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Control of Caenorhabditis elegans germ-line stem-cell cycling speed meets requirements of design to minimize mutation accumulation.

Chiang M, Cinquin A, Paz A, Meeds E, Price CA, Welling M, Cinquin O - BMC Biol. (2015)

Bottom Line: Computational simulations of mutation accumulation characterize a tradeoff between fast development and low mutation accumulation, and show that slow-cycling stem cells allow for an advantageous compromise to be reached.Experimental measurements of cell cycle lengths derived using a new, quantitative technique are consistent with these predictions.Our findings shed light both on design principles that underlie the role of stem cells in delaying aging and on evolutionary forces that shape stem-cell gene regulatory networks.

View Article: PubMed Central - PubMed

Affiliation: Department of Developmental & Cell Biology, University of California, Irvine, California, USA.

ABSTRACT

Background: Stem cells are thought to play a critical role in minimizing the accumulation of mutations, but it is not clear which strategies they follow to fulfill that performance objective. Slow cycling of stem cells provides a simple strategy that can minimize cell pedigree depth and thereby minimize the accumulation of replication-dependent mutations. Although the power of this strategy was recognized early on, a quantitative assessment of whether and how it is employed by biological systems is missing.

Results: Here we address this problem using a simple self-renewing organ - the C. elegans gonad - whose overall organization is shared with many self-renewing organs. Computational simulations of mutation accumulation characterize a tradeoff between fast development and low mutation accumulation, and show that slow-cycling stem cells allow for an advantageous compromise to be reached. This compromise is such that worm germ-line stem cells should cycle more slowly than their differentiating counterparts, but only by a modest amount. Experimental measurements of cell cycle lengths derived using a new, quantitative technique are consistent with these predictions.

Conclusions: Our findings shed light both on design principles that underlie the role of stem cells in delaying aging and on evolutionary forces that shape stem-cell gene regulatory networks.

No MeSH data available.


Related in: MedlinePlus

Slow-cycling stem cells allow for an advantageous tradeoff between pedigree-depth minimization and early production of differentiated cells. a Average pedigree depth (P.D.) of differentiated cells, defined as the average number of divisions between differentiated cells and the founding progenitor, is minimized by balanced trees (i.e. trees where no pair of cells at the bottom of the tree has pedigree depths that differ by more than one), but differentiated cells (yellow) are not produced until all cells have finished dividing. In this optimal configuration, P.D. = log2(n) where the total number of cells to be produced n = 8. β is the tree balance as defined by [39] (range: 0–0.5, with 0.5 corresponding to perfect balance). The gray outline indicates sister subtrees that are the least balanced (most relevant to b and c). The time axis units are given in rounds of cell division. The individual pedigree depth of differentiated cells is shown as the inset number. b Early production of differentiated cells can be obtained by successive rounds of asymmetric divisions of a progenitor cell (blue), at the cost of a substantial increase in average pedigree depth. c Pedigree trees can be shaped to allow for early differentiated cell production without incurring a large pedigree-depth penalty. d–f Pedigree tree shape can be controlled by modulating the cycling speed of a stem cell located at the distal end of a model tubular organ. Cells are pushed out toward the proximal end as a result of proliferation, and differentiate when reaching a threshold distance from the distal end (yellow). α is the ratio of the cycling speed of non-stem cells to the cycling speed of the stem cell (the higher α, the lower the relative stem-cell cycle speed). Inset numbers show cell pedigree depth as in (a–c). d If only the stem cell cycles, the pedigree tree is similar to that in (b) and the average pedigree depth is high. e If the stem-cell cycles are ~30 % slower than other cells in the MZ, the pedigree-depth tree is more balanced. f It is not beneficial for the stem cell to cycle more slowly than in (e): pedigree depth increases as a result of the increased cycling that other cells in the MZ must undergo to produce the desired cell number. g There exists a single optimal value of α that minimizes the average pedigree depth within the context of models shown in (d–f); the optimal α increases as the total number n of cells to be produced increases (compare blue, red, and green curves). In other words, the more cells in total are to be produced, the slower stem cells should cycle to preserve the low pedigree depth
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Fig2: Slow-cycling stem cells allow for an advantageous tradeoff between pedigree-depth minimization and early production of differentiated cells. a Average pedigree depth (P.D.) of differentiated cells, defined as the average number of divisions between differentiated cells and the founding progenitor, is minimized by balanced trees (i.e. trees where no pair of cells at the bottom of the tree has pedigree depths that differ by more than one), but differentiated cells (yellow) are not produced until all cells have finished dividing. In this optimal configuration, P.D. = log2(n) where the total number of cells to be produced n = 8. β is the tree balance as defined by [39] (range: 0–0.5, with 0.5 corresponding to perfect balance). The gray outline indicates sister subtrees that are the least balanced (most relevant to b and c). The time axis units are given in rounds of cell division. The individual pedigree depth of differentiated cells is shown as the inset number. b Early production of differentiated cells can be obtained by successive rounds of asymmetric divisions of a progenitor cell (blue), at the cost of a substantial increase in average pedigree depth. c Pedigree trees can be shaped to allow for early differentiated cell production without incurring a large pedigree-depth penalty. d–f Pedigree tree shape can be controlled by modulating the cycling speed of a stem cell located at the distal end of a model tubular organ. Cells are pushed out toward the proximal end as a result of proliferation, and differentiate when reaching a threshold distance from the distal end (yellow). α is the ratio of the cycling speed of non-stem cells to the cycling speed of the stem cell (the higher α, the lower the relative stem-cell cycle speed). Inset numbers show cell pedigree depth as in (a–c). d If only the stem cell cycles, the pedigree tree is similar to that in (b) and the average pedigree depth is high. e If the stem-cell cycles are ~30 % slower than other cells in the MZ, the pedigree-depth tree is more balanced. f It is not beneficial for the stem cell to cycle more slowly than in (e): pedigree depth increases as a result of the increased cycling that other cells in the MZ must undergo to produce the desired cell number. g There exists a single optimal value of α that minimizes the average pedigree depth within the context of models shown in (d–f); the optimal α increases as the total number n of cells to be produced increases (compare blue, red, and green curves). In other words, the more cells in total are to be produced, the slower stem cells should cycle to preserve the low pedigree depth

