Citation: Qiaojun Situ, Jinzhi Lei. A mathematical model of stem cell regeneration with epigenetic state transitions[J]. Mathematical Biosciences and Engineering, 2017, 14(5&6): 1379-1397. doi: 10.3934/mbe.2017071
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Stem cells play crucial roles during development, tissue regeneration and healthy homeostasis in a whole life cycle. Stem cells provide regeneration in self-renewing tissues through proliferation, differentiation, and apoptosis. A well controlled population dynamics of stem cells is essential for healthy tissue physiological functions [18,27]. However, despite the long-running investigation of stem cell biology, the mechanisms by which stem cell numbers and activity are regulated are still not completely understood [22].
Stem cell biology is population biology. Many mathematical models of the population dynamics have been widely studied in understanding how stem cell regeneration is modulated in different context [6,10,15,17,24,25,26,27,33,39,43]. In most models, the dynamics of a homogeneous cell pool or the lineage of several homogeneous subpopulations are formulated through a set of differential equations. However, the heterogeneity of stem cells is highlighted in recent years due to novel experimental techniques at single cell level [7,11,12,14,36,41]. The heterogeneity is mostly originated from random changes of epigenetic state at each cell cycle, including DNA methylations, histone modifications, and transcriptions of genes and noncoding RNAs. For heterogeneous populations in which qualitatively different subpopulations of cells coexist and transit to each other, the validity of traditional population models is not clear [23].
Fifty years ago, Till et al. proposed a mathematical model of stem cell proliferation to consider the inherently random dynamics of individual cells based on a stochastic birth-death process [38]. This work opened up a perspective on stem cell biology of stochastic heterogenous dynamics of stem cell behavior [22]. In 2014, Lei et al. offered another approach to this problem [18]. The authors outline a general mathematical framework that applies tools from optimization theory to understand stem cell dynamics. In their model, stem cell numbers are regulated by rates of proliferation, differentiation, and apoptosis that are continually tuned by both genetic and epigenetic feedback mechanisms to maximize population performance. Key to the process is the classification of the stem cell population over a variety of different epigenetic states, and the association of different epigenetic states with proliferation, differentiation, and apoptosis. Both total cell numbers and the distribution of epigenetic states of the population are regulated by system-level feedbacks [22]. By adapting ideas from evolutionary theory and population biology, Lei et al. have investigated the cell population dynamics under various control strategies and the evolution of the optimal strategy through numerical simulations [18]. Nevertheless, many questions related to the dynamical properties of the model questions are not considered. In this paper, we present mathematical analysis on the existence and stability of the steady states, which are essential for the homeostasis of the long-term stem cell regeneration dynamics.
The model studied in this paper is an extension from a discrete dynamical model of heterogeneity of stem-cell regeneration [18], which was established based on the
To establish the formulation of the above model of stem cell regeneration, we introduce
N(t)=∑Xi∈ΩN(t,Xi). | (1) |
Here we always assume discrete epigenetic states. Mathematically, it is easy to extend the discussions to the continuous situation by replacing the summation with an integral over all
Each cell in the resting phase reenters cell division at a rate of
∑Xi∈Ωp(Xi,Xj)=1,∀Xj∈Ω. | (2) |
At a small time interval
N(t+Δt,Xi)=N(t,Xi)−N(t,Xi)(β(N,Xi)+γ(Xi))Δt+2∑Xj∈Ωβ(N,Xj)N(t,Xj)(1−μ(Xj))p(Xi,Xj)(1−κ(Xi))Δt, |
which gives the following differential equation
{∂N(t,Xi)∂t=−N(t,Xi)(β(N,Xi)+γ(Xi))+2∑Xj∈Ωβ(N,Xj)N(t,Xj)(1−μ(Xj))p(Xi,Xj)(1−κ(Xi)),N=∑Xi∈ΩN(t,Xi), | (3) |
for all
Equation (3) gives the basic dynamical equation of our model of stem cell regeneration with epigenetic transition. In the equation,
β(N,Xi),γ(Xi)>0,0≤μ(Xi),κ(Xi),p(Xi,Xj)≤1. | (4) |
Furthermore, the function
Remark 1. The cell division process usually takes some time. Thus, a delay
{∂N(t,Xi)∂t=−N(t,Xi)(β(N,Xi)+γ(Xi))+2∑Xj∈Ωβ(Nτ,Xj)N(t−τ,Xj)(1−μ(Xj))p(Xi,Xj)(1−κ(Xi)),N=∑Xi∈ΩN(t,Xi), | (5) |
here
Remark 2. Adding equations (3) with respect to all
dNdt=∑Xi∈ΩN(t,Xi)[β(N,Xi)(2σ(Xi)(1−μ(Xi))−1)−γ(Xi)], | (6) |
where
σ(Xi)=∑Xj∈Ω(1−κ(Xj))p(Xj,Xi). | (7) |
If we omit the heterogeneity so that all functions are independent of
dNdt=˜β(N)N−γN. | (8) |
If the time delay in cell division is considered, we obtain a delay differential equation
dNdt=˜β(Nτ)Nτ−γN. | (9) |
Thus, we again obtain the ordinary/delay differential equation model of stem cell regeneration [5,17,20,27].
