Inheritance entropy quantifies epigenetic regulation of cell-cycle exit in human bone marrow stromal cells

TL;DR

This study introduces a novel entropy measure to quantify heritable epigenetic regulation of cell-cycle exit in human bone marrow stromal cell colonies, revealing significant hereditary influence on colony heterogeneity.

Contribution

It presents a new entropy-based metric to assess non-genetic inheritance in cell lineage topology, demonstrating its effectiveness in understanding epigenetic regulation in BMSC colonies.

Findings

Heritable traits influence cell-cycle exit in BMSC colonies.

Entropy measure distinguishes hereditary from non-hereditary lineage patterns.

Hereditary epigenetic factors significantly impact colony heterogeneity.

Abstract

Human bone marrow stromal cells (BMSC) include skeletal stem cells with ground-breaking therapeutic potential. However, BMSC colonies have very heterogeneous in vivo behaviour, due to their different potency; this unpredictability is the greatest hurdle to the development of skeletal regeneration therapies. Colony-level heterogeneity urges a fundamental question: how is it possible that one colony as a collective unit behaves differently from another one? If cell-to-cell variability were just an uncorrelated random process, a million cells in a transplant-bound colony would be enough to yield statistical homogeneity, hence washing out any colony-level traits. A possible answer is that the differences between two originating cells are transmitted to their progenies and collectively persist through an hereditary mechanism. But non-genetic inheritance remains an elusive notion, both at the experimental and at the theoretical level. Here, we prove that heterogeneity in the lineage topology of BMSC clonal colonies is determined by heritable traits that regulate cell-cycle exit. The cornerstone of this result is the definition of a novel entropy of the colony, which measures the hereditary ramifications in the distribution of inactive cells across different branches of the proliferation tree. We measure the entropy in 32 clonal colonies, obtained from single-cell lineage tracing experiments, and show that in the greatest majority of clones this entropy is decisively smaller than that of the corresponding non-hereditary lineage. This result indicates that hereditary epigenetic factors play a major role in determining cycle exit of bone marrow stromal cells.