Research Laboratories, Department of Surgery, Leipzig University, 04107 Leipzig, Germany.
Interdisciplinary Institute for Bioinformatics (IZBI), Leipzig University, 04107 Leipzig, Germany.
Int J Mol Sci. 2021 Jul 8;22(14):7345. doi: 10.3390/ijms22147345.
Intestinal cylindrical growth peaks in mice a few weeks after birth, simultaneously with crypt fission activity. It nearly stops after weaning and cannot be reactivated later. Transgenic mice expressing / in the intestinal epithelium develop a mega-intestine with normal microscopic morphology in adult mice. Here, we demonstrate premature intestinal differentiation in / transgenic mice at both the cellular and molecular levels until postnatal day 14. Subsequently, the growth of the intestinal epithelium becomes activated and its maturation suppressed. These changes are paralleled by postnatal regulation of growth factors and by an increased expression of secretory cell markers, suggesting growth activation of non-epithelial tissue layers as the origin of enforced tissue growth. To understand postnatal intestinal growth mechanistically, we study epithelial fate decisions during this period with the use of a 3D individual cell-based computer model. In the model, the expansion of the intestinal stem cell (SC) population, a prerequisite for crypt fission, is largely independent of the tissue growth rate and is therefore not spontaneously adaptive. Accordingly, the model suggests that, besides the growth activation of non-epithelial tissue layers, the formation of a mega-intestine requires a released growth control in the epithelium, enabling accelerated SC expansion. The similar intestinal morphology in / transgenic and wild type mice indicates a synchronization of tissue growth and SC expansion, likely by a crypt density-controlled contact inhibition of growth of intestinal SC proliferation. The formation of a mega-intestine with normal microscopic morphology turns out to originate in changes of autonomous and conditional specification of the intestinal cell fate induced by the activation of /
肠圆柱状生长在小鼠出生后几周达到高峰，与隐窝分裂活动同时发生。在断奶后几乎停止，以后不能再被激活。在肠上皮细胞中表达 / 的转基因小鼠在成年小鼠中表现出具有正常微观形态的巨型肠。在这里，我们在 / 转基因小鼠中在细胞和分子水平上证明了过早的肠分化，直到出生后第 14 天。随后，肠上皮的生长被激活，其成熟受到抑制。这些变化与生长因子的出生后调节以及分泌细胞标志物的表达增加相平行，表明非上皮组织层的生长激活是强制组织生长的起源。为了从机制上理解出生后肠生长，我们在这一时期使用基于单个细胞的三维计算机模型研究上皮细胞命运决定。在该模型中，隐窝分裂所必需的肠干细胞（SC）群体的扩张在很大程度上独立于组织生长速率，因此不是自发适应性的。因此，该模型表明，除了非上皮组织层的生长激活外，巨型肠的形成还需要上皮细胞中释放的生长控制，从而能够加速 SC 扩张。/ 转基因和野生型小鼠相似的肠形态表明组织生长和 SC 扩张的同步，可能是通过隐窝密度控制肠 SC 增殖的生长接触抑制。具有正常微观形态的巨型肠的形成原来是由 / 的激活诱导的肠细胞命运的自主和条件特异性变化引起的。