Remark 3. If the epigenetic state space
{∂N(t,X)∂t=−N(t,X)(β(N,X)+γ(X))+2∫Ωβ(N,Y)N(t,Y)(1−μ(Y))p(X,Y)(1−κ(X))dYN=∫ΩN(t,X)dX. | (10) |
Here, an integral term is used when the epigenetic state space is continuous. This idea of using an integral to represent the continuous properties of stem cell dynamics has also been used in previous studies [2,3,4].
Upon the establishment of mathematical models, basic dynamical analysis of the model equations are important for our understanding of the system behavior and future extension of the model. In the next section, we give preliminary analysis results for the modeling equation.
In this section, we discuss the existence and stability of the equilibrium states of (3). It is easy to see that equation (3) always has a trivial equilibrium state
In general, equation (3) includes a huge number (as many as possible epigenetic states) of differential equations that are coupled to each other. Thus, it is difficult to analyze the dynamics in general. Here, to make the analysis possible, we introduce a homogenous proliferation assumption:
(A1) The proliferation rate
Assuming the condition (A1), equation (3) can be rewritten as
{∂N(t,Xi)∂t=−N(t,Xi)(β(N)+γ(Xi))+β(N)∑Xj∈Ω2(1−μ(Xj))p(Xi,Xj)(1−κ(Xi))N(t,Xj),N=∑Xi∈ΩN(t,Xi). | (11) |
In the following discussions, we always assume that there are finite epigenetic states
qij=(1−μ(Xj))p(Xi,Xj)(1−κ(Xi)),si=n∑j=12qijγ(Xi)−1γ(Xi), |
s=min1≤i≤nsi,S=max1≤i≤nsi, |
βmin=infN∈R+β(N),βmax=supN∈R+β(N). |
Here we note that
Theorem 3.1. Consider equation (11) and the general assumption (4), if the following conditions are satisfied
(1)
(2)
1βmax<s≤S<1βmin, | (12) |
(3) the transition matrix defined with
Proof. Let
N0=n∑i=1N∗(Xi) |
denote the equilibrium state. From (11), we have
−N∗(Xi)(β(N0)+γ(Xi))+β(N0)n∑j=12qijN∗(Xj)=0,∀i=1,⋯,n. | (13) |
Multiplying the i'th equation in (13) with
−N∗(Xi)(1γ(Xi)+1β(N0))+1γ(Xi)n∑j=12qijN∗(Xj)=0, |
which gives
−1γ(Xi)N∗(Xi)+1γ(Xi)n∑j=12qijN∗(Xj)=1β(N0)N∗(Xi),i=1,⋯,n. | (14) |
Thus, introducing a coefficient matrix
A=[2q11−1γ(X1)2q12γ(X1)⋯2q1nγ(X1)2q21γ(X2)2q22−1γ(X2)⋯2q2nγ(X2)⋮⋮⋱⋮2qn1γ(Xn)2qn2γ(Xn)⋯2qnn−1γ(Xn)], |
(14) yields the following linear equation
AN∗=1β(N0)N∗. | (15) |
Now, equation (15) indicates that
β(N0)=1λ∗,N∗(Xi)=N0zi‖z‖1,‖z‖1=n∑i=1|zi|. | (16) |
Next, we show that conditions (1)-(3) ensure the existence of the eigenvalue
First, when
1The matrix
A=Λ1PΛ2−Λ3, | (17) |
where
Λ1=diag(2(1−κ(X1))γ(X1),⋯,2(1−κ(Xn))γ(Xn)),Λ2=diag(1−μ(X1),⋯,1−μ(Xn)),Λ3=diag(1γ(X1),⋯,1γ(Xn)). |
Thus, the two matrices
1. The spectral radius of
2.
s≤λ∗≤S. |
3.
4.