Mentions: Many organs are generated and subsequently self-renew by amplification of a progenitor cell through multiple rounds of cell division. The magnitude of the accumulation of DNA replication-dependent mutations that results from this amplification is heavily dependent on the cell cycle control strategy that is followed. Accumulation of replication-dependent mutations is best understood by considering the pedigree of all cells that descend from the primordial progenitor (Fig. 2a–c). This pedigree forms a structure known in computer science as a binary tree, where in this case each cell has either zero or two descendants. We define the pedigree depth of a cell as the number of divisions separating a cell from the primordial germ cell. The average number of replication-dependent mutations in an organ is then proportional to the average pedigree depth. Average pedigree depth is minimized when trees are balanced, i.e. when no pairs of cells at the bottom of the tree have pedigree depths that differ by more than one [38, 39]. The performance of cell cycle control strategies in terms of replication-dependent mutation accumulation can thus be assayed by the balance in the cell pedigree trees that they produce.Fig. 2


Control of Caenorhabditis elegans germ-line stem-cell cycling speed meets requirements of design to minimize mutation accumulation.

Chiang M, Cinquin A, Paz A, Meeds E, Price CA, Welling M, Cinquin O - BMC Biol. (2015)

Slow-cycling stem cells allow for an advantageous tradeoff between pedigree-depth minimization and early production of differentiated cells. a Average pedigree depth (P.D.) of differentiated cells, defined as the average number of divisions between differentiated cells and the founding progenitor, is minimized by balanced trees (i.e. trees where no pair of cells at the bottom of the tree has pedigree depths that differ by more than one), but differentiated cells (yellow) are not produced until all cells have finished dividing. In this optimal configuration, P.D. = log2(n) where the total number of cells to be produced n = 8. β is the tree balance as defined by [39] (range: 0–0.5, with 0.5 corresponding to perfect balance). The gray outline indicates sister subtrees that are the least balanced (most relevant to b and c). The time axis units are given in rounds of cell division. The individual pedigree depth of differentiated cells is shown as the inset number. b Early production of differentiated cells can be obtained by successive rounds of asymmetric divisions of a progenitor cell (blue), at the cost of a substantial increase in average pedigree depth. c Pedigree trees can be shaped to allow for early differentiated cell production without incurring a large pedigree-depth penalty. d–f Pedigree tree shape can be controlled by modulating the cycling speed of a stem cell located at the distal end of a model tubular organ. Cells are pushed out toward the proximal end as a result of proliferation, and differentiate when reaching a threshold distance from the distal end (yellow). α is the ratio of the cycling speed of non-stem cells to the cycling speed of the stem cell (the higher α, the lower the relative stem-cell cycle speed). Inset numbers show cell pedigree depth as in (a–c). d If only the stem cell cycles, the pedigree tree is similar to that in (b) and the average pedigree depth is high. e If the stem-cell cycles are ~30 % slower than other cells in the MZ, the pedigree-depth tree is more balanced. f It is not beneficial for the stem cell to cycle more slowly than in (e): pedigree depth increases as a result of the increased cycling that other cells in the MZ must undergo to produce the desired cell number. g There exists a single optimal value of α that minimizes the average pedigree depth within the context of models shown in (d–f); the optimal α increases as the total number n of cells to be produced increases (compare blue, red, and green curves). In other words, the more cells in total are to be produced, the slower stem cells should cycle to preserve the low pedigree depth
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Related In: Results  -  Collection

