Abstract
Fibroblasts are ubiquitous mesenchymal cells with many vital functions during development, tissue repair, and disease. Fibroblasts from different anatomic sites have distinct and characteristic gene expression patterns, but the principles that govern their molecular specialization are poorly understood. Spatial organization of cellular differentiation may be achieved by unique specification of each cell type; alternatively, organization may arise by cells interpreting their position along a coordinate system. Here we test these models by analyzing the genome-wide gene expression profiles of primary fibroblast populations from 43 unique anatomical sites spanning the human body. Large-scale differences in the gene expression programs were related to three anatomic divisions: anterior-posterior (rostral-caudal), proximal-distal, and dermal versus nondermal. A set of 337 genes that varied according to these positional divisions was able to group all 47 samples by their anatomic sites of origin. Genes involved in pattern formation, cell-cell signaling, and matrix remodeling were enriched among this minimal set of positional identifier genes. Many important features of the embryonic pattern of HOX gene expression were retained in fibroblasts and were confirmed both in vitro and in vivo. Together, these findings suggest that site-specific variations in fibroblast gene expression programs are not idiosyncratic but rather are systematically related to their positional identities relative to major anatomic axes.
Highlights
The problem of how genetic information gives rise to the spatial organization has long intrigued developmental biologists [1,2,3]
Fibroblasts from different anatomic sites are morphologically similar, we previously showed that fibroblasts from several sites exhibit large-scale differences in their gene expression programs depending on their anatomic site of origin [13]
Based on the spatial patterns suggested by the unsupervised analysis, we developed a global model and identified specific genes that were predictive of the anatomic site of origin of fibroblasts
Summary
The problem of how genetic information gives rise to the spatial organization has long intrigued developmental biologists [1,2,3]. While cellular differentiation addresses the control of expression of specific genes within a cell, pattern formation addresses the spatial arrangement of distinct cell types. A major mechanism of pattern formation in the embryo is the use of positional information. By linking differentiation programs to cell positions on a coordinate system, an assembly of cells can be programmed to develop into well-defined spatial patterns that are not perturbed by the removal or addition of cells. While spatial boundaries are first defined during embryonic development, these spatial patterns of cellular specialization need to be maintained throughout adulthood as the tissues undergo continual self-renewal. In contrast to embryonic development, the higher-order patterns of cellular specialization in adult animals and mechanisms of their maintenance are less well understood
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