Acute brain vascular regeneration occurs via lymphatic transdifferentiation
Acute brain vascular regeneration occurs via lymphatic transdifferentiation
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急性脑血管再生通过淋巴转分化发生
DOI：
10.1016/j.devcel.2021.09.005
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发表时间：
2021-11-22
影响因子：
11.8
通讯作者：
Luo, Lingfei
中科院分区：
文献类型：
--
作者：
Chen, Jingying;Li, Xiuhua;Luo, Lingfei
急性缺血性中风损害局部脑血管(BV)网络。基础血流的急性恢复是由最早再生的BV完成的，这对于改善临床结果和将致死率降至最低至关重要。虽然晚期再生的BV是通过沿着脑膜来源的内生淋巴管(IVV)生长形成的，但早期、急性BV再生的机制仍然不清楚。利用斑马鱼脑血管损伤模型，我们证明了最早再生的BV来自淋巴转分化，这是迄今为止在脊椎动物中尚未被认识的过程。从机制上讲，LV到BV的转分化仅发生在独立的ILV中，通过Notch激活。在晚期再生的BV附着的轨道IVV中，由于表达BV的EPhinB2a旁细胞激活表达iLV的EphB4a以抑制Notch激活，因此从未发生转分化。抑制LV到BV的转分化会阻止BV的急性再生，并变得致命。这些结果表明，急性BV的再生是通过淋巴管转分化发生的，这一过程和关键调控分子EPhinB2a/EphB4a/Notch可能是新的缺血后治疗靶点。
Acute ischemic stroke damages the regional brain blood vessel (BV) network. Acute recovery of basic blood flows, which is carried out by the earliest regenerated BVs, are critical to improve clinical outcomes and minimize lethality. Although the late-regenerated BVs form via growing along the meninge-derived ingrown lymphatic vessels (iLVs), mechanisms underlying the early, acute BV regeneration remain elusive. Using zebrafish cerebrovascular injury models, we show that the earliest regenerated BVs come from lymphatic trans differentiation, a hitherto unappreciated process in vertebrates. Mechanistically, the LV-to-BV transdifferentiation occurs exclusively in the stand-alone iLVs through Notch activation. In the track iLVs adhered by late regenerated BVs, transdifferentiation never occurs because the BV-expressing EphrinB2a paracellularly activates the iLV-expressing EphB4a to inhibit Notch activation. Suppression of LV-to-BV transdifferentiation blocks acute BV regeneration and becomes lethal. These results demonstrate that acute BV regeneration occurs via lymphatic transdifferentiation, suggesting this process and key regulatory molecules EphrinB2a/ EphB4a/Notch as new postischemic therapeutic targets.