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Age-dependent transition from cell-level to population-level control in murine intestinal homeostasis revealed by coalescence analysis.

Hu Z, Fu YX, Greenberg AJ, Wu CI, Zhai W - PLoS Genet. (2013)

Bottom Line: This equilibrium can be achieved either at the single cell level (a.k.a. cell asymmetry), where stem cells follow strict asymmetric divisions, or the population level (a.k.a. population asymmetry), where gains and losses in individual stem cell lineages are randomly distributed, but the net effect is homeostasis.In this work, using population genetic theory together with previously published crypt single-cell data obtained at different mouse life stages, we reveal a strikingly dynamic pattern of stem cell homeostatic control.This lifelong process has important developmental and evolutionary implications in understanding how adult tissues maintain their homeostasis integrating the trade-off between intrinsic and extrinsic regulations.

View Article: PubMed Central - PubMed

Affiliation: Center for Computational Biology and Laboratory of Disease Genomics and Individualized Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.

ABSTRACT
In multi-cellular organisms, tissue homeostasis is maintained by an exquisite balance between stem cell proliferation and differentiation. This equilibrium can be achieved either at the single cell level (a.k.a. cell asymmetry), where stem cells follow strict asymmetric divisions, or the population level (a.k.a. population asymmetry), where gains and losses in individual stem cell lineages are randomly distributed, but the net effect is homeostasis. In the mature mouse intestinal crypt, previous evidence has revealed a pattern of population asymmetry through predominantly symmetric divisions of stem cells. In this work, using population genetic theory together with previously published crypt single-cell data obtained at different mouse life stages, we reveal a strikingly dynamic pattern of stem cell homeostatic control. We find that single-cell asymmetric divisions are gradually replaced by stochastic population-level asymmetry as the mouse matures to adulthood. This lifelong process has important developmental and evolutionary implications in understanding how adult tissues maintain their homeostasis integrating the trade-off between intrinsic and extrinsic regulations.

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Phylogenetic relationships for the crypt single cells and likelihood curve for the proportion of asymmetric divisions.(A) Unweighted Pair Group Method with Arithmetic mean(UPGMA) tree [66] for the cells sampled from the two crypts at day 52. Distances were calculated using the two-step mutation model. (B) UPGMA tree for day 340. (C) Likelihood curve as a function of the proportion of asymmetric divisions for one of the crypts at day 52. (D) The same plot as panel C, but for the other crypt at day 52. (E) Likelihood curve as a function of the proportion of asymmetric divisions for one of the crypt at day 340. (F) The same plot as panel E, but for the other crypt at day 340. (G) Likelihood curve as a function of the proportion of asymmetric divisions for day 52 (combining two crypts). The horizontal dashed line marks the level of likelihood that is 1.92 units (0.5×) below the maximal value. The confidence interval (CI) for the proportion of asymmetric division rate is shown as the arrow between the two vertical dashed lines. (H). Likelihood curve as a function of the proportion of asymmetric divisions for day 340 (combining two crypts). The horizontal dashed line marks the level of likelihood that is 1.92 units below the maximal value. The confidence interval (CI) for the proportion of asymmetric division rate is shown as the arrow between the two vertical dashed lines. (I) A demonstration of the phenomena that the gene tree will increase in size as the crypt population reaches equilibrium (stationarity). The genealogical tree size (indicated as the mean pairwise divergence for two randomly picked cells) at different cell generation (generation 10, 30, 80 as well as equilibrium point) for the crypt population are shown (β = 0.4). The observed pairwise divergence for day 52 and day 340 are also plotted.
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pgen-1003326-g002: Phylogenetic relationships for the crypt single cells and likelihood curve for the proportion of asymmetric divisions.(A) Unweighted Pair Group Method with Arithmetic mean(UPGMA) tree [66] for the cells sampled from the two crypts at day 52. Distances were calculated using the two-step mutation model. (B) UPGMA tree for day 340. (C) Likelihood curve as a function of the proportion of asymmetric divisions for one of the crypts at day 52. (D) The same plot as panel C, but for the other crypt at day 52. (E) Likelihood curve as a function of the proportion of asymmetric divisions for one of the crypt at day 340. (F) The same plot as panel E, but for the other crypt at day 340. (G) Likelihood curve as a function of the proportion of asymmetric divisions for day 52 (combining two crypts). The horizontal dashed line marks the level of likelihood that is 1.92 units (0.5×) below the maximal value. The confidence interval (CI) for the proportion of asymmetric division rate is shown as the arrow between the two vertical dashed lines. (H). Likelihood curve as a function of the proportion of asymmetric divisions for day 340 (combining two crypts). The horizontal dashed line marks the level of likelihood that is 1.92 units below the maximal value. The confidence interval (CI) for the proportion of asymmetric division rate is shown as the arrow between the two vertical dashed lines. (I) A demonstration of the phenomena that the gene tree will increase in size as the crypt population reaches equilibrium (stationarity). The genealogical tree size (indicated as the mean pairwise divergence for two randomly picked cells) at different cell generation (generation 10, 30, 80 as well as equilibrium point) for the crypt population are shown (β = 0.4). The observed pairwise divergence for day 52 and day 340 are also plotted.

Mentions: Using a two-step mutation model for micro-satellite markers, we first calculated the genetic distances between all sampled cells (Materials and Methods). As shown in Figure 2, individual cells within an intestinal crypt are monophyletic and are clonally related. Between-crypt divergence rapidly increases with age (Figure 2B), in agreement with previous observations of fast clonal turnover in intestinal crypts [23].


