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. 2011 Jun 14;50(25):5734-6.
doi: 10.1002/anie.201101042. Epub 2011 May 5.

Pan-Src family kinase inhibitors replace Sox2 during the direct reprogramming of somatic cells

Judith Staerk  1 , Costas A Lyssiotis, Lea A Medeiro, Michael Bollong, Ruth K Foreman, Shoutian Zhu, Michael Garcia, Qing Gao, Laure C Bouchez, Luke L Lairson, Bradley D Charette, Lubica Supekova, Jeffrey Janes, Achim Brinker, Charles Y Cho, Rudolf Jaenisch, Peter G Schultz
Affiliations

Pan-Src family kinase inhibitors replace Sox2 during the direct reprogramming of somatic cells

Judith Staerk et al. Angew Chem Int Ed Engl. .
No abstract available

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Figures

Figure 1
Figure 1. Chemical complementation of Sox2
(a) OKM-transduced NL-MEFs were treated for 7 days with Dasatinib (0.5 μM), iPYrazine (10 μM), LY-364947 (a positive control; 1 μM) or vehicle (0.1% DMSO, v/v). The Nanog signal from treated cells is compared to that of non-transduced NL-MEFs, NL-ES cells and NL-iPS cells. Nanog activity is reported in relative light units (RLU). Error bars, standard deviation (n = 3). (b) O4NR-MEFs were transduced with Klf4 and c-Myc and grown in Dox (blue bars); transduced with OKM (no Dox; green bars); or transduced with OKM (no Dox) and grown in 1 mM VPA (red bars). Oct4-transduced O4NR-MEFs were used in order to take advantage of the stringent pluripotency marker, the Oct4-NeoR selection cassette. The OKM-expressing MEFs were treated with iPY (10 μM), DMSO (0.1%), or transduced with Sox2. At day 12, resultant colonies were selected upon supplementation of growth media with neomycin. Colonies that survived were stained for AP and counted 3 days later. Error bars, standard deviation (n = 3). (c) iPS cells derived from KM-transduced, Dox and iPY-treated O4NR-MEFs stain positive for the pluripotency-associated markers Oct4 and SSEA-1. (d) iPY-derived iPS cells form teratomas consisting of all three germ layers and contribute to live chimeras.
Figure 2
Figure 2. Src family kinase and TGFβ-inhibitors recapitulate the Sox2 replacement activity of iPY
(a) Chemical structures of selected kinase inhibitors used in this study. (b) Inhibition of Src-kinase signaling by dasatinib (0.5 μM) or PP1 (10 μM) replaces Sox2 during reprogramming. O4NR-MEFs were transduced with Klf4 and c-Myc and grown in Dox (blue bars); transduced with OKM (no Dox; green bars); or transduced with OKM (no Dox) and grown in 1 mM VPA (red bars). OKM-expressing MEFs were transduced with Sox2 or treated with kinase inhibitors or vehicle (0.1% DMSO, v/v) for 10 days. At day 12, resultant colonies were selected upon supplementation of growth media with neomycin. Colonies that survived were stained for AP and counted 3 days later. Error bars, standard deviation (n = 3). Complete names, descriptions and concentrations of the kinase inhibitors used in this assay are provided in Table S2. (c) Activation of c-Src signaling by JK239 (10 μM) or TGFβ signaling with TGFβ1 ligand (10 ng/mL) inhibits 4-factor reprogramming. O4NR-MEFs were transduced with Sox2, c-Myc, Klf4 and treated with Dox to initiate Oct4 expression. 12 days later, resultant colonies were selected upon supplementation of growth media with neomycin. Colonies that survived were AP stained and counted 3 days later. Error bars, standard deviation (n = 3).
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