![]() Stem cells can divide asymmetrically, where one daughter is another stem cell and the other is a differentiating cell. Adult tissues are maintained by tissue stem cells that can both self-renew and differentiate to give rise to transit amplifying cells, which in turn give rise to terminally differentiated cells. Tissue homeostasis is central to the functioning and survival of higher organisms. Summer Salary was obtained from grant DMS-1815406 (DW and NK), DMS-1763272 (NK), U54-CA217378 (DW and JL).Ĭompeting interests: The authors have declared that no competing interests exist. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.ĭata Availability: All relevant data are within the manuscript and its Supporting Information files.įunding: The work was funded by grant NSF DMS-1815406 (DW, NK), grant NIH/NCI U54-CA217378 (JL, DW, NK), and NSF-Simons Center for Multiscale Cell Fate Research, CMCF NSF DMS-1763272 (NK). Received: AugAccepted: MaPublished: May 6, 2022Ĭopyright: © 2022 Uhl et al. ![]() PLoS Comput Biol 18(5):Įditor: Feng Fu, Dartmouth College, UNITED STATES ![]() We further show that control loops can maintain homeostasis in this spatial setting if the negative feedback on stem cell divisions is combined with other, experimentally documented, spatially explicit control mechanisms, indicating that more complex combinations of control loops are instrumental.Ĭitation: Uhl P, Lowengrub J, Komarova N, Wodarz D (2022) Spatial dynamics of feedback and feedforward regulation in cell lineages. Reduction of negative feedback control in the model results in a breakdown of these spatial structures and stem cell enrichment. Negative feedback on stem cell division, however, can lead to the organization of stem and differentiated cells into distinct, spatially separated islands, where stem cells comprise a small fraction of the cell population. Here, we show that this negative feedback mechanism loses the ability to maintain tissue homeostasis in spatially explicit computational models. Typically, however, such models are based on ordinary differential equations, which assume perfect mixing of cells and molecule, while in vivo, tissues are characterized by pronounced spatial structure. This is in part based on the analysis of mathematical models. Negative feedback loops from differentiated cells onto stem cell division patterns, which have been experimentally documented, are thought to contribute to homeostatic regulation. Tissues in higher organisms are maintained at a homeostatic setpoint level, which is determined by a complex set of regulatory mechanisms. This indicates that the dynamics of feedback regulation in tissue cell lineages are more complex than previously thought, and that combinations of spatially explicit control mechanisms are likely instrumental. Tissue homeostasis, however, can be achieved if spatially restricted negative feedback on self-renewal is combined with an experimentally documented spatial feedforward loop, in which stem cells regulate the fate of transit amplifying cells. Although homeostasis cannot be maintained, this feedback can regulate cell density and promote the formation of spatial structures in the model. ![]() According to these models, the negative feedback loop on stem cell self-renewal fails to maintain homeostasis, both under the assumption of strong spatial restrictions and fast migration / diffusion. Here, we investigate these dynamics using spatially explicit computational models, including cell division, differentiation, death, and migration / diffusion processes. Cell lineage dynamics, however, are characterized by spatial structure, which can lead to different properties. Mathematical models that assume well-mixed cell populations, together with experimental data, have suggested that negative feedback from differentiated cells on the stem cell self-renewal probability can maintain a stable equilibrium and hence homeostasis. Feedback mechanisms within cell lineages are thought to be important for maintaining tissue homeostasis. ![]()
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |