Mechanisms controlling cellular identity of stem cells identified

Mechanisms controlling cellular identity of stem cells identified

Researchers have identified for the first time the mechanisms by which communication between cells controls the identity of stem cells from the mammary gland and prostate.

The mammary gland and prostate are composed of two different cell types: basal cells and luminal cells. These two cell types are maintained by separate basal and luminal stem cells. Under normal conditions, adult basal stem cells only give rise to basal cells. In contrast, during a transplant or cancer initiation, basal stem cells are likely to generate both basal and luminal stem cells and thus become multipotent (giving rise to more than one cell type).

The mechanisms by which basal stem cells can restrict this multipotency under normal conditions or activate multipotency under tissue repair conditions remain unknown. In a new study published on 26 August and featured on the cover of the prestigious journal Nature, a team of researchers led by Professor CÚdric Blanpain - a WELBIO investigator and director of the Stem Cells and Cancer Laboratory at the Faculty of Medicine of the Free University of Brussels - found that communication between basal and luminal cells restricts the multipotency of stem cells from the mammary gland and prostate. She also identified the signals that restrict multipotency under normal conditions and activate it under conditions of tissue regeneration and repair.

In order to determine whether communication between basal and luminal cells controls basal stem cell multipotency, Alessia Centonze and her colleagues have developed a new genetic approach that allows basal cells to be specifically labelled with a fluorescent marker, to kill luminal cells and to assess the fate of basal stem cells over time. They were able to discover that the removal of luminal cells led to the activation of basal stem cell multipotency and the replenishment of luminal stem cells with basal stem cells in many tissues, including the mammary gland, prostate, sweat glands and salivary glands. Researchers have shown that activation of stem cell multipotency leads to the formation of a hybrid cell population with a basal and luminal differentiation programme. In order to identify the molecular mechanisms leading to the activation of multipotency, ULB researchers, in collaboration with Professor Thierry Voet (KULeuven), carried out RNA sequencing of single cells, thus enabling them to study the molecular identity of individual cells after the ablation of luminal cells. They were thus able to define the trajectory of basal stem cells and the unique genetic signature of multipotent basal stem cells, as well as how these cells give rise to new luminal cells.

"It was fascinating to identify this new cellular state that accompanies the regeneration of different tissues and shows that the differentiation of basal cells into luminal cells is a dynamic process in which basal cells lose their basal identity while acquiring luminal characteristics, passing through a hybrid state evocative of the cellular state observed during embryonic development", comments Alessia Centonze, the first author of this study.

The researchers then identified the molecules that restrict multipotency under normal conditions as well as the molecules that promote multipotency when luminal cells are ablated.

"Given that multipotency is associated with the formation of breast and prostate cancer, the identification of molecules that control stem cell multipotency will hopefully serve to inhibit cancer formation", commented Professor CÚdric Blanpain, the latest author of this study.
In conclusion, this new study identifies the key role of cell interaction in controlling the multipotency of adult stem cells. It also uncovers the molecular mechanisms that control the multipotency of stem cells in different tissues, which has important implications for understanding the mechanisms of cancer formation.