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人类内皮祖细胞中促血管生成信号通路的表观遗传激活增加血管生成。

Epigenetic Activation of Pro-angiogenic Signaling Pathways in Human Endothelial Progenitors Increases Vasculogenesis.

机构信息

Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, General Hospital, Mailbox 511, 501 Smyth Road, Ottawa, ON K1H8L6, Canada; University of Ottawa, Department of Cellular and Molecular Medicine, Ottawa, ON K1H8L6, Canada; Ottawa Institute of Systems Biology, Ottawa, ON K1H8M5, Canada.

Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, General Hospital, Mailbox 511, 501 Smyth Road, Ottawa, ON K1H8L6, Canada.

出版信息

Stem Cell Reports. 2017 Nov 14;9(5):1573-1587. doi: 10.1016/j.stemcr.2017.09.009. Epub 2017 Oct 12.

DOI:10.1016/j.stemcr.2017.09.009
PMID:29033304
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5830028/
Abstract

Human endothelial colony-forming cells (ECFCs) represent a promising source of adult stem cells for vascular repair, yet their regenerative capacity is limited. Here, we set out to understand the molecular mechanism restricting the repair function of ECFCs. We found that key pro-angiogenic pathways are repressed in ECFCs due to the presence of bivalent (H3K27me3/H3K4me3) epigenetic marks, which decreases the cells' regenerative potential. Importantly, ex vivo treatment with a combination of epigenetic drugs that resolves bivalent marks toward the transcriptionally active H3K4me3 state leads to the simultaneous activation of multiple pro-angiogenic signaling pathways (VEGFR, CXCR4, WNT, NOTCH, SHH). This in turn results in improved capacity of ECFCs to form capillary-like networks in vitro and in vivo. Furthermore, restoration of perfusion is accelerated upon transplantation of drug-treated ECFCs in a model of hindlimb ischemia. Thus, ex vivo treatment with epigenetic drugs increases the vascular repair properties of ECFCs through transient activation of pro-angiogenic signaling pathways.

摘要

人内皮细胞集落形成细胞（ECFCs）是血管修复的一种有前途的成体干细胞来源，但它们的再生能力有限。在这里，我们着手了解限制 ECFC 修复功能的分子机制。我们发现，由于存在二价（H3K27me3/H3K4me3）表观遗传标记，关键的促血管生成途径在 ECFCs 中受到抑制，这降低了细胞的再生潜力。重要的是，体外使用一组能够去除二价标记并使转录活跃的 H3K4me3 状态的表观遗传药物处理，可同时激活多种促血管生成信号通路（VEGFR、CXCR4、WNT、NOTCH、SHH）。这反过来又导致 ECFC 形成体外和体内毛细血管样网络的能力得到改善。此外，在下肢缺血模型中移植经药物处理的 ECFC 可加速灌注恢复。因此，体外使用表观遗传药物通过短暂激活促血管生成信号通路来增加 ECFC 的血管修复特性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b8f/5830028/01235595ed40/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b8f/5830028/28910c7a9883/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b8f/5830028/832afe0c1fc4/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b8f/5830028/a1f720232591/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b8f/5830028/30a71640b3d4/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b8f/5830028/61a81a78ef27/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b8f/5830028/e948a4b5aade/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b8f/5830028/01235595ed40/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b8f/5830028/28910c7a9883/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b8f/5830028/832afe0c1fc4/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b8f/5830028/a1f720232591/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b8f/5830028/30a71640b3d4/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b8f/5830028/61a81a78ef27/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b8f/5830028/e948a4b5aade/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b8f/5830028/01235595ed40/gr6.jpg

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