Next, since
1βmax<s≤λ∗≤S<1βmin, |
there exists at least one
1β(N0)=λ∗. |
Finally, letting
N∗(Xi)=N0zi‖z‖1, |
it is easy to see that
Remark 4. Biologically,
Remark 5. From the proof, each eigenvalue of
Remark 6. If the transition matrix
Now, to further simplify the equations, we introduce additional assumptions below:
(A2) During cell cycle, cell apoptosis is mainly caused by serious DNA damage, which is mostly dependent on the number of initial damage sites and the activity of the DNA damage response pathways [30,31,42]. Here we assumed that the probability of apoptosis
(A3) The transition probability
With assumptions (A1)-(A3), we further rewrite the equation (3) as
{∂N(t,Xi)∂t=−N(t,Xi)(β(N)+γ(Xi))+2p(Xi)(1−μ)(1−κ(Xi))β(N)N,N=∑Xi∈ΩN(t,Xi). | (18) |
The following theorem gives a necessary and sufficient condition for the existence of a positive equilibrium state of the equation (18).
Theorem 3.2. Assume that
β(N)>0,∀N∈R+,and γ(X)>0, 0≤μ,κ(X),p(X)≤1,∀X∈Ω. |
Let
βmin=infN∈R+β(N),βmax=supN∈R+β(N), | (19) |
and
F(β)=2∑Xi∈Ωββ+γ(Xi)p(Xi)(1−κ(Xi))(1−μ). | (20) |
Equation (18) has at least one positive equilibrium state if and only if
F(βmin)<1<F(βmax), | (21) |
and the equilibrium state is given by
N(t,Xi)≡N0(Xi)=2β(N0)N0β(N0)+γ(Xi)p(Xi)(1−κ(Xi))(1−μ), | (22) |
where
Proof. At the equilibrium state, equation (18) gives
−N∗(Xi)(β(N0)+γ(Xi))+2(1−μ)p(Xi)(1−κ(Xi))N0β(N0)=0 | (23) |
for all
N0=∑Xi∈ΩN∗(Xi). | (24) |
Hence, we obtain
N∗(Xi)=2β(N0)N0β(N0)+γ(Xi)p(Xi)(1−κ(Xi))(1−μ). | (25) |
Substituting (25) into (24), we have
F(β(N0))=1. | (26) |
Thus, from (19), equation (26) has at least one positive solution if and only if (20) is satisfied, and when (20) is satisfied, the equilibrium is given by (25).
If
Remark 7. Theorem 3.2 indicates that the fraction of
f(Xi)=2(1−μ)p(Xi)(1−κ(Xi))β(N0)β(N0)+γ(Xi). | (27) |
Now, we study the linear stability of the equilibrium state under assumptions (A1)-(A3). Hereinafter, we always assume that
Theorem 3.3. Consider equation (18) with two states, i.e.,
Proof. When
{∂N(t,X1)∂t=−N(t,X1)(β(N(t))+γ(X1))+2(1−μ)p(X1)(1−κ(X1))N(t)β(N(t)):=f1(N(t,X1),N(t,X2))∂N(t,X2)∂t=−N(t,X2)(β(N(t))+γ(X2))+2(1−μ)p(X2)(1−κ(X2))N(t)β(N(t)):=f2(N(t,X1),N(t,X2))N(t)=N(t,X1)+N(t,X2). | (28) |
The linearization near the equilibrium state
dxdt=Ax, | (29) |
where
A=[∂f1∂N(t,X1)∂f1∂N(t,X2)∂f2∂N(t,X1)∂f2∂N(t,X2)]|N=N∗, |
where
