Elaine Emmerson Research Group

The role of macrophages in salivary gland development

The correct growth, morphogenesis and patterning of an organ or tissue during development is essential for its function in adulthood. The majority of organs (such as heart, lungs, intestine), develop during the embryonic period in order to be functional by birth, while others (e.g. lymphoid structures and the salivary glands) continue to mature into the neonatal period or into puberty (such as the mammary glands). The salivary glands develop through a process known as branching morphogenesis, where the glandular epithelium undergoes rounds of branching and clefting, to create a branched organ which is capable, by the time of weaning, of saliva production. A number of precisely timed signalling events are necessary for this correct growth and patterning, and the phenomenon involves multiple cells working together. 

Recent studies have implicated macrophages as having a pivotal role in organ development, in addition to their classical phagocytic roles. Mouse mammary gland macrophages are recruited to the epithelium and provide vital cues for branching morphogenesis during embryogenesis. Furthermore, macrophage-deficient mice experience altered mammary gland branching and elongation during puberty and pregnancy, resulting in a lactational defect. Similarly, macrophages are recruited to the developing pancreas and kidney, and their absence results in abnormal development. In collaboration with Dr Rebecca Gentek and Dr Calum Bain, we are exploring whether macrophages play a key role in salivary gland development.

The role of macrophages in epithelial regeneration

Macrophages are attractive therapeutic targets due to their unrivalled capacity to drive tissue repair and regeneration. We have used a suite of complementary approaches to map the heterogeneity of the salivary gland macrophage compartment throughout development and following radiotherapy injury. Furthermore, we have demonstrated an essential role for macrophages in the clearance of cells with DNA damage, as well as effective tissue repair following injury, absence of which leads to salivary gland dysfunction. Taken together, our data place macrophages at the heart of effective tissue repair following radiation-induced injury in the salivary gland and provide strong rationale for exploring the therapeutic potential of manipulating these cells to promote tissue repair. Using genetic lineage tracing we find that radiation injury alters SG macrophage replenishment kinetics, a phenomenon that parallels degeneration in SG architecture and function, which is suggestive of a failure of the supportive niche over time. Given that macrophages are considered to be in constant crosstalk with their structural neighbours, these data suggest that the effects of radiation may alter the SG niche so that it cannot support macrophage longevity/function; and conversely, that macrophages cannot support the SG niche. In collaboration with Dr. Calum Bain, we are exploring the niche-derived factors that control SG macrophage maintenance and function, how these change in the context of SG injury, regeneration and degeneration and whether exogenous supplement can rescue this effect, and could ultimately provide new therapeutic avenues to target macrophages to promote tissue regeneration.

Translational approaches to promote epithelial regeneration

In the field of regenerative medicine, significant progress has been made in cell-based therapies, while the manipulation of the stem cell niche to promote tissue regeneration has received less attention. A major component of the niche is peripheral nerves, which also provide a range of essential signals to the organs of the body, controlling functions such as heart rate and digestion. There is evidence that peripheral nerves are essential for the development, function and replacement of cells in numerous tissues and furthermore that neuronal signals are themselves vital within all three of these areas. We have previously shown that cholinergic muscarinic signalling maintains SOX2+ progenitor cells in the SG. However, use of cholinergic drugs is limited by their serious side-effects when delivered systemically. In collaboration with Prof. Asier Unciti-Broceta, we are testing the use of a novel technology to safely and locally deliver a cholinergic drug to radiation-injured SG. This project aims to develop a completely new way of delivering a pharmacological therapy (based on neuronal signalling) to radiotherapy-injured SG without the typical systemic side-effects associated with cholinergic drugs.