Fgf10/Fgfr2b Signaling Orchestrates the Symphony of Molecular, Cellular, and Physical Processes Required for Harmonious Airway Branching Morphogenesis

Abstract

Airway branching morphogenesis depends on the intricate orchestration of numerous biological and physical factors connected across different spatial scales. One of the key regulatory pathways controlling airway branching is fibroblast growth factor 10 (Fgf10) signaling via its epithelial fibroblast growth factor receptor 2b (Fgfr2b). Fine reviews have been published on the molecular mechanisms, in general, involved in branching morphogenesis, including those mechanisms, in particular, connected to Fgf10/Fgfr2b signaling. However, a comprehensive review looking at all the major biological and physical factors involved in branching, at the different scales at which branching operates, and the known role of Fgf10/Fgfr2b therein, is missing. In the current review, we attempt to summarize the existing literature on airway branching morphogenesis by taking a broad approach. We focus on the biophysical and mechanical forces directly shaping epithelial bud initiation, branch elongation, and branch tip bifurcation. We then shift focus to more passive means by which branching proceeds, via extracellular matrix remodeling and the influence of the other pulmonary arborized networks: the vasculature and nerves. We end the review by briefly discussing work in computational modeling of airway branching. Throughout, we emphasize the known or speculative effects of Fgfr2b signaling at each point of discussion. It is our aim to promote an understanding of branching morphogenesis that captures the multi-scalar biological and physical nature of the phenomenon, and the interdisciplinary approach to its study.

Reconstructing the pulmonary niche with stem cells: a lung story

“…At E10.5 in mice, the Nkx2.1 positive progenitor cells evaginate to initiate lung budding at the ventral wall of the AFE. This is facilitated by Fgf10 signaling from the surrounding mesenchyme [ 55 ]. Besides Fgf10, RA signaling also plays a crucial role in lung bud formation as it promotes Wnt2/2b signaling by suppressing the Wnt inhibitor Dickkopf-related protein 1 (Dkk1); this is vital for conserving Nkx2.1 identity among the progenitors [ 56 ].…”

Characterization of alveolar epithelial lineage heterogeneity during the late pseudoglandular stage of mouse lung development

“…There is still much to elucidate concerning the journey of Nkx2-1 positive multipotent progenitors towards an alveolar lineage specification and eventual commitment to an AT1 or AT2 fate. Most likely, a complex interplay of signalling pathways, biomechanical, and physical factors regulates the spatial and temporal emergence of alveolar progenitor cells during development (Jones et al, 2021; Li et al, 2018; Tang et al, 2018). At a basic level, however, it is still unclear when the alveolar lineage emerges, and what are the characteristics of the progenitor cell(s).…”

“…Prior to the initiation of the alveolar differentiation program, Fgfr2b signalling also tightly regulates branching morphogenesis (Jones et al, 2021). Research continues on the regulatory mechanisms downstream of Fgfr2b signalling which control, at the level of the multipotent epithelium, the transition from a branching program during the pseudoglandular stage (E11.5 to E16.5) to an alveolar program at the canalicular/saccular stages (E16.6 to E18.5).…”

Organ-Specific Branching Morphogenesis

“…The developmental process during which epithelial buds branch into the surrounding mesenchyme and thereby construct a complex epithelial tree is called branching morphogenesis. The biochemical and mechanical interactions between epithelium and mesenchyme that regulate branching morphogenesis have been studied in great detail, and the key regulatory factors that control branching morphogenesis are largely well known (Shah, 2004;Warburton et al, 2005;Jones et al, 2021). How the commonly used principle of branching morphogenesis can create organs of different shapes and functions, nonetheless, remains elusive.…”