∂f1∂N(t,X2)=−N(t,X1)β′+2(1−μ)p(X1)(1−κ(X1))(β+β′N), | (30) |
∂f2∂N(t,X1)=−N(t,X2)β′+2(1−μ)p(X2)(1−κ(X2))(β+β′N), | (31) |
∂f1∂N(t,X1)=∂f1∂N(t,X2)−(β+γ(X1)), | (32) |
∂f2∂N(t,X2)=∂f2∂N(t,X1)−(β+γ(X2)). | (33) |
Here we write
Thus, we obtain
Det(A)=(∂f1∂N(t,X1)∂f2∂N(t,X2)−∂f1∂N(t,X2)∂f2∂N(t,X1))|N=N∗=(β(N0)+γ(X1))(β(N0)+γ(X2))−(β(N0)+γ(X1))∂f2∂N(t,X1)|N=N∗−(β(N0)+γ(X2))∂f1∂N(t,X2)|N=N∗=(β(N0)+γ(X1))(β(N0)+γ(X2))×(1−1β(N0)+γ(X2)∂f2∂N(t,X1)−1β(N0)+γ(X1)∂f1∂N(t,X2))|N=N∗. | (34) |
Next, we analyze the last term in (34), which determines the sign of
(1−1β(N0)+γ(X2)∂f2∂N(t,X1)−1β(N0)+γ(X1)∂f1∂N(t,X2))|N=N∗=1−−N∗(X2)β′(N0)+2(1−μ)p(X2)(1−κ(X2))(β(N0)+β′(N0)N0)β(N0)+γ(X2)−−N∗(X1)β′(N0)+2(1−μ)p(X1)(1−κ(X1))(β(N0)+β′(N0)N0)β(N0)+γ(X1)=N∗(X2)β′(N0)−2(1−μ)p(X2)(1−κ(X2))N0β′(N0)β(N0)+γ(X2)+N∗(X1)β′(N0)−2(1−μ)p(X1)(1−κ(X1))N0β′(N0)β(N0)+γ(X1)=−β′(N0)β(N0)(γ(X2)N∗(X2)β(N0)+γ(X2)+γ(X1)N∗(X1)β(N0)+γ(X1)). |
Hence, it is easy to see that
Next, we have
tr(A)=−(2β(N0)+γ(X1)+γ(X2))−N0β′(N0)+β(N0)(2(1−μ)p(X1)(1−κ(X1))+2(1−μ)p(X2)(1−κ(X2)))+N0β′(N0)(2(1−μ)p(X1)(1−κ(X1))+2(1−μ)p(X2)(1−κ(X2)))=−(β(N0)+γ(X1)+γ(X2))+β(N0)(N∗(X1)(β(N0)+γ(X1))N0β(N0)+N∗(X2)(β(N0)+γ(X2))N0β(N0)−1)+N0β′(N0)(N∗(X1)(β(N0)+γ(X1))N0β(N0)+N∗(X2)(β(N0)+γ(X2))N0β(N0)−1)=−(β(N0)+γ(X1)+γ(X2))+(N∗(X1)N0γ(X1)+N∗(X2)N0γ(X2))+β′(N0)β(N0)(N∗(X1)γ(X1)+N∗(X2)γ(X2))=−β(N0)−(γ(X1)+γ(X2)−N∗(X1)N0γ(X1)−N∗(X2)N0γ(X2))+β′(N0)β(N0)(N∗(X1)γ(X1)+N∗(X2)γ(X2)). |
It is easy to verify that
Now, if
Now, we consider the linear stability of general cases with multiple epigenetic states under assumptions (A1)-(A3).
Theorem 3.4. Consider equation (18) with
(ⅰ) (The condition
(ⅱ) If
(β′(N0)N0γ(Xi)β(N0)+γ(Xi)+β(N0)),(n=1,⋯,n) |
are either all non-negative or all non-positive, then the equilibrium state
Proof. First, we introduce functions
fi=−N(t,Xi)(β(N(t))+γ(Xi))+2(1−μ)p(Xi)(1−κ(Xi))N(t)β(N(t)). |
Equations in (18) are rewritten as
∂N(t,Xi)∂t=fi,(i=1,2,⋯,n) | (35) |
N=n∑i=1N(t,Xi). | (36) |
Let
fi|N=N∗=0. | (37) |
Similar to the calculations in the proof of Theorem 3.3, we obtain
∂fi∂N(t,Xj)|N=N∗={bi−aii=jbii≠j | (38) |
where
ai=(β(N0)+γ(Xi)), | (39) |
bi=2(1−μ)p(Xi)(1−κ(Xi))(β(N0)+β′(N0)N0)−N∗(Xi)β′(N0). | (40) |
Hence, the coefficient matrix
A=[∂f1∂N(t,X1)∂f1∂N(t,X2)⋯∂f1∂N(t,Xn)∂f2∂N(t,X1)∂f2∂N(t,X2)⋯∂f2∂N(t,Xn)⋮⋮⋱⋮∂fn∂N(t,X1)∂fn∂N(t,X2)⋯∂fn∂N(t,Xn)]|N=N∗=[b1−a1b1⋯b1b2b2−a2⋯b2⋮⋮⋱⋮bnbn⋯bn−an]. |
