Age-associated changes in lineage composition of the enteric nervous system regulate gut health and disease.
Age-associated changes in lineage composition of the enteric nervous system regulate gut health and disease.
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DOI：
10.7554/elife.88051
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发表时间：
2023-12-18
期刊：
影响因子：
7.7
通讯作者：
Pasricha PJ
中科院分区：
文献类型：
--
作者：
Kulkarni S;Saha M;Slosberg J;Singh A;Nagaraj S;Becker L;Zhang C;Bukowski A;Wang Z;Liu G;Leser JM;Kumar M;Bakhshi S;Anderson MJ;Lewandoski M;Vincent E;Goff LA;Pasricha PJ
肠道神经系统(ENS)是肠壁内神经细胞的集合，对胃肠道和全身健康至关重要。根据流行的范式，ENS起源于从神经脊迁移而来的前体细胞，此后基本保持不变。在这里，我们表明成熟的ENS的谱系组成随着时间的变化而变化，随着神经脊源性神经元的标准谱系的下降，他们被新发现的中胚层来源的神经元谱系所取代。单细胞转录学和免疫化学方法建立了中胚层来源神经元的独特表达谱。这两种不同来源的神经元在出生后肠道中的比例之间的动态平衡取决于它们各自的营养信号GDNF-RET和HGF-MET的可用性。随着年龄的增长，中胚层来源的神经元成为ENS中神经元的主要形式，这一变化与对肠道运动的显著功能影响有关，而GDNF的补充可以逆转这一变化。对人类肠道组织的转录分析显示，肠运动障碍患者的GDNF-RET信号减少，这与神经脊源性神经元标志物的减少以及中胚层来源神经元特异性转录模式的增加有关。因此，成人胃肠道的正常肠道功能似乎需要在ENS内的这两个不同血统之间实现最佳平衡。
The enteric nervous system (ENS), a collection of neural cells contained in the wall of the gut, is of fundamental importance to gastrointestinal and systemic health. According to the prevailing paradigm, the ENS arises from progenitor cells migrating from the neural crest and remains largely unchanged thereafter. Here, we show that the lineage composition of maturing ENS changes with time, with a decline in the canonical lineage of neural-crest derived neurons and their replacement by a newly identified lineage of mesoderm-derived neurons. Single cell transcriptomics and immunochemical approaches establish a distinct expression profile of mesoderm-derived neurons. The dynamic balance between the proportions of neurons from these two different lineages in the post-natal gut is dependent on the availability of their respective trophic signals, GDNF-RET and HGF-MET. With increasing age, the mesoderm-derived neurons become the dominant form of neurons in the ENS, a change associated with significant functional effects on intestinal motility which can be reversed by GDNF supplementation. Transcriptomic analyses of human gut tissues show reduced GDNF-RET signaling in patients with intestinal dysmotility which is associated with reduction in neural crest-derived neuronal markers and concomitant increase in transcriptional patterns specific to mesoderm-derived neurons. Normal intestinal function in the adult gastrointestinal tract therefore appears to require an optimal balance between these two distinct lineages within the ENS.
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DOI：
10.1002/stem.3295
发表时间：
2021-01
期刊：
Stem cells (Dayton, Ohio)
影响因子：
--
作者：
Hu X;Wu Q;Zhang J;Kim J;Chen X;Hartman AA;Eastman AE;Park IH;Guo S
通讯作者：
Guo S
影响因子：
--
作者：
Qiu X;Wei R;Li Y;Zhu Q;Xiong C;Chen Y;Zhang Y;Lu K;He F;Zhang L
通讯作者：
Zhang L
影响因子：
3.5
作者：
de Jonge HR;Ardelean MC;Bijvelds MJC;Vergani P
通讯作者：
Vergani P
影响因子：
3.7
作者：
Becker L;Peterson J;Kulkarni S;Pasricha PJ
通讯作者：
Pasricha PJ
影响因子：
11
作者：
Honig G;Liou A;Berger M;German MS;Tecott LH
通讯作者：
Tecott LH