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Analyzing Metabolic States of Adipogenic and Osteogenic Differentiation in Human Mesenchymal Stem Cells via Genome Scale Metabolic Model Reconstruction.

ABSTRACT: Since their initial discovery in 1976, mesenchymal stem cells (MSCs) have been gathering interest as a possible tool to further the development and enhancement of various therapeutics within regenerative medicine. However, our current understanding of both metabolic function and existing differences within the varying cell lineages (e.g., cells in either osteogenesis or adipogenesis) is severely lacking making it more difficult to fully realize the therapeutic potential of MSCs. Here, we reconstruct the MSC metabolic network to understand the activity of various metabolic pathways and compare their usage under different conditions and use these models to perform experimental design. We present three new genome-scale metabolic models (GEMs) each representing a different MSC lineage (proliferation, osteogenesis, and adipogenesis) that are biologically feasible and have distinctive cell lineage characteristics that can be used to explore metabolic function and increase our understanding of these phenotypes. We present the most distinctive differences between these lineages when it comes to enriched metabolic subsystems and propose a possible osteogenic enhancer. Taken together, we hope these mechanistic models will aid in the understanding and therapeutic potential of MSCs.

SUBMITTER: Sigmarsdottir TB

PROVIDER: S-EPMC8212021 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Gene Expression analysis of a differentiation timeseries of human Mesenchymal Stem Cells (hMSCs) in the presence of adipogenic/osteogenic factors. hMSCs differentiate into fat cells when treated with dexamethasone (10^-6 M), insulin (10 ug/ml), rosiglitazone (10^-7 M) and IBMX (250 uM). TGFbeta (5 ng/ml) inhibits this process and redirects these cells to differentiate into bone cells. Introduction: Patients suffering from osteoporosis show an increased number of adipocytes in their bone marrow, concomitant with a reduction in the pool of human mesenchymal stem cells (hMSCs) that are able to differentiate into osteoblasts, thus leading to suppressed osteogenesis. Methods: In order be able to interfere with this process, we have investigated in vitro culture conditions whereby adipogenic differentiation of hMSCs is impaired and osteogenic differentiation is promoted. By means of gene expression microarray analysis, we have investigated genes which are potential targets for prevention of fat cell differentiation. Results: Our data show that BMP2 promotes both adipogenic and osteogenic differentiation of hMSCs, while TGFÎ² inhibits differentiation into both lineages. However, when cells are cultured under adipogenic differentiation conditions, which contains cAMP-enhancing agents such as IBMX of PGE2, TGFÎ² promotes osteogenic differentiation, while at the same time inhibiting adipogenic differentiation. Gene expression and immunoblot analysis indicated that cAMP-induced suppression of HDAC5 levels plays an important role in the inhibitory effect of TGFÎ² on osteogenic differentiation. By means of gene expression microarray analysis, we have investigated genes which are downregulated by TGFÎ² under adipogenic differentiation conditions and may therefore be potential targets for prevention of fat cell differentiation. We thus identified 9 genes for which FDA-approved drugs are available. Our results show that drugs directed against the nuclear hormone receptor PPARG, the metalloproteinase ADAMTS5 and the aldo-keto reductase AKR1B10 inhibit adipogenic differentiation in a dose-dependent manner, although in contrast to TGFÎ² they do not appear to promote osteogenic differentiation. Conclusions: The approach chosen in this study has resulted in the identification of new targets for inhibition of fat cell differentiation, which may not only be relevant for prevention of osteoporosis, but also of obesity. hMSCs were induced to differentiate in the presence dexamethasone, insulin and rosiglitazone, to which was added either 50 ng/ml BMP2; BMP2 + TGFbeta; BMP2 + IBMX; BMP2 + TGFbeta + IBMX.

Dataset Information

Analyzing Metabolic States of Adipogenic and Osteogenic Differentiation in Human Mesenchymal Stem Cells via Genome Scale Metabolic Model Reconstruction.

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