Therefore, the eigenfunction of the coefficient matrix is given by
h(λ)=|λI−A|=|λ+a1−b1−b1⋯−b1−b2λ+a2−b2⋯−b2⋮⋮⋱⋮−bn−bn⋯λ+an−bn|=(1−b1λ+a1−⋯−bnλ+an)(λ+a1)⋯(λ+an). | (41) |
From (41), we have the following results for
h(+∞)=+∞>0, | (42) |
h(0)=(1−b1a1−b2a2−⋯−bnan)n∏i=1ai, | (43) |
h(−ai)=−bi∏j≠i(aj−ai), | (44) |
4h(−∞)=sgn((−1)n)⋅∞. | (45) |
From (25) and (40),
bi=−N∗(Xi)β′(N0)+2(1−μ)p(Xi)(1−κ(Xi))(β(N0)+β′(N0)N0)=2(1−μ)p(Xi)(1−κ(Xi))β′(N0)N0(−β(N0)β(N0)+γ(Xi)+1)+2(1−μ)p(Xi)(1−κ(Xi))β(N0)=2(1−μ)p(Xi)(1−κ(Xi))(β′(N0)N0γ(Xi)β(N0)+γ(Xi)+β(N0)). | (46) |
First, we assume that
biai=2(1−μ)p(Xi)(1−κ(Xi))β(N0)β(N0)+γ(Xi)+N0β′(N0)2γ(Xi)(1−μ)p(Xi)(1−κ(Xi))(β(N0)+γ(Xi))2. | (47) |
Thus, from (26), we obtain
1−n∑i=1biai=1−n∑i=12(1−μ)p(Xi)(1−κ(Xi))β(N0)β(N0)+γ(Xi)−N0β′(N0)n∑i=12γ(Xi)(1−μ)p(Xi)(1−κ(Xi))(β(N0)+γ(Xi))2=−N0β′(N0)n∑i=12γ(Xi)(1−μ)p(Xi)(1−κ(Xi))(β(N0)+γ(Xi))2. | (48) |
Now, we are ready to prove the main results.
(ⅰ). If
(ⅱ). First, we assume that
(a) If
h(0)>0,h(−a1)<0,h(−a2)>0,⋯,sgn(h(−an))=sgn(−1)n, |
and there are
(b) If otherwise,
h(−a1)>0,h(−a2)<0,⋯,sgn(h(−an))=sgn((−1)n+1), |
sgn(h(−∞))=sgn((−1)n), |
and there are
Next, if
Thus, in all situations, all
Remark 8. Since
β′(N0)N01β(N0)+1+β(N0)>0 | (49) |
is enough to ensure the linear stability of the positive equilibrium. Moreover, if
β(N)=β0θnθn+Nn, | (50) |
the condition (49) is equivalent to
(β0+1)>(n−1)(N0/θ)n. | (51) |
Interestingly, we note that (51) is always satisfied when
Here, we study the stability of the zero solution
Theorem 3.5. Consider the equation (18), and
F(β)=n∑i=12(1−μ)p(Xi)(1−κ(Xi))ββ+γ(Xi). | (52) |
(1) If there exists
(2) If
Proof. Consider the linearization of (18) near the zero solution, the coefficient matrix is given by
ˉA=[ˉb1−ˉa1ˉb1⋯ˉb1ˉb2ˉb2−ˉa2⋯ˉb2⋮⋮⋱⋮ˉbnˉbn⋯ˉbn−ˉan], |
where
ˉai=(β(0)+γ(Xi))>0ˉbi=2(1−μ)p(Xi)(1−κ(Xi))β(0)>0. |
Thus, similar to the above argument, let
ˉh(+∞)=+∞>0,ˉh(0)=(1−ˉb1ˉa1−ˉb2ˉa2−⋯−ˉbnˉan)n∏i=1ˉai,ˉh(−ˉai)=−ˉbi∏j≠i(ˉaj−ˉai). |
(1) If there exists
1−n∑i=1ˉbiˉai=1−n∑i=12(1−μ)p(Xi)(1−κ(Xi))β(0)β(0)+γ(Xi)=F(β(N0))−F(β(0)). |
From the proof of Theorem 3.2,
(2) If
ˉh(0)>0,ˉh(−ˉa1)<0,ˉh(−ˉa2)>0,⋯ |
and all roots of
Remark 9. From the discussions in Theorem 3.2, equation (18) has at least one positive equilibrium state if and only if there exists
In this section, we present simulations of applying our model equation (3) to stem cell population dynamics.
