Renardy Marissa, Jilkine Alexandra, Shahriyari Leili, Chou Ching-Shan
Department of Mathematics, Ohio State University, Columbus, OH, USA.
Department of Applied and Computational Mathematics and Statistics, University of Notre Dame, Notre Dame, IN, USA.
J Theor Biol. 2018 May 14;445:33-50. doi: 10.1016/j.jtbi.2018.02.017. Epub 2018 Feb 20.
Multicellular tissues are continually turning over, and homeostasis is maintained through regulated proliferation and differentiation of stem cells and progenitors. Following tissue injury, a dramatic increase in cell proliferation is commonly observed, resulting in rapid restoration of tissue size. This regulation is thought to occur via multiple feedback loops acting on cell self-renewal or differentiation. Models of ordinary differential equations have been widely used to study the cell lineage system. Prior modeling studies have suggested that loss of homeostasis and initiation of tumorigenesis can be contributed to the loss of control of these processes, and the rate of symmetric versus asymmetric division of the stem cells may also be altered. While most of the previous works focused on analysis of stability, existence and uniqueness of steady states of multistage cell lineage models, in this work we attempt to understand the cell lineage model from a different perspective. We compare three variants of hierarchical stem cell lineage tissue models with different combinations of negative feedbacks and use sensitivity analysis to examine the possible strategies for the cells to achieve certain performance objectives. Our results suggest that multiple negative feedback loops must be present in the stem cell lineage to keep the fractions of stem cells to differentiated cells in the total population as robust as possible to variations in cell division parameters, and to minimize the time for tissue recovery in a non-oscillatory manner.
多细胞组织在不断更新，通过干细胞和祖细胞的增殖与分化调控来维持体内平衡。组织损伤后，通常会观察到细胞增殖显著增加，从而使组织大小迅速恢复。这种调控被认为是通过作用于细胞自我更新或分化的多个反馈回路来实现的。常微分方程模型已被广泛用于研究细胞谱系系统。先前的建模研究表明，体内平衡的丧失和肿瘤发生的起始可能归因于这些过程控制的丧失，并且干细胞对称与不对称分裂的速率也可能发生改变。虽然之前的大多数工作都集中在分析多阶段细胞谱系模型稳态的稳定性、存在性和唯一性，但在这项工作中，我们试图从不同的角度理解细胞谱系模型。我们比较了具有不同负反馈组合的分层干细胞谱系组织模型的三种变体，并使用敏感性分析来研究细胞实现某些性能目标的可能策略。我们的结果表明，干细胞谱系中必须存在多个负反馈回路，以使干细胞在总群体中相对于分化细胞的比例对细胞分裂参数的变化尽可能稳健，并以非振荡的方式最小化组织恢复时间。
