest biology. hNCSC transduced with an EWS-FLI1 lentivirus tolerated expression of the oncoprotein. Moreover, EWS-FLI1-transduced hNCSC continued to proliferate and maintain EWS-FLI1 expression in culture for several weeks after transduction. Affymetrix HuEx 1.0 expression profiling of hNCSC cells five days post-transduction with EWS-FLI1 demonstrated the expected induction and repression of well-established EWS-FLI1 targets and also identified numerous other novel EWS-FLI1-regulated genes that are likely to be cell-type and situation specific. In particular, the EWS-FLI1 repressive signature was found to be highly context dependent. Moreover, while control vector transduced cells displayed an MSC-like phenotype, EWS-FLI1-transduced cells maintained a NCSC-like phenotype and genetic profiling revealed reprogramming towards a more pluriopotent, neuroectodermal state. Finally, EWS-FLI1 expressing cells upregulated expression of the polycomb proteins BMI-1 and EZH2. These data implicate neural crest-derived cells in the origin of ESFT and suggest that EWS-FLI1 enables malignant transformation by inducing maintenance of a multipotent, NCSC-state through deregulation of polycomb genes. 3 replicate samples for 4 different stem cell populations were analyzed by HuEx arrays. The 4 sample types were adult human bone marrow-derived mesenchymal stem cells, human embryonic stem cell-derived nueral crest stem cells (hNCSC), control vector-transduced hNCSC-derived mesenchymal stem cells (NC-MSC), and EWS-FLI1-transduced hNCSC-derived mesenchymal stem cells (NC-MSC EF). Control and EWS-FLI1 transduced NC-MSC were isolated 5 days after lentiviral transduction. Transcript level expression data was compared among the different populations to determine differences and similarities between NCSC, BM-MSC and NC-MSC with/without EWS-FLI1 expression. These data were used to identify EWS-FLI1 targets in NC-MSC and to characterize the genetic changes that occur in NCSC as they generate NC-MSC progeny.

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Functional differences among human postnatal stem cells of different origin are reflected by their transcriptome

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