Follistatin-Like 3 Enhances the Function of Endothelial Cells Derived from Pluripotent Stem Cells by Facilitating β-Catenin Nuclear Translocation Through Inhibition of Glycogen Synthase Kinase-3β Activity.
Follistatin-Like 3 Enhances the Function of Endothelial Cells Derived from Pluripotent Stem Cells by Facilitating β-Catenin Nuclear Translocation Through Inhibition of Glycogen Synthase Kinase-3β Activity.
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DOI：
10.1002/stem.2820
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发表时间：
2018-07
期刊：
影响因子：
--
通讯作者：
Margariti A
中科院分区：
文献类型：
--
作者：
Kelaini S;Vilà-González M;Caines R;Campbell D;Eleftheriadou M;Tsifaki M;Magee C;Cochrane A;O'neill K;Yang C;Stitt AW;Zeng L;Grieve DJ;Margariti A
对抗血管疾病需要功能性内皮细胞（EC），其可以通过大量诱导多能干细胞（iPS细胞）的分化提供以用于临床。然而，由于iPS-EC在保持其表型和功能方面的挑战，所产生的EC（iPS-EC）在治疗中的巨大前景往往受到限制。我们发现卵泡抑素样3（FSTL 3）在iPS-ECs中高度表达，因此，我们试图阐明其在保留和改善iPS-ECs功能和表型方面的可能作用，这对于增加细胞作为治疗工具的潜力至关重要。我们在iPS-EC中过表达FSTL 3，发现FSTL 3可以通过抑制糖原合成酶激酶-3 β活性和诱导内皮素-1促进β-连环蛋白核转位来诱导和增强内皮特征。FSTL 3的血管生成潜力也在体外和体内得到证实。当将过表达FSTL 3的iPS-EC皮下注射到体内血管生成模型中或肌肉注射到后肢缺血NOD.CB17-Prkdcscid/NcrCrl SCID小鼠模型中时，FSTL 3分别显著诱导血管生成和血流恢复。这项研究首次证明FSTL 3可以大大增强iPS‐ EC的功能和成熟度。它推进了我们对iPS-EC的理解，并确定了一种可应用于细胞治疗的新途径。因此，这些发现可能有助于提高效率和产生治疗相关数量的EC，用于患者特异性细胞治疗。此外，它对于治疗EC功能障碍引起的血管疾病特别有用。干细胞2018;36：1033-1044
The fight against vascular disease requires functional endothelial cells (ECs) which could be provided by differentiation of induced Pluripotent Stem Cells (iPS Cells) in great numbers for use in the clinic. However, the great promise of the generated ECs (iPS‐ECs) in therapy is often restricted due to the challenge in iPS‐ECs preserving their phenotype and function. We identified that Follistatin‐Like 3 (FSTL3) is highly expressed in iPS‐ECs, and, as such, we sought to clarify its possible role in retaining and improving iPS‐ECs function and phenotype, which are crucial in increasing the cells’ potential as a therapeutic tool. We overexpressed FSTL3 in iPS‐ECs and found that FSTL3 could induce and enhance endothelial features by facilitating β‐catenin nuclear translocation through inhibition of glycogen synthase kinase‐3β activity and induction of Endothelin‐1. The angiogenic potential of FSTL3 was also confirmed both in vitro and in vivo. When iPS‐ECs overexpressing FSTL3 were subcutaneously injected in in vivo angiogenic model or intramuscularly injected in a hind limb ischemia NOD.CB17‐Prkdcscid/NcrCrl SCID mice model, FSTL3 significantly induced angiogenesis and blood flow recovery, respectively. This study, for the first time, demonstrates that FSTL3 can greatly enhance the function and maturity of iPS‐ECs. It advances our understanding of iPS‐ECs and identifies a novel pathway that can be applied in cell therapy. These findings could therefore help improve efficiency and generation of therapeutically relevant numbers of ECs for use in patient‐specific cell‐based therapies. In addition, it can be particularly useful toward the treatment of vascular diseases instigated by EC dysfunction. Stem Cells 2018;36:1033–1044
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影响因子：
56.9
作者：
Behrens, J;Jerchow, BA;Birchmeier, W
通讯作者：
Birchmeier, W
DOI：
10.1074/jbc.m113.495531
发表时间：
2014-02-07
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Di Bernardini E;Campagnolo P;Margariti A;Zampetaki A;Karamariti E;Hu Y;Xu Q
通讯作者：
Xu Q
影响因子：
3.3
作者：
Cho T;Romagnuolo R;Scipione C;Boffa MB;Koschinsky ML
通讯作者：
Koschinsky ML
DOI：
10.1002/stem.2594
发表时间：
2017-04
期刊：
Stem cells (Dayton, Ohio)
影响因子：
--
作者：
Cochrane A;Kelaini S;Tsifaki M;Bojdo J;Vilà-González M;Drehmer D;Caines R;Magee C;Eleftheriadou M;Hu Y;Grieve D;Stitt AW;Zeng L;Xu Q;Margariti A
通讯作者：
Margariti A
影响因子：
4.1
作者：
Maguer-Satta, W;Rimokh, R
通讯作者：
Rimokh, R