Macrophages support mammary stem cells via chemical signalling

An international team of scientists has discovered that one of the biggest hitters in the immune system, macrophages, provide a cradle for mammary stem cells. They have investigated the interactions between these cells with a view to potentially gaining better information about the origins of breast cancer.

The study found that macrophages play an important role in maintaining the mammary gland’s stem cell niche – an area of tissue that maintains the microenvironment for breast stem cells.  

Commenting on their ambitions for the study outcomes, team leader Yibin Kang, the Warner-Lambert/Parke-Davis Professor of Molecular Biology at Princeton University and an associate director of the Rutgers Cancer Institute of New Jersey, said: “Learning more about the factors that keep mammary stem cells alive and healthy may provide insights into the development of breast cancer when such regulation goes awry,”  

Stem cells are cells that have the potential to mature, or differentiate, into several different types of cells. Mammary stem cells shepherd breast development during puberty and are active during pregnancy and lactation. The team found that the macrophage helps create a special environment, known as a stem-cell niche, that keeps stem cells in their premature state and able to duplicate and differentiate into mature cells when needed.

Stem cells come in various types, from ones that are already committed to develop into certain organs (as in the mammary glands), to ones that can form nearly any cell in the body. However, these cells may also become cancerous, leading to tumours and eventually the spread of cancer to other organs.

These signalling mechanisms involve a protein called Notch, which acts as a receptor for a signalling molecule called Dll1. Previous research in Kang’s lab found that mammary stem cells make a lot of Dll1. In the current study, researchers knocked out the Dll1 gene in mice and found that there is a significant delay in breast development during puberty, as well as delayed breast expansion during pregnancy and lactation. Furthermore, the number of mammary stem cells was reduced – both during mammary gland development and during pregnancy. Meanwhile, mice with the Dll1 gene intact contained mammary glands with a greater ability to regenerate and to differentiate into mature mammary cells compared to the Dll1-knockout mice.

The mice lacking Dll1 also had fewer macrophage cells in their mammary glands. The researchers found that the binding of Dll1 to Notch2 and Notch3 receptors is important for keeping the number of macrophages high in the mammary stem cell niche, and important for keeping the mammary cells in their stem-cell state.

The researchers also found that the presence of Dll1 is linked to the expression of genes for another signalling pathway involving a molecule called Wnt. The expression of Dll1 caused the macrophages to express genes for Wnt3, 10 and 16, which further enhanced the stem-cell behaviour of the mammary stem cells. When the researchers used genetic or chemical methods to inactivate the macrophages in the mammary glands of mice, the mammary stem cell activity decreased.

“We conclude that the signalling molecule Dll1, which is produced by the mammary stem cells, activates the signal in macrophages to sustain the mammary stem cells,” Kang said. “The survival and function of these mammary stem cells and the macrophages are dependent on each other and they communicate through these cellular messaging systems.”

The first author and co-corresponding author on the study was Rumela Chakrabarti, who was a postdoctoral research associate at Princeton and is now an assistant professor of biomedical sciences at the University of Pennsylvania School of Veterinary Medicine.

Jeffrey Rosen, who is the C.C. Bell Professor, Vice-Chair of Molecular and Cellular Biology, and Distinguished Service Professor at Baylor College of Medicine, and not directly involved in the study, said, “The study by Yibin Kang and colleagues helps expand our knowledge about the role of macrophages in mammary gland development first demonstrated by other research groups almost two decades ago and more recently by researchers who found that macrophages influence stem-cell activity in the mammary gland.

“The study also raises several questions about the specific roles of multiple Wnt molecules expressed in mammary cells and surrounding cells as well as in tissue-resident macrophages in mammary stem cells,” he said. “These studies on normal mammary gland development may provide important clues about the roles of macrophages in breast cancer progression.”

The study was published in the journal Science.