First, we apply our model to a virtual tissue dynamics of stem cell regenerations. We assumed that in this virtual tissue the space of epigenetic states is given by
μ(Xi)=0.1,κ(Xi)=0.1+0.21+(Xi/30),κ(Xi)=0.05+0.351+(Xi/50). | (53) |
The proliferation rate function is given by
β(N)=β0θnθn+Nn,β0=0.7,θ=500,n=3. | (54) |
The transition probability
p(Xi,Xj)=(300−Xi)(1+νe−0.2(Xi−Xj)2)∑300i=1(300−Xi)(1+νe−0.2(Xi−Xj)2). | (55) |
Here the parameter
Simulation results are shown at Fig. 2. Both cell population and the percentage of different epigenetic states converge to a stable equilibrium state after a long time simulation. We note that when
Experiments have found that in human breast cancer cell lines there are distinct phenotypic cells (stem-like (S), basal (B), or luminal (L)) [13]. The proportion of distinct cell-state subpopulations remain stable in the cell line (proportion of B, S, and L =
The model includes three subpopulations of cells (
Parameter | S | B | L | S | B | L | ||
γ | 0.95 | 0.7 | 0.65 | S | 0.58 | 0.04 | 0.01 | |
κ | 0.02 | 0.03 | 0 | B | 0.07 | 0.47 | 0 | |
μ | 0.1 | 0.1 | 0.1 | L | 0.35 | 0.49 | 0.09 |
Stem cell regeneration is essential during development and the maintaining of homeostasis. Epigenetic state transition is inherent to cell cycling due to the random dynamics of biochemical reactions involved in histone modification and DNA methylation during cell division. Here we have described a general form of continuous dynamical model of stem cell regeneration with epigenetic state transition. In the model, an individual cell is represented by its epigenetic state, and each cell can give two daughter cells with alterations in the epigenetic state. During cell division, the death rate and the probabilities of cell differentiation are assumed to be dependent on the epigenetic state. We give mathematical analysis to the model equations, basic dynamical properties, including existence and linear stability of the equilibrium state, are discussed under general assumptions.
The current study is intended to bring a general consideration of the population dynamics of stem cell regeneration with epigenetic transition. Therefore, no molecular or mechanistic details were involved on our model. This leaves a wide space for the extension of our study. To investigate specific functions of a particular type of stem cells, one can add an additional layer of complexity into the model by incorporating corresponding genetic and molecular regulations into the equation of proliferation, differentiation, and apoptosis. In additional to the biological problems, further mathematical questions can be arisen when such details are added to the model, for example, the population dynamics with feedback regulations to stem cell differentiation [17], the signaling pathway to control to oscillatory dynamics in developing hair follicles [1,32], the complex dynamics in hematopoiesis and dynamical blood disease [8,9,44]. This study offers a new approach and mathematical framework to these issues of stem cell biology.
[1] | [ R. C. Adam,H. Yang,S. Rockowitz,S. B. Larsen,M. Nikolova,D. S. Oristian,L. Polak,M. Kadaja,A. Asare,D. Zheng,E. Fuchs, Pioneer factors govern super-enhancer dynamics in stem cell plasticity and lineage choice, Nature, 521 (2015): 366-370. |
[2] | [ M. Adimy,F. Crauste,S. Ruan, A mathematical study of the hematopoiesis process with applications to chronic myelogenous leukemia, SIAM journal on applied mathematics, 65 (2005): 1328-1352. |
[3] | [ M. Adimy,F. Crauste,S. Ruan, Stability and Hopf bifurcation in a mathematical model of pluripotent stem cell dynamics, Nonlinear Analysis: Real World Applications, 6 (2005): 651-670. |
[4] | [ M. Adimy,F. Crauste,S. Ruan, Periodic oscillations in leukopoiesis models with two delays, J Theor Biol, 242 (2006): 288-299. |
