Research On Cell Fate Decision Based On Network Dynamics

Cell fate decision is involved in the whole life process,as in mammals,from a single fertilized egg through continuous proliferation and differentiation,and the formation of more than 200 different cell types.These different types of cells are not only different in shape,but also have specific functions.The normal process of cell differentiation is highly stable,but the process of cell differentiation is plasticity under some special conditions,such as cell reprogramming and transdifferentiation.Intercellular communication plays an important role in cell fate decision and tissue development in both unicellular and multicellular organisms.In the community of unicellular organisms,communication between cells is usually realized by cell secretion and sensing diffusible autoinducer,and this communication is called quorum sensing.For multicellular organisms,intercellular communicate by secreting and sensing small diffusible signaling molecules and by contacting molecules on the surface of the cell membrane.Such as,pancreatic β cells can secrete and sense insulin,human T cells regulate their growth by secreting and sensing the cytokine interleukin-2(IL-2),and Notch signaling is activated by binding of the membrane surface receptor Notch to the ligand Delta for differentiation decision of pancreatic cells.In this paper,we construct mathematical models based on the related biomolecular regulatory networks by using nonlinear differential equations,and analyze and understand the mechanism of cell fate decision based on intercellular communication from the bifurcation theory of dynamic systems.Our work focuses on the following two areas:1)In chapter two,we mainly explore the mechanisms of cell reprogramming and transdifferentiation based on intercellular communication.In recent years,many researches have focused on the single-cell regulatory network level,and explored how gene expression perturbation,random perturbation of internal environment and chemical inducers control cell type switching(e.g.,cell reprogramming and transdifferentiation).In addition,little attention has been paid to how intercellular communication regulates cell type switching.However,in unicellular communities and multicellular biological tissues,intercellular communication plays an important role in cell fate determinations(such as,cell differentiation,cell reprogramming,and cell transdifferentiation,etc.).To reveal the regulatory mechanism,first,a two-gene circuit with mutual inhibition and self-activation is selected as the basic model.Then,a specific signaling molecule is introduced into the gene regulatory network to obtain the coupling mechanism of intercellular communication.Further,we use bifurcation theory to explore the dynamic mechanisms of cell reprogramming and transdifferentiation based on the coupled dynamical system of intercellular communication.Our results suggest that cell reprogramming and transdifferentiation can be achieved through intercellular communication under the condition of appropriate coupling strength.The work discussed in this chapter is based on the phenomena and results of previous related biological experiments to analyze and understand the regulatory mechanism of cell fate selection from the perspective of dynamics,and its significance can not only help people to better understand the mechanism of cell fate decision,but also guide us to control the direction of cell fate decision through artificial intercellular communication mechanism,so as to realize the anticipated or targeted cell fate decision.Finally,we give some theoretical analyses of the stability and bifurcation conditions of dynamic systems.2)The endocrine and exocrine cells of the pancreas originated from the early intestinal endoderm cells,while the endocrine(exocrine tissues)of the pancreas are mainly composed of islet cells(acinar and duct cells).A large number of biological experiments have shown that cell-cell communication plays a key regulatory role in the formation of pancreatic exocrine and exocrine cells.Therefore,it is significant to study this regulatory mechanism from the perspective of molecular network dynamics.In chapter three,we focus on the mechanism of pancreatic cell fate based on cell-cell communication.To investigate the mechanism of pancreatic cell fate regulation,we first constructed a simple mathematical model of a simple regulatory network based on the pancreatic cell differentiation.Then,the dynamic properties of this model are analyzed by bifurcation theory,and the regulatory mechanism behind the transdifferentiation of acinar cells to islet cells is revealed.In addition,Notch signaling plays an important role in the regulation of pancreatic endocrine and exocrine fate decisions,and it acts as a typical lateral inhibitory mediator that instructs neighboring cells to make different fate decisions.Further,we constructed a multicellular model of cell-cell communication mediated by Notch signaling with trans-activation and cisinhibition.Finally,we investigate how Notch signals control the fate decision of endocrine and exocrine cells during pancreatic cell differentiation from the perspective of multicellular coupling system dynamics.The results show that high(or low)levels of Notch signal drive the differentiation of pancreatic progenitor cells towards the fate of exocrine(or endocrine)progenitor cells.The network and model proposed here may be good candidates for qualitative study of the mechanism of pancreatic cell fate selection,and these results may also provide some insights and inspirations for further experimental analysis on selection perturbation strategies.