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Fig2: Slow-cycling stem cells allow for an advantageous tradeoff between pedigree-depth minimization and early production of differentiated cells. a Average pedigree depth (P.D.) of differentiated cells, defined as the average number of divisions between differentiated cells and the founding progenitor, is minimized by balanced trees (i.e. trees where no pair of cells at the bottom of the tree has pedigree depths that differ by more than one), but differentiated cells (yellow) are not produced until all cells have finished dividing. In this optimal configuration, P.D. = log2(n) where the total number of cells to be produced n = 8. β is the tree balance as defined by [39] (range: 0–0.5, with 0.5 corresponding to perfect balance). The gray outline indicates sister subtrees that are the least balanced (most relevant to b and c). The time axis units are given in rounds of cell division. The individual pedigree depth of differentiated cells is shown as the inset number. b Early production of differentiated cells can be obtained by successive rounds of asymmetric divisions of a progenitor cell (blue), at the cost of a substantial increase in average pedigree depth. c Pedigree trees can be shaped to allow for early differentiated cell production without incurring a large pedigree-depth penalty. d–f Pedigree tree shape can be controlled by modulating the cycling speed of a stem cell located at the distal end of a model tubular organ. Cells are pushed out toward the proximal end as a result of proliferation, and differentiate when reaching a threshold distance from the distal end (yellow). α is the ratio of the cycling speed of non-stem cells to the cycling speed of the stem cell (the higher α, the lower the relative stem-cell cycle speed). Inset numbers show cell pedigree depth as in (a–c). d If only the stem cell cycles, the pedigree tree is similar to that in (b) and the average pedigree depth is high. e If the stem-cell cycles are ~30 % slower than other cells in the MZ, the pedigree-depth tree is more balanced. f It is not beneficial for the stem cell to cycle more slowly than in (e): pedigree depth increases as a result of the increased cycling that other cells in the MZ must undergo to produce the desired cell number. g There exists a single optimal value of α that minimizes the average pedigree depth within the context of models shown in (d–f); the optimal α increases as the total number n of cells to be produced increases (compare blue, red, and green curves). In other words, the more cells in total are to be produced, the slower stem cells should cycle to preserve the low pedigree depth
Mentions: Many organs are generated and subsequently self-renew by amplification of a progenitor cell through multiple rounds of cell division. The magnitude of the accumulation of DNA replication-dependent mutations that results from this amplification is heavily dependent on the cell cycle control strategy that is followed. Accumulation of replication-dependent mutations is best understood by considering the pedigree of all cells that descend from the primordial progenitor (Fig. 2a–c). This pedigree forms a structure known in computer science as a binary tree, where in this case each cell has either zero or two descendants. We define the pedigree depth of a cell as the number of divisions separating a cell from the primordial germ cell. The average number of replication-dependent mutations in an organ is then proportional to the average pedigree depth. Average pedigree depth is minimized when trees are balanced, i.e. when no pairs of cells at the bottom of the tree have pedigree depths that differ by more than one [38, 39]. The performance of cell cycle control strategies in terms of replication-dependent mutation accumulation can thus be assayed by the balance in the cell pedigree trees that they produce.Fig. 2

Bottom Line: Computational simulations of mutation accumulation characterize a tradeoff between fast development and low mutation accumulation, and show that slow-cycling stem cells allow for an advantageous compromise to be reached.Experimental measurements of cell cycle lengths derived using a new, quantitative technique are consistent with these predictions.Our findings shed light both on design principles that underlie the role of stem cells in delaying aging and on evolutionary forces that shape stem-cell gene regulatory networks.

View Article: PubMed Central - PubMed

Affiliation: Department of Developmental & Cell Biology, University of California, Irvine, California, USA.

ABSTRACT

Background: Stem cells are thought to play a critical role in minimizing the accumulation of mutations, but it is not clear which strategies they follow to fulfill that performance objective. Slow cycling of stem cells provides a simple strategy that can minimize cell pedigree depth and thereby minimize the accumulation of replication-dependent mutations. Although the power of this strategy was recognized early on, a quantitative assessment of whether and how it is employed by biological systems is missing.

Results: Here we address this problem using a simple self-renewing organ - the C. elegans gonad - whose overall organization is shared with many self-renewing organs. Computational simulations of mutation accumulation characterize a tradeoff between fast development and low mutation accumulation, and show that slow-cycling stem cells allow for an advantageous compromise to be reached. This compromise is such that worm germ-line stem cells should cycle more slowly than their differentiating counterparts, but only by a modest amount. Experimental measurements of cell cycle lengths derived using a new, quantitative technique are consistent with these predictions.

Conclusions: Our findings shed light both on design principles that underlie the role of stem cells in delaying aging and on evolutionary forces that shape stem-cell gene regulatory networks.

No MeSH data available.


Related in: MedlinePlus