BioModels Database logo

BioModels Database

spacer

BIOMD0000000209 - Chickarmane2008 - Stem cell lineage determination

 

 |   |   |  Send feedback
Reference Publication
Publication ID: 18941526
Chickarmane V, Peterson C.
A computational model for understanding stem cell, trophectoderm and endoderm lineage determination.
PLoS ONE 2008; 3(10): e3478
Division of Biology, California Institute of Technology, Pasadena, California, United States of America.  [more]
Model
Original Model: BIOMD0000000209.xml.origin
Submitter: Vijayalakshmi Chelliah
Submission ID: MODEL8390025091
Submission Date: 05 Dec 2008 15:52:32 UTC
Last Modification Date: 05 Jun 2013 16:45:56 UTC
Creation Date: 05 Dec 2008 14:17:42 UTC
Encoders:  Vijayalakshmi Chelliah
   Carsten Peterson
   Vijay Chickarmane
set #1
bqbiol:occursIn Taxonomy Homo sapiens
bqbiol:isVersionOf Gene Ontology stem cell differentiation
Gene Ontology trophectodermal cell fate commitment
Gene Ontology regulation of endodermal cell fate specification
bqmodel:isDerivedFrom BioModels Database Chickarmane2006 - Stem cell switch reversible
BioModels Database Chickarmane2006_StemCell_Switchirreversible
Notes
Chickarmane2008 - Stem cell lineage determination

In this work, a dynamical model of lineage determination based upon a minimal circuit, as discussed in PMID: 17215298 , which contains the Oct4/Sox2/Nanog core as well its interaction with a few other key genes is discussed.

This model is described in the article:

Chickarmane V, Peterson C
PloS one. 2008, 3(10):e3478

Abstract:

BACKGROUND: Recent studies have associated the transcription factors, Oct4, Sox2 and Nanog as parts of a self-regulating network which is responsible for maintaining embryonic stem cell properties: self renewal and pluripotency. In addition, mutual antagonism between two of these and other master regulators have been shown to regulate lineage determination. In particular, an excess of Cdx2 over Oct4 determines the trophectoderm lineage whereas an excess of Gata-6 over Nanog determines differentiation into the endoderm lineage. Also, under/over-expression studies of the master regulator Oct4 have revealed that some self-renewal/pluripotency as well as differentiation genes are expressed in a biphasic manner with respect to the concentration of Oct4. METHODOLOGY/

PRINCIPAL FINDINGS: We construct a dynamical model of a minimalistic network, extracted from ChIP-on-chip and microarray data as well as literature studies. The model is based upon differential equations and makes two plausible assumptions; activation of Gata-6 by Oct4 and repression of Nanog by an Oct4-Gata-6 heterodimer. With these assumptions, the results of simulations successfully describe the biphasic behavior as well as lineage commitment. The model also predicts that reprogramming the network from a differentiated state, in particular the endoderm state, into a stem cell state, is best achieved by over-expressing Nanog, rather than by suppression of differentiation genes such as Gata-6.

CONCLUSIONS: The computational model provides a mechanistic understanding of how different lineages arise from the dynamics of the underlying regulatory network. It provides a framework to explore strategies of reprogramming a cell from a differentiated state to a stem cell state through directed perturbations. Such an approach is highly relevant to regenerative medicine since it allows for a rapid search over the host of possibilities for reprogramming to a stem cell state.

To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Model
Publication ID: 18941526 Submission Date: 05 Dec 2008 15:52:32 UTC Last Modification Date: 05 Jun 2013 16:45:56 UTC Creation Date: 05 Dec 2008 14:17:42 UTC
Mathematical expressions
Reactions
R1 R2 R3 R4
R5 R6 R7 R8
R9 R10 R11 R12
Physical entities
Compartments Species
cell OCT4_Gene NANOG_Gene SOX2_Gene
GATA6_Gene CDX2_Gene GCNF_Gene
targetGene degradation p53
A SG SN
OCT4 SOX2 NANOG
GATA6 CDX2 GCNF
OCT4_SOX2 Protein  
Global parameters
a0 a1 a2 a3
b0 b1 b2 b3
b4 b5 gamma1 c0
c1 c2 d0 d1
d2 d3 gamma2 e0
e1 e2 e3 f0
f1 f2 f3 f4
gamma3 g0 g1 h0
h1 gamma4 i0 i1
i2 j0 j1 gamma5
p0 p1 p2 q0
q1 q2 q3 gammag
gamman      
Reactions (12)
 
 R1 [OCT4_Gene] → [OCT4];   {A} , {SOX2} , {NANOG} , {CDX2} , {GCNF}
 
 R2 [OCT4] → [degradation];  
 
 R3 [SOX2_Gene] → [SOX2];   {OCT4} , {NANOG}
 
 R4 [SOX2] → [degradation];  
 
 R5 [NANOG_Gene] → [NANOG];   {OCT4} , {SOX2} , {GATA6} , {SN}
 
 R6 [NANOG] → [degradation];  
 
 R7 [CDX2_Gene] → [CDX2];   {OCT4}
 
 R8 [CDX2] → [degradation];  
 
 R9 [GCNF_Gene] → [GCNF];   {CDX2} , {GATA6}
 
 R10 [GCNF] → [degradation];  
 
