Abstract
Successful maintenance of cellular lineages critically depends on the fate decision dynamics of stem cells (SCs) upon division. There are three possible strategies with respect to SC fate decision symmetry: (a) asymmetric mode, when each and every SC division produces one SC and one non-SC progeny; (b) symmetric mode, when 50% of all divisions produce two SCs and another 50%—two non-SC progeny; (c) mixed mode, when both the asymmetric and two types of symmetric SC divisions co-exist and are partitioned so that long-term net balance of the lineage output stays constant. Theoretically, either of these strategies can achieve lineage homeostasis. However, it remains unclear which strategy(s) are more advantageous and under what specific circumstances, and what minimal control mechanisms are required to operate them. Here we used stochastic modeling to analyze and quantify the ability of different types of divisions to maintain long-term lineage homeostasis, in the context of different control networks. Using the example of a two-component lineage, consisting of SCs and one type of non-SC progeny, we show that its tight homeostatic control is not necessarily associated with purely asymmetric divisions. Through stochastic analysis and simulations we show that asymmetric divisions can either stabilize or destabilize the lineage system, depending on the underlying control network. We further apply our computational model to biological observations in the context of a two-component lineage of mouse epidermis, where autonomous lineage control has been proposed and notable regional differences, in terms of symmetric division ratio, have been noted—higher in thickened epidermis of the paw skin as compared to ear and tail skin. By using our model we propose a possible explanation for the regional differences in epidermal lineage control strategies. We demonstrate how symmetric divisions can work to stabilize paw epidermis lineage, which experiences high level of micro-injuries and a lack of hair follicles as a back-up source of SCs.
Highlights
All cells within the body organize into distinct phylogenetic lineages
We ask the question: what engineering design principles might be responsible for optimization of stem cell division strategies? simple intuition may suggest that asymmetric divisions are better suited for stable maintenance of cell population numbers, our analysis shows that asymmetric divisions can destabilize the system, depending on the particular “wiring” of the control loops that govern cellular fate decision making
We apply our theory to one particular unresolved question in mouse epidermis studies— why symmetric division percentage in paw epidermis is twice as high as that in ear and tail? The answer may be related to the fact that paw epidermis lacks hair follicles, and it is more injury-prone: symmetric divisions help stabilize skin in face of physical stresses from running, digging, grooming, and fighting—things that mice do with their paws
Summary
All cells within the body organize into distinct phylogenetic lineages. At the end of each lineage are the non-dividing, terminally differentiated cells. Tissue-specific SCs are long lasting and self-renewing (i.e. at least 50% of SC progeny remain as SCs) [2, 3] They maintain high proliferative potential and assure lifelong lineage survival both under physiological steady-state conditions, and upon lineage depletion after injury or disease. Transplantation of a single hematopoietic SC can reconstitute the entire bone marrow in lethally irradiated mice that would otherwise die from the inability to make new blood [5,6,7] Another example is scarring alopecia, the type of baldness caused by the autoimmune attack on hair SCs—once SCs are lost, hairs can never grow again [8, 9]
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