Age-dependent transition from cell-level to population-level control in murine intestinal homeostasis revealed by coalescence analysis.

Hu Z, Fu YX, Greenberg AJ, Wu CI, Zhai W - PLoS Genet. (2013)

Phylogenetic relationships for the crypt single cells and likelihood curve for the proportion of asymmetric divisions.(A) Unweighted Pair Group Method with Arithmetic mean(UPGMA) tree [66] for the cells sampled from the two crypts at day 52. Distances were calculated using the two-step mutation model. (B) UPGMA tree for day 340. (C) Likelihood curve as a function of the proportion of asymmetric divisions for one of the crypts at day 52. (D) The same plot as panel C, but for the other crypt at day 52. (E) Likelihood curve as a function of the proportion of asymmetric divisions for one of the crypt at day 340. (F) The same plot as panel E, but for the other crypt at day 340. (G) Likelihood curve as a function of the proportion of asymmetric divisions for day 52 (combining two crypts). The horizontal dashed line marks the level of likelihood that is 1.92 units (0.5×) below the maximal value. The confidence interval (CI) for the proportion of asymmetric division rate is shown as the arrow between the two vertical dashed lines. (H). Likelihood curve as a function of the proportion of asymmetric divisions for day 340 (combining two crypts). The horizontal dashed line marks the level of likelihood that is 1.92 units below the maximal value. The confidence interval (CI) for the proportion of asymmetric division rate is shown as the arrow between the two vertical dashed lines. (I) A demonstration of the phenomena that the gene tree will increase in size as the crypt population reaches equilibrium (stationarity). The genealogical tree size (indicated as the mean pairwise divergence for two randomly picked cells) at different cell generation (generation 10, 30, 80 as well as equilibrium point) for the crypt population are shown (β = 0.4). The observed pairwise divergence for day 52 and day 340 are also plotted.
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pgen-1003326-g002: Phylogenetic relationships for the crypt single cells and likelihood curve for the proportion of asymmetric divisions.(A) Unweighted Pair Group Method with Arithmetic mean(UPGMA) tree [66] for the cells sampled from the two crypts at day 52. Distances were calculated using the two-step mutation model. (B) UPGMA tree for day 340. (C) Likelihood curve as a function of the proportion of asymmetric divisions for one of the crypts at day 52. (D) The same plot as panel C, but for the other crypt at day 52. (E) Likelihood curve as a function of the proportion of asymmetric divisions for one of the crypt at day 340. (F) The same plot as panel E, but for the other crypt at day 340. (G) Likelihood curve as a function of the proportion of asymmetric divisions for day 52 (combining two crypts). The horizontal dashed line marks the level of likelihood that is 1.92 units (0.5×) below the maximal value. The confidence interval (CI) for the proportion of asymmetric division rate is shown as the arrow between the two vertical dashed lines. (H). Likelihood curve as a function of the proportion of asymmetric divisions for day 340 (combining two crypts). The horizontal dashed line marks the level of likelihood that is 1.92 units below the maximal value. The confidence interval (CI) for the proportion of asymmetric division rate is shown as the arrow between the two vertical dashed lines. (I) A demonstration of the phenomena that the gene tree will increase in size as the crypt population reaches equilibrium (stationarity). The genealogical tree size (indicated as the mean pairwise divergence for two randomly picked cells) at different cell generation (generation 10, 30, 80 as well as equilibrium point) for the crypt population are shown (β = 0.4). The observed pairwise divergence for day 52 and day 340 are also plotted.
Mentions: Using a two-step mutation model for micro-satellite markers, we first calculated the genetic distances between all sampled cells (Materials and Methods). As shown in Figure 2, individual cells within an intestinal crypt are monophyletic and are clonally related. Between-crypt divergence rapidly increases with age (Figure 2B), in agreement with previous observations of fast clonal turnover in intestinal crypts [23].

Bottom Line: This equilibrium can be achieved either at the single cell level (a.k.a. cell asymmetry), where stem cells follow strict asymmetric divisions, or the population level (a.k.a. population asymmetry), where gains and losses in individual stem cell lineages are randomly distributed, but the net effect is homeostasis.In this work, using population genetic theory together with previously published crypt single-cell data obtained at different mouse life stages, we reveal a strikingly dynamic pattern of stem cell homeostatic control.This lifelong process has important developmental and evolutionary implications in understanding how adult tissues maintain their homeostasis integrating the trade-off between intrinsic and extrinsic regulations.

View Article: PubMed Central - PubMed

Affiliation: Center for Computational Biology and Laboratory of Disease Genomics and Individualized Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.

ABSTRACT
In multi-cellular organisms, tissue homeostasis is maintained by an exquisite balance between stem cell proliferation and differentiation. This equilibrium can be achieved either at the single cell level (a.k.a. cell asymmetry), where stem cells follow strict asymmetric divisions, or the population level (a.k.a. population asymmetry), where gains and losses in individual stem cell lineages are randomly distributed, but the net effect is homeostasis. In the mature mouse intestinal crypt, previous evidence has revealed a pattern of population asymmetry through predominantly symmetric divisions of stem cells. In this work, using population genetic theory together with previously published crypt single-cell data obtained at different mouse life stages, we reveal a strikingly dynamic pattern of stem cell homeostatic control. We find that single-cell asymmetric divisions are gradually replaced by stochastic population-level asymmetry as the mouse matures to adulthood. This lifelong process has important developmental and evolutionary implications in understanding how adult tissues maintain their homeostasis integrating the trade-off between intrinsic and extrinsic regulations.

Show MeSH
Related in: MedlinePlus