[5] | [ S. Bernard,J. Bélair,M. C. Mackey, Oscillations in cyclical neutropenia: New evidence based on mathematical modeling, J Theor Biol, 223 (2003): 283-298. |
[6] | [ F. J. Burns,I. F. Tannock, On the existence of a G0-phase in the cell cycle, Cell Proliferation, 3 (1970): 321-334. |
[7] | [ H. H. Chang,M. Hemberg,M. Barahona,D. E. Ingber,S. Huang, Transcriptome-wide noise controls lineage choice in mammalian progenitor cells, Nature, 453 (2008): 544-547. |
[8] | [ S. J. Corey, M. Kimmel and J. N. Leonard (eds.), A Systems Biology Approach to Blood, vol. 844 of Advances in Experimental Medicine and Biology, Springer, London, 2014. |
[9] | [ D. C. Dale,M. C. Mackey, Understanding, treating and avoiding hematological disease: better medicine through mathematics?, Bull Math Biol, 77 (2015): 739-757. |
[10] | [ D. Dingli,A. Traulsen,J. M. Pacheco, Stochastic dynamics of hematopoietic tumor stem cells, Cell Cycle (Georgetown, Tex), 6 (2007): 461-466. |
[11] | [ B. Dykstra,D. Kent,M. Bowie,L. McCaffrey,M. Hamilton,K. Lyons,S.-J. Lee,R. Brinkman,C. Eaves, Long-term propagation of distinct hematopoietic differentiation programs in vivo, Stem Cell, 1 (2007): 218-229. |
[12] | [ T. M. Gibson,C. A. Gersbach, Single-molecule analysis of myocyte differentiation reveals bimodal lineage commitment, Integr Biol (Camb), 7 (2015): 663-671. |
[13] | [ P. B. Gupta,C. M. Fillmore,G. Jiang,S. D. Shapira,K. Tao,C. Kuperwasser,E. S. Lander, Stochastic State Transitions Give Rise to Phenotypic Equilibrium in Populations of Cancer Cells, Cell, 146 (2010): 633-644. |
[14] | [ K. Hayashi,S. M. C. de Sousa Lopes,F. Tang,M. A. Surani, Dynamic equilibrium and heterogeneity of mouse pluripotent stem cells with distinct functional and epigenetic states, Stem Cell, 3 (2008): 391-401. |
[15] | [ G. M. Hu,C. Y. Lee,Y.-Y. Chen,N. N. Pang,W. J. Tzeng, Mathematical model of heterogeneous cancer growth with an autocrine signalling pathway, Cell Prolif, 45 (2012): 445-455. |
[16] | [ D. Huh,J. Paulsson, Non-genetic heterogeneity from stochastic partitioning at cell division, Nat Genet, 43 (2011): 95-100. |
[17] | [ A. D. Lander,K. K. Gokoffski,F. Y. M. Wan,Q. Nie,A. L. Calof, Cell lineages and the logic of proliferative control, PLoS biology, 7 (2009): e15-e15. |
[18] | [ J. Lei,S. A. Levin,Q. Nie, Mathematical model of adult stem cell regeneration with cross-talk between genetic and epigenetic regulation, Proc Natl Acad Sci USA, 111 (2014): E880-E887. |
[19] | [ J. Lei,M. C. Mackey, Stochastic differential delay equation, moment stability, and application to hematopoietic stem cell regulation system, SIAM journal on applied mathematics, 67 (2007): 387-407. |
[20] | [ J. Lei,M. C. Mackey, Multistability in an age-structured model of hematopoiesis: Cyclical neutropenia, J Theor Biol, 270 (2011): 143-153. |
[21] | [ J. Lei,C. Wang, On the reducibility of compartmental matrices, Comput Biol Med, 38 (2008): 881-885. |
[22] | [ B. D. MacArthur, Collective dynamics of stem cell populations, Proc Natl Acad Sci USA, 111 (2014): 3653-3654. |
[23] | [ B. D. MacArthur,I. R. Lemischka, Statistical mechanics of pluripotency, Cell, 154 (2013): 484-489. |
[24] | [ M. C. Mackey, Unified hypothesis for the origin of aplastic anemia and periodic hematopoiesis, Blood, 51 (1978): 941-956. |
[25] | [ M. C. Mackey, Cell kinetic status of haematopoietic stem cells, Cell Prolif, 34 (2001): 71-83. |
[26] | [ M. Mangel and M. B. Bonsall, Phenotypic evolutionary models in stem cell biology: Replacement, quiescence, and variability, PLoS ONE, 3 (2008), e1591. |
[27] | [ M. Mangel,M. B. Bonsall, Stem cell biology is population biology: Differentiation of hematopoietic multipotent progenitors to common lymphoid and myeloid progenitors, Theor Biol Med Model, 10 (2012): 5-5. |
