Narrow Results

The Notch–Delta signaling pathway is a highly conserved signaling system that partakes in a diverse process of growth, patterns and differentiation. Experiments have shown that Delta from different cells activates this pathway (trans-activation) while Delta from the same cell inhibits this pathway (cis-inhibition). The Notch–Delta interactions could switch a cell to one of the two opposite fates: either Sender (high Delta/low Notch) or Receiver (low Delta/high Notch). We studied a Notch–Delta signaling model from Sprinzak et al., (2010), to investigate the cell fate through steady state analysis. The focus was placed on a fundamental case of one single cell with fixed external Delta and Notch supplies. First, we proved there exists a unique steady state which is asymptotically stable. Second, we derived the increasing/decreasing and asymptotic properties of the steady state with respect to all the parameters. Third, we studied the sensitivity and discovered the cell fate is only sensitive to the production rates of Notch and Delta under strong cis-inhibition. Finally, we applied this model to multi-cellular cases and found that the lateral inhibition pattern could be created with the spatially varied Delta production rate. The Hopf bifurcation is not observed in the current model.

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New data have recently accumulated on how stem cell behave, self-renew and differentiate. Many studies have also focused on defining stem cells, and determination of the properties, including the mode of cell division and polarity, and regulatory environment(s) of both embryonic and tissue-specific stem cells in the last decades. In the lung, recent data show evidences that lung epithelial stem and progenitor cells are polarized, highly mitotic, have characteristic perpendicular cell divisions, and show a mode of division that is similar to other systems. They further show that the asymmetric division is probably the common mode of division in the mitotically dividing distal epithelial stem and progenitor cells of the embryonic lung. Both symmetric and asymmetric mode of cell divisions are tightly regulated in different stem cell types during tissue development and morphogenesis. How to choose between a symmetric and asymmetric cell division is one of the major questions in the stem cell field. It largely affects tissue development, morphogenesis and disease in different organs since improper asymmetric divisions badly affect organ morphogenesis, whereas uncontrolled symmetric division can lead to tumor formation. Moreover, the proper balance between self-renewal and differentiation of lung epithelial stem and progenitor cells is absolutely required for maintaining normal lung morphogenesis and for lung repair and regeneration since a deficiency of this balance probably can lead to a premature or injured lung. Therefore, identification of lung-specific stem cell types, understanding their behavior, and how they balance their self-renewal and differentiation could lead to the identification of innovative solutions for restoring normal lung morphogenesis and/or regeneration and repair of the lung. Furthermore, understanding the molecular mechanisms that control the asymmetrical cell division and both cell polarity and fate of lung epithelial stem and progenitor cells can help identifying new targets for prevention and rescuing lethal lung diseases in infants and children, and for regeneration of injured lungs. In this chapter, we will discuss recently accumulated data on the lung cell polarity, and the mode of division of lung epithelial stem and progenitor cells. In addition, we will describe the functions of Numb in stem cell fate and mode of division, and compare cell polarity and mode of division in the lung stem cells with other systems, as well as discuss the regulatory mechanisms of lung stem cell polarity, fate, behavior and mode of division.