title: 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 small interfering RNA (siRNA) to promote wound closure and regeneration. In vitro, depletion of FL2 from mammalian tissue culture cells results in a more than twofold increase in the rate of cell movement, in part due 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.
authors.affiliation: Department of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Rabab A
authors.initials: RA
authors.lastname: Charafeddine
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Joy
authors.initials: J
authors.lastname: Makdisi
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: David
authors.initials: D
authors.lastname: Schairer
authors.affiliation: Department of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Brian P
authors.initials: BP
authors.lastname: O'Rourke
authors.affiliation: Department of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Juan D
authors.initials: JD
authors.lastname: Diaz-Valencia
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Chouake
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Allison
authors.initials: A
authors.lastname: Kutner
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Aimee
authors.initials: A
authors.lastname: Krausz
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Brandon
authors.initials: B
authors.lastname: Adler
authors.affiliation: Department of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Parimala
authors.initials: P
authors.lastname: Nacharaju
authors.affiliation: Department of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Hongying
authors.initials: H
authors.lastname: Liang
authors.affiliation: Department of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Suranjana
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Department of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Friedman
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA; These authors contributed equally to this work.
authors.forename: Adam
authors.initials: A
authors.lastname: Friedman
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA; These authors contributed equally to this work.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Nosanchuk
authors.affiliation: Department of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, New York, USA; These authors contributed equally to this work. Electronic address: david.sharp@einstein.yu.edu.
authors.forename: David J
authors.initials: DJ
authors.lastname: Sharp
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000818:Animals; D001707:Biopsy, Needle; D015153:Blotting, Western; D002465:Cell Movement; D002478:Cells, Cultured; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D051379:Mice; D008869:Microtubule-Associated Proteins; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism*; D053758:Nanoparticles; D009687:Nuclear Proteins / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology*; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D014945:Wound Healing / Q000502:physiology*; D014947:Wounds and Injuries / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology
chemical_list: D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D000251:Adenosine Triphosphatases; D000074183:ATPases Associated with Diverse Cellular Activities; C498542:Fign protein, mouse