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Neurotrophic factor-secreting autologous muscle stem cell therapy for the treatment of laryngeal denervation injury§

Authors

  • Stacey L. Halum MD,

    Corresponding author
    1. Department of Otolaryngology–Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, Indiana, U.S.A.
    • Department of Otolaryngology–Head and Neck Surgery, Indiana University, 702 Barnhill Dr., Suite #860, Indianapolis, IN 46202
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  • Bryan McRae MD,

    1. Department of Otolaryngology–Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, Indiana, U.S.A.
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  • Khadijeh Bijangi-Vishehsaraei PhD,

    1. Department of Otolaryngology–Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, Indiana, U.S.A.
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  • Kelly Hiatt MD, PhD

    1. Department of Otolaryngology–Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, Indiana, U.S.A.
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  • Dr. Stacey Halum's Triological thesis was presented at the Triological Society Meeting at COSM, Chicago, Illinois, U.S.A., April 29–30, 2011.

  • These projects were supported by Indiana University School of Medicine, Department Otolaryngology–Head and Neck Surgery funds, and by award number K08DC009583 from the National Institute on Deafness and Other Communication Disorders (NIDCD) within the National Institutes of Health (NIH). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIDCD or NIH

  • §

    The authors have no other funding, financial relationships, or conflicts of interest to disclose.

Abstract

Objectives/Hypothesis:

To determine if the spontaneous reinnervation that characteristically ensues after recurrent laryngeal nerve (RLN) injury could be selectively promoted and directed to certain laryngeal muscles with the use of neurotrophic factor (NF)-secreting muscle stem cell (MSC) vectors while antagonistic reinnervation is inhibited with vincristine (VNC).

Study Design:

Basic science investigation involving primary cell cultures, gene cloning/transfer, and animal experiments.

Methods:

MSC survival assays were used to test multiple individual NFs in vitro. Motoneuron outgrowth assays assessed the trophic effects of identified NF on cranial nerve X (CNX)-derived motoneurons in vitro. Therapeutic NF was cloned into a lentiviral vector, and MSCs were tranduced to secrete NF. Sixty rats underwent left RLN transection injury, and at 3 weeks received injections of either MSCs (n = 24), MSCs secreting NF (n = 24), or saline (n = 12) into the left thyroarytenoid muscle complex; half of the animals in the MSC groups simultaneously received left posterior cricoarytenoid injections of VNC, whereas half of the animals received saline.

Results:

Ciliary neurotrophic factor (CNTF) had the greatest survival-promoting effect on MSCs in culture. The addition of CNTF (50 ng/mL) to CNX motoneuron cultures resulted in enhanced neurite outgrowth and branching. In the animal model, the injected MSCs fused with the denervated myofibers, immunohistochemistry demonstrated enhanced reinnervation based on motor endplate to nerve contact, and reverse transcriptase-polymerase chain reaction confirmed stable CNTF expression at longest follow-up (4 months) in the CNTF-secreting MSC treated groups.

Conclusions:

MSC therapy may have a future role in selectively promoting and directing laryngeal reinnervation after RLN injury. Laryngoscope, 2012

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