Repurposing Ferumoxytol Nanoparticles to Promote Orofacial Stem Cell Function for Autotherapies

Project Description
The advancement of regenerative medicine has provided many new potential treatments for craniofacial bone
defects, in which mesenchymal stem/progenitor cells (MSCs) play a critical role in maintaining constant
remodeling of tissue architecture. The neural crest derived orofacial MSCs (OMSCs), such as stem cells from
apical papilla (SCAP) are attractive postnatal stem cells for hard tissue regeneration, based on their superior
osteogenic properties compared to their bone marrow counterparts. However, clinical translation remains
challenging due to limited knowledge about the mechanisms of action. Ferumoxytol, an FDA-approved iron
oxide nanoparticle formulation, exhibits several biomedical properties including anticancer and
immunomodulation, based on its inherent physicochemical properties that activates cell proliferation, migration,
and differentiation. Given these properties, ferumoxytol could be applied in MSC-based tissue regeneration, an
unexplored avenue. Specifically, our goal is to identify whether ferumoxytol can activate orofacial MSCs and
promote their multipotent differentiation capabilities and immunomodulation for endogenous tissue
regeneration. Using RNA sequencing (RNA-seq) analysis and in vitro MSC characterization, we found
intriguing data demonstrating that: 1) ferumoxytol significantly promotes stemness of SCAP through elevation
of MSC markers and osteogenic progenitor markers, 2) proliferation and osteogenic capabilities are highly
activated in SCAP after ferumoxytol treatment, 3) ferumoxytol largely increased immunomodulation of SCAP
via PGE2/IDO cascades, and 4) YAP/TAZ are required mediators in ferumoxytol-mediated metabolic
reconfiguration of SCAP for tissue regeneration. Based on these findings, we hypothesize that ferumoxytol
activates YAP/TAZ signaling and promotes stemness of orofacial MSCs, which provides a favorable
physiochemical microenvironment for enhancement of MSC viability and osteogenesis for
autotherapies. During this proposal, I will explore the role of ferumoxytol in activation of somatic OMSCs to
address how YAP/TAZ-mediated metabolic switch regulates OMSC homeostasis (Aim 1). Since immune
components can impair somatic stem cell function and ferumoxytol treatment significantly elevated cell
proliferation and osteogenesis through activation of YAP/TAZ cascades, we will determine whether activation
of YAP/TAZ by ferumoxytol treatment may elevate endogenous craniofacial tissue regeneration in a ligature-
induced periodontitis mouse model. A tetracycline-inducible postnatal neural-crest-specific YAP/TAZ knockout
mouse model will be generated to examine in vivo stem cell behavior and endogenous tissue regeneration
ability (Aim 2). Upon successful completion of the Specific Aims, this translational study will extend our
knowledge in activating somatic stem cell abilities through repurposing an FDA approved nanoformulation for a
new biomedical application.

Grant Number: 5R21DE033128-02
NIH Institute/Center: NIH
Principal Investigator: Chi-Der Chen