Hierarchical tissue organization as a general mechanism to limit the accumulation of somatic mutations

TL;DR

This paper presents a general model showing that hierarchical tissue organization can effectively minimize the accumulation of somatic mutations by reducing the divisional load, independent of specific differentiation processes.

Contribution

It introduces a universal analytical framework linking tissue structure to mutation risk, highlighting the role of slow-dividing cell types in cancer prevention.

Findings

Divisional load depends only on structural and dynamical parameters.

Hierarchical organization can nearly match non-renewing tissues in efficiency.

Stem cells and differentiation hierarchies help prevent cancer.

Abstract

How can tissues generate large numbers of cells, yet keep the divisional load (the number of divisions along cell lineages) low in order to curtail the accumulation of somatic mutations and reduce the risk of cancer? To answer the question we consider a general model of hierarchically organized self-renewing tissues and show that the lifetime divisional load of such a tissue is independent of the details of the cell differentiation processes, and depends only on two structural and two dynamical parameters. Our results demonstrate that a strict analytical relationship exists between two seemingly disparate characteristics of self-renewing tissues: divisional load and tissue organization. Most remarkably, we find that a sufficient number of progressively slower dividing cell types can be almost as efficient in minimizing the divisional load, as non-renewing tissues. We argue that one of the main functions of tissue-specific stem cells and differentiation hierarchies is the prevention of cancer.