Abstract
We used human fetal bone marrow-derived mesenchymal stromal cells (hfMSCs) differentiating towards chondrocytes as an alternative model for the human growth plate (GP). Our aims were to study gene expression patterns associated with chondrogenic differentiation to assess whether chondrocytes derived from hfMSCs are a suitable model for studying the development and maturation of the GP. hfMSCs efficiently formed hyaline cartilage in a pellet culture in the presence of TGFβ3 and BMP6. Microarray and principal component analysis were applied to study gene expression profiles during chondrogenic differentiation. A set of 232 genes was found to correlate with in vitro cartilage formation. Several identified genes are known to be involved in cartilage formation and validate the robustness of the differentiating hfMSC model. KEGG pathway analysis using the 232 genes revealed 9 significant signaling pathways correlated with cartilage formation. To determine the progression of growth plate cartilage formation, we compared the gene expression profile of differentiating hfMSCs with previously established expression profiles of epiphyseal GP cartilage. As differentiation towards chondrocytes proceeds, hfMSCs gradually obtain a gene expression profile resembling epiphyseal GP cartilage. We visualized the differences in gene expression profiles as protein interaction clusters and identified many protein clusters that are activated during the early chondrogenic differentiation of hfMSCs showing the potential of this system to study GP development.
Highlights
Longitudinal bone growth is the result of a tightly orchestrated proliferation and differentiation program called endochondral ossification
The shortcoming of the mouse model is demonstrated by the contrast between the marginally affected growth phenotype of the estrogen receptor alpha (ERa) knock out mouse [3] and the prominent growth phenotype of a male patient lacking functional ERa [4], which is characterized by the absence of epiphyseal fusion and continuation of growth into adulthood
Multipotent human mesenchymal stromal cells are promising for studying chondrogenesis in vitro. hMSCs are an alternative cell source for articular cartilage reconstruction and for studying endochondral ossification as it occurs in the epiphyseal growth plate [8]
Summary
Longitudinal bone growth is the result of a tightly orchestrated proliferation and differentiation program called endochondral ossification. Used animal models for studying growth plate regulation represent the human epiphyseal growth plate poorly. Human growth plate specimens are difficult to obtain [5] In vitro models such as chondrosarcoma cell lines or articular cartilage-derived chondrocyte cultures have limited differentiation capacity, are often difficult to maintain under laboratory conditions or tend to dedifferentiate [6,7]. HMSCs are an alternative cell source for articular cartilage reconstruction and for studying endochondral ossification as it occurs in the epiphyseal growth plate [8]. Gene expression profiles of the differentiating hfMSCs were compared with global gene expression patterns of human articular and growth plate cartilage to assess whether differentiating hfMSCs represent either articular or growth plate chondrocytes
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