A Simulated Cell Reprogramming from a Pharmacological Perspective

By means of mathematical models, we propose a strategy for identifying the functional changes required to reprogram one type of cell into another. Here, we focus on altering the activity or expression of key transport proteins rather than manipulation of the cell nucleus or the use of embryonic stem cells. We illustrate this strategy by simulating the reprogramming of a sensory macula densa (MD) cell into a transporting cortical thick ascending limb (cTAL). Models of each of these two renal epithelial cell types were developed, and each contains sub‐models of an array of transport proteins and channels known to be expressed in both cell types although in different quantities. The MD‐to‐cTAL cell reprogramming simulations showed that just increasing (~4‐fold) basolateral Na + /K + ATPase expression in MD cells and fixing to zero the apical membrane water permeability was sufficient to elicit behaviors exhibited by cTAL cells (low and essentially constant cytosolic [Na + ] and cell volume when apical [NaCl] varies). In summary, the MD cell reprogramming only required alteration in less than 20% of the transport processes included in the models. These results illustrate how mathematical models can be used to explore possible pathways for pharmacological and genetic manipulation to functionally transform cells by augmenting or diminishing protein expression or activity without the need of reversing the cell differentiation process. Research supported in part by the NIH MBRS‐RISE Grant 2R25GM061151 and the NIH‐NIGMS Grant SC1GM084744.