Fidgetin-Like 2: A Microtubule-Based Regulator of Wound Healing

Abstract

Wound healing is a complex process driven largely by the migration of a variety of distinct cell types from the wound margin into the wound zone. In this study, we identify the previously uncharacterized microtubule-severing enzyme, Fidgetin-like 2 (FL2), as a fundamental regulator of cell migration that can be targeted in vivo using nanoparticle-encapsulated siRNA to promote wound closure and regeneration. In vitro, depletion of FL2 from mammalian tissue culture cells results in a more than two-fold increase in the rate of cell movement, due in part to a significant increase in directional motility. Immunofluorescence analyses indicate that FL2 normally localizes to the cell edge, importantly to the leading edge of polarized cells, where it regulates the organization and dynamics of the microtubule cytoskeleton. To clinically translate these findings, we utilized a nanoparticle-based siRNA delivery platform to locally deplete FL2 in both murine full-thickness excisional and burn wounds. Topical application of FL2 siRNA nanoparticles to either wound type results in a significant enhancement in the rate and quality of wound closure both clinically and histologically relative to controls. Taken together, these results identify FL2 as a promising therapeutic target to promote the regeneration and repair of cutaneous wounds.

Microtubules in 3D cell motility

“…Furthermore, a recent study has shown that inhibition of the microtubule-severing protein fidgetinlike protein 2 (FIGNL2) promotes epidermal cell migration in vivo (Charafeddine et al, 2015), suggesting that the members of this protein family have important roles in 3D cell migration.…”

Targeting Microtubules for Wound Repair

“…12 This discovery stemmed from an siRNA screen that was used to find the human equivalent of katanin, the severing enzyme whose depletion enhances the rate of Drosophila cell migration. 55 We assumed that if we could harness the same activity in human cells, we would have a potentially viable therapeutic target for enhancing wound healing.…”

Light-Triggered RNA Release and Induction of Hmsc Osteogenesis Via Photodegradable, Dual-Crosslinked Hydrogels

“…Delivering small interfering RNA (siRNA) or microRNA (miRNA) [17,18] to inhibit gene expression post-transcriptionally is a promising biomedical technology that has been investigated for many applications including cancer therapeutics [19][20][21][22][23], wound healing [24][25][26], and tissue regeneration [6][7][8][9][10][27][28][29][30][31][32]. For example, RNAs have been used in tissue regeneration to induce the differentiation of human MSCs (hMSCs) [6][7][8][9][10], canine MSCs [30] and rat MSCs [31] into osteoblasts [6][7][8][9]30,31], chondrocytes [10] or adipocytes [7,8].…”