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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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Anatomy of intestinal crypts and coalescent processes for the two-deme model.(A) Anatomical structure of the intestinal crypt. The dark green cells represent stem cells and light green cells are transit-amplifying cells. There are three types of stem cells divisions (I, II and III, see main text). (B) A cartoon illustration of a coalescent process in the two deme model. One cell from stem cell deme and two cells from the transit-amplifying cell deme were sampled. Their ancestral relationship is depicted as the gene tree connecting their ancestors. (C) The state transition for the Markov Chain in one step. The current state of the chain is (m,n) and the state in the previous generation is (m′,n′). In the example here, (m,n) = (1,3) and (m′,n′) = (2,1). (D) The expected time to the most recent common ancestor for two lineages (denoted as TMRCA2) was calculated using three different approaches. The solid line is calculated using a first-step analysis of the Markov Chain. Blue squares are the results from the forward simulation and triangles are from the direct simulation following the Markov Chain.
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pgen-1003326-g001: Anatomy of intestinal crypts and coalescent processes for the two-deme model.(A) Anatomical structure of the intestinal crypt. The dark green cells represent stem cells and light green cells are transit-amplifying cells. There are three types of stem cells divisions (I, II and III, see main text). (B) A cartoon illustration of a coalescent process in the two deme model. One cell from stem cell deme and two cells from the transit-amplifying cell deme were sampled. Their ancestral relationship is depicted as the gene tree connecting their ancestors. (C) The state transition for the Markov Chain in one step. The current state of the chain is (m,n) and the state in the previous generation is (m′,n′). In the example here, (m,n) = (1,3) and (m′,n′) = (2,1). (D) The expected time to the most recent common ancestor for two lineages (denoted as TMRCA2) was calculated using three different approaches. The solid line is calculated using a first-step analysis of the Markov Chain. Blue squares are the results from the forward simulation and triangles are from the direct simulation following the Markov Chain.

Mentions: We consider a discrete-generation model of tissue homeostasis. In each cell generation, a proportion α of the cells divides symmetrically and gives rise to two descendant stem cells (type I, Figure 1A). A fraction β of the cells divides asymmetrically (type III) and 1-α-β cells divide symmetrically and produce two differentiated cells (type II). Because type II divisions do not give rise to any stem cell descendants, the number of stem cells in generation t will be Nt = (2α+β)t×N0, where N0 is the population size at time 0.


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)

Anatomy of intestinal crypts and coalescent processes for the two-deme model.(A) Anatomical structure of the intestinal crypt. The dark green cells represent stem cells and light green cells are transit-amplifying cells. There are three types of stem cells divisions (I, II and III, see main text). (B) A cartoon illustration of a coalescent process in the two deme model. One cell from stem cell deme and two cells from the transit-amplifying cell deme were sampled. Their ancestral relationship is depicted as the gene tree connecting their ancestors. (C) The state transition for the Markov Chain in one step. The current state of the chain is (m,n) and the state in the previous generation is (m′,n′). In the example here, (m,n) = (1,3) and (m′,n′) = (2,1). (D) The expected time to the most recent common ancestor for two lineages (denoted as TMRCA2) was calculated using three different approaches. The solid line is calculated using a first-step analysis of the Markov Chain. Blue squares are the results from the forward simulation and triangles are from the direct simulation following the Markov Chain.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3585040&req=5

pgen-1003326-g001: Anatomy of intestinal crypts and coalescent processes for the two-deme model.(A) Anatomical structure of the intestinal crypt. The dark green cells represent stem cells and light green cells are transit-amplifying cells. There are three types of stem cells divisions (I, II and III, see main text). (B) A cartoon illustration of a coalescent process in the two deme model. One cell from stem cell deme and two cells from the transit-amplifying cell deme were sampled. Their ancestral relationship is depicted as the gene tree connecting their ancestors. (C) The state transition for the Markov Chain in one step. The current state of the chain is (m,n) and the state in the previous generation is (m′,n′). In the example here, (m,n) = (1,3) and (m′,n′) = (2,1). (D) The expected time to the most recent common ancestor for two lineages (denoted as TMRCA2) was calculated using three different approaches. The solid line is calculated using a first-step analysis of the Markov Chain. Blue squares are the results from the forward simulation and triangles are from the direct simulation following the Markov Chain.
Mentions: We consider a discrete-generation model of tissue homeostasis. In each cell generation, a proportion α of the cells divides symmetrically and gives rise to two descendant stem cells (type I, Figure 1A). A fraction β of the cells divides asymmetrically (type III) and 1-α-β cells divide symmetrically and produce two differentiated cells (type II). Because type II divisions do not give rise to any stem cell descendants, the number of stem cells in generation t will be Nt = (2α+β)t×N0, where N0 is the population size at time 0.

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