In Vitro Conditioned Bone Marrow-Derived Mesenchymal Stem Cells Promote De Novo Functional Enteric Nerve Regeneration, but Not Through Direct-Transdifferentiation.
In Vitro Conditioned Bone Marrow-Derived Mesenchymal Stem Cells Promote De Novo Functional Enteric Nerve Regeneration, but Not Through Direct-Transdifferentiation.
复制标题
DOI：
10.1002/stem.2197
复制
发表时间：
2015-12
期刊：
影响因子：
--
通讯作者：
Li X
中科院分区：
文献类型：
--
作者：
Lin R;Ding Z;Ma H;Shi H;Gao Y;Qian W;Shi W;Sun Z;Hou X;Li X
肠神经系统（ENS）的损伤或神经退行性疾病会导致胃肠功能障碍，而目前尚无有效的治疗方法。本研究采用 BAC 诱导的大鼠胃去神经模型，旨在确定骨髓间充质干细胞 (BMSC) 移植是否可以促进 ENS 神经元再生，如果可以，则阐明其机制。从 WT [用双苯甲亚胺 (BBM) 标记的 BMSC] 或 GFP 转基因大鼠中分离出荧光标记的 BMSC，使用含有胶质细胞源性神经营养因子 (GDNF) 的胎儿肠道培养基在体外进行预处理，然后将其移植到浆膜下大鼠幽门的去神经区域。在神经消融的幽门中，移植的BMSC存活并在移植后28天从浆膜下层迁移到粘膜下层，没有明显的去分化。大量 PGP9.5/NSE/HuC/D/Tuj1 阳性（但 GFP 和 BBM 阴性）神经元在移植有预处理 BMSC 的去神经幽门中有效再生，表明它们是从头再生的，而不是源自移植的 BMSC 的转分化。 BMSC 移植恢复了幽门基底收缩力和 EFS 诱导的松弛。在体外预处理的 BMSC 以及移植预处理的 BMSC 后先前去神经的幽门中均诱导出高水平的 GDNF。因此，BMSC 启动的 GDNF 正反馈机制被认为可以促进神经元再生和生长。总之，我们已经证明，同种异体移植的预处理 BMSC 启动胃神经元细胞/结构的从头再生，从而恢复幽门去神经大鼠的胃收缩力。这些神经元结构并非源自移植的骨髓间充质干细胞。我们的数据表明，预处理的同种异体 BMSC 在治疗肠神经疾病方面可能具有治疗价值。
Injury or neurodegenerative disorders of the enteric nervous system (ENS) cause gastrointestinal dysfunctions for which there is no effective therapy. This study, using the BAC-induced rat gastric denervation model, aimed to determine whether transplantation of bone marrow-derived mesenchymal stem cells (BMSC) could promote ENS neuron regeneration and if so, to elucidate the mechanism. Fluorescently-labeled BMSC, isolated from either WT [BMSC labeled with bis-benzimide (BBM)] or GFP-transgenic rats, were preconditioned in vitro using fetal gut culture media containing glial cell derived neurotrophic factor (GDNF), and transplanted subserosally into the denervated area of rat pylorus. In the nerve-ablated pylorus, grafted BMSC survived and migrated from the subserosa to the submucosa 28 days after transplantation, without apparent dedifferentiation. A massive number of PGP9.5/NSE/HuC/D/Tuj1-positive (but GFP- and BBM-negative) neurons were effectively regenerated in denervated pylorus grafted with preconditioned BMSC, suggesting that they were regenerated de novo, not originating from trans-differentiation of the transplanted BMSC. BMSC transplantation restored both basal pyloric contractility and EFS-induced relaxation. High levels of GDNF were induced in both in vitro-preconditioned BMSC as well as the previously denervated pylorus after transplantation of preconditioned BMSC. Thus, a BMSC-initiated GDNF-positive feedback mechanism is suggested to promote neuron regeneration and growth. In summary, we have demonstrated that allogeneically transplanted preconditioned BMSC initiate de novo regeneration of gastric neuronal cells/structures that in turn restore gastric contractility in pylorus-denervated rats. These neuronal structures did not originate from the grafted BMSC. Our data suggest that preconditioned allogeneic BMSC may have therapeutic value in treating enteric nerve disorders.
登录
查看更多内容
DOI：
10.4049/jimmunol.0901657
发表时间：
2010-04-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Alex P;Ye M;Zachos NC;Sipes J;Nguyen T;Suhodrev M;Gonzales L;Arora Z;Zhang T;Centola M;Guggino SE;Li X
通讯作者：
Li X
影响因子：
24.5
作者：
Kulkarni S;Becker L;Pasricha PJ
通讯作者：
Pasricha PJ
影响因子：
5
作者：
Depoortere, I;De Winter, B;Peeters, T
通讯作者：
Peeters, T
DOI：
10.1073/pnas.0910012107
发表时间：
2010-03-02
影响因子：
11.1
作者：
Hu, Bao-Yang;Weick, Jason P.;Zhang, Su-Chun
通讯作者：
Zhang, Su-Chun
影响因子：
4.1
作者：
Dasari, Venkata Ramesh;Veeravalli, Krishna Kumar;Dinh, Dzung H
通讯作者：
Dinh, Dzung H