Characterization and function of a new p75-NTR+ cellular network in craniofacial bone

Washington University, Saint Louis MO

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Abstract

PROJECT SUMMARY There is a critical need for new methods to accelerate and enhance skeletal regeneration. This is generally dependent on two main factors. First, the recruitment and differentiation of suitable osteoprogenitor cells. Second, the upregulation of key osteoanabolic pathways that coordinate cell proliferation and the osteogenic cascade. Novel methods to enhance one or both of these factors are needed to significantly advance the field. In 2010, it was discovered that regions of neural crest-derived bone within the craniofacial skeleton have superior regenerative capacity; this is true in terms of both the speed of the skeletal regeneration and the total amount of bone formed. In 2015, it was further established that these regions have enhanced osteoanabolic signaling and increased expression of genes related to proliferation, self-renewal, and the stem cell niche. In 2021, it was confirmed that these findings extend to humans. However, the upstream mechanisms driving this remain as yet unknown. In addition, the ability to replicate this pro-regenerative program at other skeletal sites has not yet been achieved. This represents a key gap in knowledge. To overcome this, we recently identified a unique p75 neurotrophin receptor-positive (p75-NTR+) periosteal cell population that forms a dense network specifically over the surface of the pro-regenerative region of neural crest-derived bone. This network is persistent even in adult animals and is absent in neighboring regions and calvarial bones of mesodermal origin. P75-NTR is a 427-amino-acid transmembrane receptor that forms heteromeric complexes with other receptors and binds to a broad array of neurotrophins such as nerve growth factor, which is also known to be osteoanabolic. P75-NTR has also been identified as a marker of neural-crest derived stem cells. Our central hypothesis is that this robust p75-NTR+ cellular network represents the basis of the superior pro-regenerative properties of neural crest-derived bone. The work in this project will begin by characterizing this unique cell network (Aim 1). Second, we will determine if this is a transplantable progenitor population that can be used to promote regeneration at other skeletal sites (Aim 2). Last, we will use a clinical p75-NTR modulator as a strategy to enhance local osteoanabolic signaling and bone formation (Aim 3). When complete, we anticipate that our results will yield valuable basic and translational information that will promote biologically inspired tissue engineering strategies to enhance craniofacial and orthopedic bone regeneration.