Four-dimensional realistic modeling of pancreatic organogenesis

Abstract

Organogenesis, the process by which organs develop from individual precursor stem cells, requires that the precursor cells proliferate, differentiate, and aggregate to form a functioning structure. This process progresses through changes in 4 dimensions: time and 3 dimensions of space-4D. Experimental analysis of organogenesis, by its nature, cuts the 4D developmental process into static, 2D histological images or into molecular or cellular markers and interactions with little or no spatial dimensionality and minimal dynamics. Understanding organogenesis requires integration of the piecemeal experimental data into a running, realistic and interactive 4D simulation that allows experimentation and hypothesis testing in silico. Here, we describe a fully executable, interactive, visual model for 4D simulation of organogenic development using the mouse pancreas as a representative case. Execution of the model provided a dynamic description of pancreas development, culminating in a structure that remarkably recapitulated morphologic features seen in the embryonic pancreas. In silico mutations in key signaling molecules resulted in altered patterning of the developing pancreas that were in general agreement with in vivo data. The modeling approach described here thus typifies a useful platform for studying organogenesis as a phenomenon in 4 dimensions.4D simulation ͉ computational biology ͉ pancreas ͉ development O rganogenesis and morphogenesis have been of interest to many scientists in different fields for a long time. Understanding organogenesis not only explains how biological systems are formed but can also offer insight into their evolution (e.g., the shape of a leaf is, in part, an adjustment to varying habitats). In this article, we present a generic approach to the realistic 4D modeling of organogenesis based on experimental data. Furthermore, we describe how we applied this approach to modeling pancreatic organogenesis. Four-Dimensional ModelingOrganogenesis, the development of a functioning, anatomically specialized organ from a relatively small number of relatively undifferentiated precursor cells, is critically influenced by factors involving multiple scales, dynamics, and 3D anatomic relationships. The importance of scales is evident in the scale-crossing chain of genetic and chemical reactions leading to cellular behavior and anatomic structuring that, in turn, feeds back down the scales to influence gene expression; indeed, the emergence of many important properties of living systems needs to take account of interactions that take place across different scales (1). The importance of dynamics is evident in the time dependency of developmental processes at every scale, and the importance of 3D anatomy is evident in the specific structure of the developing organ and its dependence on interactions with adjacent cells and molecular inducers.Experimental data, because of the analytical nature of science, rarely, if ever, provide a smooth transition across scales; they are usually limited to snapshots of proc...

Network as biomarker

“…The integrative effort of piecing basic findings together has perhaps not been given proper attention. Such integrative effort, from a computational point of view, can be seen in work such as, [76][77][78] in which the objective is to collect basic information and integrate it into a whole biological process. This integrative computational biology is the bridge between the reduction we see in screening thousands of patients into their core genes or core molecular pathways, and the intensity with which these basic findings are brought to the clinic.…”

On Using Divide and Conquer in Modeling Natural Systems

“…In the case of pancreatic organogenesis, the 'divide and conquer' approach emphasized the need for cross-scaling in organogenesis, and served as a significant milestone in our work toward the model described in [40], which employs the 'autonomous cell' approach.…”

“…This approach was found very beneficial for modeling pancreatic organogenesis and conduct multi-scale, cross-scale, and dynamics as well as emergence of the 3D organ structure from a collection of molecular interactions. The approach enables integration of the genetic, molecular, and cellular components, along with environmental signaling into a dynamically running, three-dimensional simulation (see [40]). …”

Recent Advances for Enhancing Drug Metabolizing Functions of Hepatocyte-like Cells Derived from Human Pluripotent Stem Cells

“…Organogenesis takes place in a 3D manner, with cell-cell interaction occurring on an ECM structure rather than a 2D flat sheet [12]. Table 1 summarizes recent studies that report on either gene expression or activity of hepatic metabolizing enzymes of human pluripotent stem cell-derived HLCs using a 2D or 3D culture system.…”