Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, 44227 Dortmund, Germany.
Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, 44227 Dortmund, Germany
Development. 2021 Feb 15;148(3):dev197608. doi: 10.1242/dev.197608.
During mammalian development and homeostasis, cells often transition from a multilineage primed state to one of several differentiated cell types that are marked by the expression of mutually exclusive genetic markers. These observations have been classically explained by single-cell multistability as the dynamical basis of differentiation, where robust cell-type proportioning relies on pre-existing cell-to-cell differences. We propose a conceptually different dynamical mechanism in which cell types emerge and are maintained collectively by cell-cell communication as a novel inhomogeneous state of the coupled system. Differentiation can be triggered by cell number increase as the population grows in size, through organisation of the initial homogeneous population before the symmetry-breaking bifurcation point. Robust proportioning and reliable recovery of the differentiated cell types following a perturbation is an inherent feature of the inhomogeneous state that is collectively maintained. This dynamical mechanism is valid for systems with steady-state or oscillatory single-cell dynamics. Therefore, our results suggest that timing and subsequent differentiation in robust cell-type proportions can emerge from the cooperative behaviour of growing cell populations during development.
在哺乳动物的发育和稳态过程中，细胞通常从多能状态转变为几种分化细胞类型之一，这些分化细胞类型的特征是表达相互排斥的遗传标记。这些观察结果经典地解释为单细胞多稳定性作为分化的动力学基础，其中稳健的细胞类型比例依赖于预先存在的细胞间差异。我们提出了一个概念上不同的动力学机制，其中细胞类型通过细胞间通讯作为耦合系统的新非均匀状态集体出现和维持。分化可以通过细胞数量的增加来触发，因为种群在大小上增长，通过在对称破缺分岔点之前对初始同质种群进行组织。在受到干扰后，稳健的比例和可靠的分化细胞类型的恢复是集体维持的非均匀状态的固有特征。这种动力学机制适用于具有稳态或振荡单细胞动力学的系统。因此，我们的结果表明，在发育过程中，生长细胞群体的协作行为可以产生稳健的细胞类型比例的定时和随后的分化。
