Heparan sulfate regulates amphiregulin signaling towards reparative lung mesenchymal cells during influenza A infection.

Amphiregulin (Areg), a growth factor produced by regulatory T (Treg) cells to facilitate tissue repair/regeneration, contains a heparan sulfate (HS) binding domain. How HS, a highly sulfated glycan subtype that alters growth factor signaling, influences Areg repair/regeneration functions is unclear. Here we report that inhibition of HS in various cell lines and primary lung mesenchymal cells (LMC) qualitatively alters downstream signaling and highlights the existence of HS-dependent vs. -independent Areg transcriptional signatures. Utilizing a panel of cell lines with targeted deletions in HS synthesis-related genes, we found that the presence of the glypican family of heparan sulfate proteoglycans is critical for Areg signaling and confirmed this dependency in primary LMC by siRNA-mediated knockdown. Furthermore, in the context of influenza A (IAV) infection in vivo , we found that an Areg-responsive subset of reparative LMC upregulate glypican-4 and HS. Conditional deletion of HS primarily within this LMC subset resulted in reduced blood oxygen saturation following infection with IAV, with no changes in viral load. Finally, we found that co-culture of HS-knockout LMC with IAV-induced Treg cells results in reduced LMC responses. Collectively, this study reveals the essentiality of HS on a specific lung mesenchymal population as a mediator of Treg cell-derived Areg reparative signaling during IAV infection.

Visions by WIMIN: BIPOC Representation Matters.

Racial, ethnic, and gender representation in an academic setting means that teachers, professors, and other leaders reflect the demographics of the student body in the educational and professional spaces that they serve. This form of representation, which is often intersectional, strengthens communities and improves student outcomes, from as early as primary and secondary education, through to college education and beyond. Representation matters because it can shape the reputation and self-image of women and Black, Indigenous, and People of Color (BIPOC) within environments dominated by over-represented majorities (ORMs). From the perspective of BIPOC women trainees, the lack of BIPOC faculty who are visible minorities, particularly at the most senior level positions, often conjures questions of whether academia is a realistic career path for aspiring minority students. This article focuses on the key component of representation in the United States (U.S.), highlighting our vision for a solution for the so-called "leaky pipeline" for BIPOC in science, technology, engineering, and mathematic with action items to end it.