Abstract
The cell lineage tree of a multicellular organism represents its history of cell divisions from the very first cell, the zygote. A new method for high-resolution reconstruction of parts of such cell lineage trees was recently developed based on phylogenetic analysis of somatic mutations accumulated during normal development of an organism. In this study we apply this method in mice to reconstruct the lineage trees of distinct cell types. We address for the first time basic questions in developmental biology of higher organisms, namely what is the correlation between the lineage relation among cells and their (1) function, (2) physical proximity and (3) anatomical proximity. We analyzed B-cells, kidney-, mesenchymal- and hematopoietic-stem cells, as well as satellite cells, which are adult skeletal muscle stem cells isolated from their niche on the muscle fibers (myofibers) from various skeletal muscles. Our results demonstrate that all analyzed cell types are intermingled in the lineage tree, indicating that none of these cell types are single exclusive clones. We also show a significant correlation between the physical proximity of satellite cells within muscles and their lineage. Furthermore, we show that satellite cells obtained from a single myofiber are significantly clustered in the lineage tree, reflecting their common developmental origin. Lineage analysis based on somatic mutations enables performing high resolution reconstruction of lineage trees in mice and humans, which can provide fundamental insights to many aspects of their development and tissue maintenance.
Highlights
All the cells in the body of a multi-cellular organism, such as a human or a mouse, descend from a single cell–the fertilized egg
In addition to obtaining knowledge regarding the general features of the lineage tree, we focused on a specific cell type–satellite cells–a small population of muscle stem cells residing beneath the basal lamina of each myofiber [10]
We analyzed correlations between lineage and cell type, and between lineage and the hierarchy of the anatomy of skeletal muscle. Such correlations are closely related to three basic questions in development: First, are lineage and biological function correlated, i.e. do cells sharing a long common developmental path tend to be of the same type and perform the same biological function? We found that for the cell types we analyzed there is no significant correlation between lineage and cell type
Summary
All the cells in the body of a multi-cellular organism, such as a human or a mouse, descend from a single cell–the fertilized egg. A variety of methods for lineage analysis, generally termed clonal assays (reviewed in [5]), rely on marking some cells and tracing their progeny. These methods have yielded many insights, but can provide only course-grain information about a cell lineage tree [1,4]. These methods are inapplicable to the study of humans because they are invasive
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