Thalheim Torsten, Quaas Marianne, Herberg Maria, Braumann Ulf-Dietrich, Kerner Christiane, Loeffler Markus, Aust Gabriela, Galle Joerg
Interdisciplinary Centre for Bioinformatics, Leipzig University, Haertelstr. 16-18, 04107 Leipzig, Germany.
Interdisciplinary Centre for Bioinformatics, Leipzig University, Haertelstr. 16-18, 04107 Leipzig, Germany; Department of Surgery, Research Laboratories, Leipzig University, .Liebigstr. 19, 04103 Leipzig, Germany.
Dev Biol. 2018 Jan 15;433(2):254-261. doi: 10.1016/j.ydbio.2017.10.013. Epub 2017 Nov 30.
Intestinal stem cells (ISCs) require well-defined signals from their environment in order to carry out their specific functions. Most of these signals are provided by neighboring cells that form a stem cell niche, whose shape and cellular composition self-organize. Major features of this self-organization can be studied in ISC-derived organoid culture. In this system, manipulation of essential pathways of stem cell maintenance and differentiation results in well-described growth phenotypes. We here provide an individual cell-based model of intestinal organoids that enables a mechanistic explanation of the observed growth phenotypes. In simulation studies of the 3D structure of expanding organoids, we investigate interdependences between Wnt- and Notch-signaling which control the shape of the stem cell niche and, thus, the growth pattern of the organoids. Similar to in vitro experiments, changes of pathway activities alter the cellular composition of the organoids and, thereby, affect their shape. Exogenous Wnt enforces transitions from branched into a cyst-like growth pattern; known to occur spontaneously during long term organoid expansion. Based on our simulation results, we predict that the cyst-like pattern is associated with biomechanical changes of the cells which assign them a growth advantage. The results suggest ongoing stem cell adaptation to in vitro conditions during long term expansion by stabilizing Wnt-activity. Our study exemplifies the potential of individual cell-based modeling in unraveling links between molecular stem cell regulation and 3D growth of tissues. This kind of modeling combines experimental results in the fields of stem cell biology and cell biomechanics constituting a prerequisite for a better understanding of tissue regeneration as well as developmental processes.
肠道干细胞（ISC）需要来自其周围环境的明确信号才能执行其特定功能。这些信号大多由形成干细胞微环境的相邻细胞提供，该微环境的形状和细胞组成会自我组织。这种自我组织的主要特征可以在源自ISC的类器官培养中进行研究。在这个系统中，对干细胞维持和分化的关键途径进行操作会导致描述清晰的生长表型。我们在此提供了一种基于单个细胞的肠道类器官模型，该模型能够对观察到的生长表型进行机制性解释。在对不断扩张的类器官的三维结构进行模拟研究时，我们研究了控制干细胞微环境形状进而控制类器官生长模式的Wnt信号和Notch信号之间的相互依赖性。与体外实验类似，途径活性的变化会改变类器官的细胞组成，从而影响其形状。外源性Wnt会促使类器官从分支状生长模式转变为囊状生长模式；已知这种转变在类器官长期扩张过程中会自发发生。基于我们的模拟结果，我们预测囊状模式与赋予细胞生长优势的生物力学变化有关。结果表明，在长期扩张过程中，干细胞通过稳定Wnt活性来持续适应体外条件。我们的研究例证了基于单个细胞的建模在揭示分子干细胞调控与组织三维生长之间联系方面的潜力。这种建模结合了干细胞生物学和细胞生物力学领域的实验结果，是更好地理解组织再生以及发育过程的先决条件。
