Makarenkova Lab
The role of fibroblast growth factors in development, regeneration, and disease
Genetic labeling of salivary gland FGF10 expressing cells (top image - brown, low images red), showing that ionocytes interact with EGF expressing duct cells and myoepithelial cells and express E-cadherin (ECAD) and cystic fibrosis transmembrane conductance regulator (CFTR).
Specifically, our research focuses on the critical role of fibroblast growth factors (FGFs) in regulating tissue development and regeneration. Our previous studies have shown that members of the (FGF) family are important regulators of lacrimal gland morphogenesis. In particular, we have found that FGF-10 is necessary for lacrimal and Harderian gland development. We also made significant progress in understanding how structural differences in various FGFs are incorporated into their functional properties. Using the lacrimal and salivary glands as a model system, our team in collaboration with Dr. Hoffman lab demonstrated that the biological activities of growth factor morphogens depend on the gradients they form in the extracellular matrix. Thus, we have shown that differences in the binding of FGF7 and FGF10 to heparan sulfate (HS) within the extracellular matrix result in the formation of different gradients that dictate distinct functional activities of these FGFs during branching morphogenesis. Our studies show how structural differences within FGFs relate to their biological function in branching morphogenesis.
Recently, we made a groundbreaking discovery that FGF10 which is a widely recognized growth factor derived from mesenchyme may have different roles during postnatal development of submandibular and parotid grands. By employing a single-cell RNA sequencing (RNA-seq) technology and utilizing a tamoxifen-inducible Fgf10CreERT2:R26-tdTomato mouse model, we have demonstrated mesenchymal to epithelial shift in FGF10 expression. Specifically, we observed a transition from mesenchymal fibroblasts to exclusively epithelial duct cells during the second week of salivary gland postnatal development. Notably, these epithelial ductal cells expressing FGF10 also exhibited the presence of ancient ionocyte signature genes, such as Forkhead box i1 and 2 (Foxi1, Foxi2), Achaete-scute homolog 3 (Ascl3), and the cystic fibrosis transmembrane conductance regulator (Cftr).
Intriguingly, our research has revealed that FGF10 possesses the capability to reduce inflammation and expedite gland regeneration. These significant findings hold tremendous therapeutic potential, particularly in the development of novel treatments for dry eye/dry mouth disease. By targeting the regenerative abilities of the cornea, lacrimal and salivary glands, we can pave the way for innovative therapeutic interventions.