Notch4 participates in mesenchymal stem cell-induced differentiation in 3D-printed matrix and is implicated in eccrine sweat gland morphogenesis.
Notch4 participates in mesenchymal stem cell-induced differentiation in 3D-printed matrix and is implicated in eccrine sweat gland morphogenesis.
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外泌汗腺（SG）在体温调节中起着至关重要的作用，但其再生潜力非常有限。虽然SG谱系限制的小生境主导SG形态发生并有益于SG再生，但在体内重建小生境对于干细胞治疗应用是具有挑战性的。因此，我们试图筛选和调整的关键生态位响应基因，双重响应生化和结构线索，这可能是一个有前途的战略SG再生。通过使用基于挤出的3D生物打印方法在体外构建由小鼠足底真皮匀浆（即生化线索）和3D架构（即结构线索）组成的人工SG谱系限制性生态位。小鼠骨髓间充质干细胞（MSCs）在人工SG谱系限制龛中诱导分化为SG细胞。为了将生化线索与结构线索分离，分别分析了纯生化线索、纯结构线索以及两种线索的协同作用引起的转录变化。值得注意的是，仅筛选出响应于生化和结构线索两者而差异表达并参与将MSC命运向SG谱系转换的小生境双重响应基因。分别通过抑制或激活候选小生境双重应答基因进行体外和体内验证，以探索其对SG分化的影响。Notch4是在体外3D打印基质中增强MSC干细胞性并促进SG分化的小生境双重响应基因之一。此外，抑制Notch4特异性减少角蛋白19阳性表皮干细胞和角蛋白14阳性SG祖细胞，从而进一步延迟体内胚胎SG形态发生。Notch4不仅参与小鼠MSC诱导的体外SG分化，而且还参与小鼠体内外分泌SG形态发生。
Eccrine sweat gland (SG) plays a crucial role in thermoregulation but exhibits very limited regenerative potential. Although SG lineage-restricted niches dominate SG morphogenesis and benefit SG regeneration, rebuilding niches in vivo is challenging for stem cell therapeutic applications. Hence, we attempted to screen and tune the critical niche-responding genes that dually respond to both biochemical and structural cues, which might be a promising strategy for SG regeneration. An artificial SG lineage-restricted niche consisting of mouse plantar dermis homogenates (i.e. biochemical cues) and 3D architecture (i.e. structural cues) was built in vitro by using an extrusion-based 3D bioprinting approach. Mouse bone marrow-derived mesenchymal stem cells (MSCs) were then differentiated into the induced SG cells in the artificial SG lineage-restricted niche. To decouple biochemical cues from structural cues, the transcriptional changes aroused by pure biochemical cues, pure structural cues and synergistic effects of both cues were analyzed pairwise, respectively. Notably, only niche-dual-responding genes that are differentially expressed in response to both biochemical and structural cues and participate in switching MSC fates towards SG lineage were screened out. Validations in vitro and in vivo were respectively conducted by inhibiting or activating the candidate niche-dual-responding gene(s) to explore the consequent effects on SG differentiation. Notch4 is one of the niche-dual-responding genes that enhanced MSC stemness and promoted SG differentiation in 3D-printed matrix in vitro. Furthermore, inhibiting Notch4 specifically reduced keratin 19-positive epidermal stem cells and keratin 14-positive SG progenitor cells, thus further delaying embryonic SG morphogenesis in vivo. Notch4 not only participates in mouse MSC-induced SG differentiation in vitro but is also implicated in mouse eccrine SG morphogenesis in vivo.
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影响因子：
6.1
作者：
Lang HL;Zhao YZ;Xiao RJ;Sun J;Chen Y;Hu GW;Xu GH
通讯作者：
Xu GH
丙戊酸的II期研究，用于治疗低度神经内分泌癌。
DOI：
10.1634/theoncologist.2011-0031
发表时间：
2011
期刊：
The oncologist
影响因子：
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作者：
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Loconte NK
DOI：
10.1042/cs20211031
发表时间：
2022-04-14
期刊：
Clinical science (London, England : 1979)
影响因子：
--
作者：
Hu N;Zhang X;Zhang X;Guan Y;He R;Xue E;Zhang X;Deng W;Yu J;Wang W;Shi Q
通讯作者：
Shi Q
影响因子：
15.9
作者：
Ho, Allen S.;Ochoa, Angelica;Morris, Luc G. T.
通讯作者：
Morris, Luc G. T.
DOI：
10.1016/j.msec.2020.111387
发表时间：
2021-01-01
影响因子：
7.9
作者：
Liu, Yufan;Li, Jianjun;Fu, Xiaobing
通讯作者：
Fu, Xiaobing