PDF(Pubmed)
Abstract：
Phosphatase and tensin homolog (Pten) is a key regulator of cell proliferation and a potential target to stimulate postnatal enteric neuro- and/or gliogenesis. To investigate this, we generated two tamoxifen-inducible Cre recombinase murine models in which Pten was conditionally ablated, (1) in glia (Plp1-expressing cells) and (2) in neurons (Calb2-expressing cells). Tamoxifen-treated adult (7-12 weeks of age; n = 4-15) mice were given DSS to induce colitis, EdU to monitor cell proliferation, and were evaluated at two timepoints: (1) early (3-4 days post-DSS) and (2) late (3-4 weeks post-DSS). We investigated gut motility and evaluated the enteric nervous system. Pten inhibition in Plp1-expressing cells elicited gliogenesis at baseline and post-DSS (early and late) in the colon, and neurogenesis post-DSS late in the proximal colon. They also exhibited an increased frequency of colonic migrating motor complexes (CMMC) and slower whole gut transit times. Pten inhibition in Calb2-expressing cells did not induce enteric neuro- or gliogenesis, and no alterations were detected in CMMC or whole gut transit times when compared to the control at baseline or post-DSS (early and late). Our results merit further research into Pten modulation where increased glia and/or slower intestinal transit times are desired (e.g., short-bowel syndrome and rapid-transit disorders).
摘要：
磷酸酶和张力蛋白同源物（Pten）是细胞增殖的关键调节剂，也是刺激出生后肠神经和/或神经胶质生成的潜在靶标。为了调查这一点，我们产生了两个他莫昔芬诱导型Cre重组酶鼠模型，其中Pten被有条件地消除，（1）在神经胶质中（表达Plp1的细胞）和（2）在神经元中（表达Calb2的细胞）。给予他莫昔芬治疗的成年（7-12周龄；n=4-15）小鼠DSS诱导结肠炎，EdU监测细胞增殖，并在两个时间点进行评估：（1）早期（DSS后3-4天）和（2）晚期（DSS后3-4周）。我们调查了肠动力并评估了肠神经系统。表达Plp1的细胞中的Pten抑制在基线和DSS后（早期和晚期）在结肠中引起神经胶质形成，和DSS后的神经发生在近端结肠晚期。它们还表现出结肠迁移运动复合物（CMMC）的频率增加和整个肠道运输时间较慢。表达Calb2的细胞中的Pten抑制不会诱导肠神经或神经胶质的形成，与基线或DSS后（早期和晚期）的对照相比，在CMMC或整个肠道运输时间中未检测到改变。我们的结果值得进一步研究Pten调制，其中需要增加胶质细胞和/或较慢的肠道运输时间（例如，短肠综合征和快速运输障碍)。