[28] | [ C. S. Potten,M. Loeffler, Stem cells: Attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt, Development, 110 (1990): 1001-1020. |
[29] | [ A. V. Probst,E. Dunleavy,G. Almouzni, Epigenetic inheritance during the cell cycle, Nat Rev Mol Cell Biol, 10 (2009): 192-206. |
[30] | [ J. E. Purvis,K. W. Karhohs,C. Mock,E. Batchelor,A. Loewer,G. Lahav, p53 dynamics control cell fate, Science, 336 (2012): 1440-1444. |
[31] | [ J. E. Purvis,G. Lahav, Encoding and decoding cellular information through signaling dynamics, Cell, 152 (2013): 945-956. |
[32] | [ A. Rezza,Z. Wang,R. Sennett,W. Qiao,D. Wang,N. Heitman,K. W. Mok,C. Clavel,R. Yi,P. Zandstra,A. Ma'ayan,M. Rendl, Signaling networks among stem cell precursors, transit-amplifying progenitors, and their niche in developing hair follicles, Cell Rep, 14 (2016): 3001-3018. |
[33] | [ I. Rodriguez-Brenes,N. Komarova,D. Wodarz, Evolutionary dynamics of feedback escape and the development of stem-cell–driven cancers, Proc Natl Acad Sci USA, 108 (2011): 18983-18988. |
[34] | [ P. Rué,A. Martinez-Arias, Cell dynamics and gene expression control in tissue homeostasis and development, Mol Syst Biol, 11 (2015): 792-792. |
[35] | [ T. Schepeler,M. E. Page,K. B. Jensen, Heterogeneity and plasticity of epidermal stem cells, Development, 141 (2014): 2559-2567. |
[36] | [ Z. S. Singer,J. Yong,J. Tischler,J. A. Hackett,A. Altinok,M. A. Surani,L. Cai,M. B. Elowitz, Dynamic heterogeneity and DNA methylation in embryonic stem cells, Mol Cell, 55 (2014): 319-331. |
[37] | [ K. Takaoka and H. Hamada, Origin of cellular asymmetries in the pre-implantation mouse embryo: A hypothesis, Philos Trans R Soc Lond B Biol Sci, 369 (2014). |
[38] | [ J. E. Till, E. A. McCulloch and L. Siminovitch, A Stochastic Model of Stem Cell Proliferation, Based on the Growth of Spleen Colony-Forming Cells, in Proceedings of the National Academy of Sciences of the United States of America, 1963, 29–36. |
[39] | [ A. Traulsen,T. Lenaerts,J. M. Pacheco,D. Dingli, On the dynamics of neutral mutations in a mathematical model for a homogeneous stem cell population, Journal of the Royal Society, Interface / the Royal Society, 10 (2013): 20120810-20120810. |
[40] | [ H. Wu,Y. Zhang, Reversing DNA methylation: Mechanisms, genomics, and biological functions, Cell, 156 (2014): 45-68. |
[41] | [ M. Zernicka-Goetz,S. A. Morris,A. W. Bruce, Making a firm decision: Multifaceted regulation of cell fate in the early mouse embryo, Nat Rev Genet, 10 (2009): 467-477. |
[42] | [ X.-P. Zhang,F. Liu,Z. Cheng,W. Wang, Cell fate decision mediated by p53 pulses, Proc Natl Acad Sci USA, 106 (2009): 12245-12250. |
[43] | [ D. Zhou,D. Wu,Z. Li,M. Qian,M. Q. Zhang, Population dynamics of cancer cells with cell state conversions, Quant Biol, 1 (2013): 201-208. |
[44] | [ C. Zhuge,X. Sun,J. Lei, On positive solutions and the Omega limit set for a class of delay differential equations, DCDS-B, 18 (2013): 2487-2503. |
1. | Jinzhi Lei, 2021, Chapter 6, 978-3-030-73032-1, 199, 10.1007/978-3-030-73033-8_6 | |
2. | Yuan-Hang Su, Wan-Tong Li, Yuan Lou, Xuefeng Wang, Principal spectral theory for nonlocal systems and applications to stem cell regeneration models, 2023, 00217824, 10.1016/j.matpur.2023.06.006 | |
3. | Aiindrila Dhara, Sangramjit Mondal, Ayushi Gupta, Princy Choudhary, Sangeeta Singh, Pritish Kumar Varadwaj, Nirmalya Sen, 2024, 9780443132223, 253, 10.1016/B978-0-443-13222-3.00017-4 | |
4. | Jinzhi Lei, 2025, Chapter 4, 978-3-031-82395-4, 37, 10.1007/978-3-031-82396-1_4 |
Parameter | S | B | L | S | B | L | ||
γ | 0.95 | 0.7 | 0.65 | S | 0.58 | 0.04 | 0.01 | |
κ | 0.02 | 0.03 | 0 | B | 0.07 | 0.47 | 0 | |
μ | 0.1 | 0.1 | 0.1 | L | 0.35 | 0.49 | 0.09 |