±1.5 (% viability) CF vs PANC-1, n=3). A lower IC 50 value for sunitinib was required to exert the same effects on CF (IC 50 5.2 mM) vs PANC-1 (IC 50 13.5 mM) cell viability.These results suggest sunitinib can cause lethal effects in cardiac cells at lower doses than those required to induce pancreatic cancer cell death. Future work will aim to identify cellular mechanisms responsible for these toxic effects. Parallel studies in cardiac and cancer cells will be beneficial in distinguishing how focused anti-cancer drug delivery could be improved to avoid CTX.
Intimal medial thickening (IMT) and vascular remodeling are hallmarks of arteriosclerotic disease. However, the origin of neointimal cells and the signaling molecules that dictate their fate and function remains controversial. Herein, we examined whether Hedgehog (Hh) responsive S100β + /Sca1 + stem cells contribute to IMT within carotid arteries of transgenic mice following ligation-induced injury in vivo and myogenic differentiation of undifferentiated multipotent S100β + /Sca1 + stem cells in vitro . Using Sca1-eGFP and S100β-eGFP transgenic mice, we demonstrated a significant accumulation in the number of eGFP + cells within the intima and medial layers of injured arteries following ligation concomitant with enhanced expression of Hh signaling components (ptch1 and Gli). Genetic lineage tracing analysis using S100β-eGFP/Cre/ERT2–dTomato transgenic mice to mark S100β + resident vascular stem cells before injury confirmed that S100β + progeny that are Sca1 + significantly contribute to IMT, an effect significantly attenuated following treatment with the Hh smoothened inhibitor, cylopamine. In vitro, recombinant SHh (rSHh) treatment of multipotent S100β + /Sca1 + resident stem cells increased Hh target gene Gli expression, decreased telomerase activity and promoted myogenic differentiation and cell growth; effects significantly attenuated following Hh inhibition. In human arteriosclerotic lesions, Hh components were upregulated concomitant with enhanced expression of S100β. Together, these findings suggest that S100β + /Sca1 + stem cells are a major source of neointimal cells contributing to IMT and suggest that this cohort may be a relevant therapeutic target to prevent arteriosclerosis.
Background: The morphogen Sonic Hedgehog (SHh) and its signaling pathway components are significantly up-regulated within adventitial and medial segments from arteriosclerotic vessels in mice concomitant with enhanced accumulation of SMCs. This vessel remodelling is attenuated in vivo following Hh receptor, Patched 1, depletion. There is evidence supporting a role for stem cell-derived vascular smooth muscle (vSMCs) in contributing to arteriosclerotic vascular disease. In this context, SHh signaling may be an important regulator of stem cell self-renewal and differentiation to SMC in vitro. Aim: Determine the effects of SHh on bone-marrow derived mesenchymal stem cell (MSC) differentiation to SMC in vitro. Methods: Murine CD44+ bone-marrow derived MSCs and Sca1+ rat adventitial progenitor stem cells (APCs) were examined for SHh components and their capacity to differentiate to SMCs before and after treatment with sonic hedgehog (rSHh, 0.5 μg/ml) for 7 d, in the absence or presence of Hh inhibitors cyclopamine (10μM) or HPI-4 (50μM). The transition to SMC was determined be examining intermediate (calponin1, CNN1) and late (myosin heavy chain, Myh11) SMC differentiation marker expression by western blot analysis and immunocytochemistry, respectively. Results: Hh signaling components were present on MSCs and APCs. Stem cell growth was unaffected by treatment with Hh inhibitors cyclopamine or HPI-4 at concentrations that inhibited Gli signalling in vitro. Recombinant SHh increased SMC differentiation marker protein protein expression after 7 days, an effect that was inhibited following SHh inhibition with smoothened inhibitors cyclopamine and HPI-4. Conclusion: in the absence of any effect on cell growth, Sonic Hedgehog controls mesenchymal stem-like cell differentiation to SMC.
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