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抑制 hedgehog 信号通路可降低人骨髓间充质干细胞的增殖和克隆形成能力。

Inhibition of hedgehog signaling decreases proliferation and clonogenicity of human mesenchymal stem cells.

机构信息

CNRS UMR6543, Institute of Biology, Development and Cancer, Faculté de Médecine, Nice, France.

出版信息

PLoS One. 2011 Feb 3;6(2):e16798. doi: 10.1371/journal.pone.0016798.

Abstract

Human mesenchymal stem cells (hMSC) have the ability to differentiate into osteoblasts, adipocytes and chondrocytes. We have previously shown that hMSC were endowed with a basal level of Hedgehog signaling that decreased after differentiation of these cells. Since hMSC differentiation is associated with growth-arrest we investigated the function of Hh signaling on cell proliferation. Here, we show that inhibition of Hh signaling, using the classical inhibitor cyclopamine, or a siRNA directed against Gli-2, leads to a decrease in hMSC proliferation. This phenomenon is not linked to apoptosis but to a block of the cells in the G0/G1 phases of the cell cycle. At the molecular level, it is associated with an increase in the active form of pRB, and a decrease in cyclin A expression and MAP kinase phosphorylation. Inhibition of Hh signaling is also associated with a decrease in the ability of the cells to form clones. By contrast, inhibition of Hh signaling during hMSC proliferation does not affect their ability to differentiate. This study demonstrates that hMSC are endowed with a basal Hedgehog signaling activity that is necessary for efficient proliferation and clonogenicity of hMSC. This observation unravels an unexpected new function for Hedgehog signaling in the regulation of human mesenchymal stem cells and highlights the critical function of this morphogen in hMSC biology.

摘要

人骨髓间充质干细胞(hMSC)具有分化为成骨细胞、脂肪细胞和成软骨细胞的能力。我们之前已经表明,hMSC 具有基础水平的 Hedgehog 信号,这些信号在这些细胞分化后会降低。由于 hMSC 分化与生长停滞有关,我们研究了 Hh 信号对细胞增殖的功能。在这里,我们表明使用经典抑制剂环巴胺或针对 Gli-2 的 siRNA 抑制 Hh 信号会导致 hMSC 增殖减少。这种现象与细胞凋亡无关,而是与细胞在细胞周期的 G0/G1 期停滞有关。在分子水平上,它与 pRB 的活性形式增加以及细胞周期蛋白 A 表达和 MAP 激酶磷酸化减少有关。Hh 信号的抑制也与细胞形成克隆的能力降低有关。相比之下,在 hMSC 增殖期间抑制 Hh 信号不会影响它们分化的能力。这项研究表明,hMSC 具有基础的 Hedgehog 信号活性,这对于 hMSC 的有效增殖和克隆形成是必要的。这一观察结果揭示了 Hedgehog 信号在调节人类间充质干细胞中的一个意外新功能,并强调了这种形态发生素在 hMSC 生物学中的关键作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f709/3033417/a1d20b2a4940/pone.0016798.g001.jpg

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