ECTS Abstracts (2015) 1 P163

Cell Fate Modulation of Human Mesenchymal Stromal/Stem Cells by Sulforaphane, a Naturally Occurring Isothiocyanate

Roman Thaler1, Markus Schreiner1, Chris Paradise1, Dakota L Jones1, Dudakovic Amel1, Allan B Dietz2 & Andre J van Wijnen1

1Department of Orthopedic Research, Mayo Clinic, Rochester, MN, USA; 2Department of Transfusion Medicine, Mayo Clinic, Rochester, MN, USA.

Nutritional drugs have unanticipated anabolic effects on skeletal development and homeostasis. We demonstrated that sulforaphane (SFN), which is abundantly present in cruciferous vegetables like broccoli, has bone anabolic effects in mice via epigenetic mechanisms that mediate active DNA demethylation. We investigated whether SFN has potential utility in skeletal tissue regeneration by controlling differentiation of clinical-grade adipose derived human mesenchymal stromal/stem cells (AMSCs). Our results show that SFN has striking short- and long-term effects on cell growth and differentiation of AMSCs. Administered at an optimal dose of 3 μM, SFN significantly enhances osteoblastic differentiation of as shown by the increased expression of BGLAP2, RUNX2, COLA1A1 and LOX and by the increased mineralisation of the extracellular matrix after 24 days. Apart from osteogenic effects, SFN suppresses adipogenic differentiation of AMSCs. SFN dramatically decreases fat droplet formation and expression of the fat-related PPARY, PLIN1 or CEBPA genes. Mechanistically, SFN induces extensive epigenetic reprogramming of the chromatin within 4 to 10 hours after treatment of the AMSCs. Gene expression profiling using qPCR with a panel of primer pairs for ~400 epigenetic regulators revealed that SFN induces >40 genes involved in chromatin remodelling, including TET3, JHDM1D and KDM6B. Interestingly, long-term effects from SFN treatment on AMSC differentiation are only achieved by treating the cells within the first 10 hours after induction of differentiation. In contrast, treatment of the cells with SFN without any differentiation media does not shift the cells to a specific cell lineage. These data indicate that SFN extensively enhances chromatin remodelling at the very early stages of differentiation. These epigenetic changes favour osteoblastic differentiation while suppressing adipogenesis. We propose that the natural food compound SFN is an effective agent for modulating cell fate determination of AMSCs, and that SFN may be an effective bone stimulatory in skeletal regenerative therapies.

Disclosure: The authors declared no competing interests. This work was supported by a CRM grant of the Mayo Clinic.

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