 R11 [GATA6_Gene] → [GATA6];   {OCT4} , {NANOG} , {SG}
 
 R12 [GATA6] → [degradation];  
 
 cell Spatial dimensions: 3.0  Compartment size: 1.0
 
 OCT4_Gene
Compartment: cell
Initial concentration: 0.0
 
 NANOG_Gene
Compartment: cell
Initial concentration: 0.0
 
 SOX2_Gene
Compartment: cell
Initial concentration: 0.0
 
 GATA6_Gene
Compartment: cell
Initial concentration: 0.0
 
 CDX2_Gene
Compartment: cell
Initial concentration: 0.0
 
 GCNF_Gene
Compartment: cell
Initial concentration: 0.0
 
   targetGene
Compartment: cell
Initial concentration: 0.01
 
   degradation
Compartment: cell
Initial concentration: 0.0
 
 p53
Compartment: cell
Initial concentration: 0.0
 
 A
Compartment: cell
Initial concentration: 25.0
 
   SG
Compartment: cell
Initial concentration: 0.0
 
   SN
Compartment: cell
Initial concentration: 0.0
 
 OCT4
Compartment: cell
Initial concentration: 0.01
 
 SOX2
Compartment: cell
Initial concentration: 0.01
 
 NANOG
Compartment: cell
Initial concentration: 0.01
 
 GATA6
Compartment: cell
Initial concentration: 0.01
 
 CDX2
Compartment: cell
Initial concentration: 0.01
 
 GCNF
Compartment: cell
Initial concentration: 0.01
 
 OCT4_SOX2
Compartment: cell
Initial concentration: 0.1
 
   Protein
Compartment: cell
Initial concentration: 0.0
 
Global Parameters (49)
 
   a0
Value: 0.0010
Constant
 
   a1
Value: 1.0
Constant
 
   a2
Value: 0.0050
Constant
 
   a3
Value: 0.025
Constant
 
   b0
Value: 1.0
Constant
 
   b1
Value: 0.0010
Constant
 
   b2
Value: 0.0050
Constant
 
   b3
Value: 0.025
Constant
 
   b4
Value: 10.0
Constant
 
   b5
Value: 10.0
Constant
 
   gamma1
Value: 0.1
Constant
 
   c0
Value: 0.0010
Constant
 
   c1
Value: 0.0050
Constant
 
   c2
Value: 0.025
Constant
 
   d0
Value: 0.0010
Constant
 
   d1
Value: 0.0050
Constant
 
   d2
Value: 0.025
Constant
 
   d3
Value: 0.05
Constant
 
   gamma2
Value: 0.1
Constant
 
   e0
Value: 0.0010
Constant
 
   e1
Value: 0.1
Constant
 
   e2
Value: 0.1
Constant
 
   e3
Value: 1.0
Constant
 
   f0
Value: 0.0010
Constant
 
   f1
Value: 0.1
Constant
 
   f2
Value: 0.1
Constant
 
   f3
Value: 10.0
Constant
 
   f4
Value: 1.0
Constant
 
   gamma3
Value: 0.1
Constant
 
   g0
Value: 0.0010
Constant
 
   g1
Value: 2.0
Constant
 
   h0
Value: 2.0
Constant
 
   h1
Value: 5.0
Constant
 
   gamma4
Value: 0.1
Constant
 
   i0
Value: 0.0010
Constant
 
   i1
Value: 0.1
Constant
 
   i2
Value: 0.1
Constant
 
   j0
Value: 0.1
Constant
 
   j1
Value: 0.1
Constant
 
   gamma5
Value: 0.1
Constant
 
   p0
Value: 0.1
Constant
 
   p1
Value: 1.0
Constant
 
   p2
Value: 2.5E-4
Constant
 
   q0
Value: 1.0
Constant
 
   q1
Value: 2.5E-4
Constant
 
   q2
Value: 15.0
Constant
 
   q3
Value: 10.0
Constant
 
   gammag
Value: 0.1
Constant
 
   gamman
Value: 0.01
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000209

Curator's comment: (updated: 28 Aug 2009 15:04:47 BST)

The model reproduces the Figure 5-right (Figure (B) here) and Figure 4 (Figure (A) here) of the reference publication. The model was simulated using Copasi v.4.4. Figure A) represents the time series concentration of OCT4, SOX2, NANOG, GATA6, CDX2 and GCNF for the three regimes (in terms of the concentration levels of signal A), indicating the final steady state values. To plot the time series against the concentrations the parameters q3, e3 and f4 were set to zero. The concentration of signal A used for the four states are i) A=1 for Trophectoderm, ii) A=10 for Stem Cell and Differentiated Stem Cell and iii) A=25 for Endoderm. The initial concentration of OCT4, SOX2 and NANOG is 5, and of CDX2, GATA6 and GCNF is 0 for Trophectoderm, Stem Cell and Endoderm. The initial concentration of OCT4,SOX2 and NANOG is 0, and of CDX2, GATA6 and GCNF is 5 for Differentiated Stem Cell. Figure B) represents the steady state concentration of OCT4, NANOG and GATA6 as functions of the external signal SN that induces NANOG (Figure 5 (right) of the paper. The concentration of signal A used is 25.

spacer
spacer