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Original Investigation
December 15, 2016

Human Induced Pluripotent Stem Cell–Derived Motor Neuron Transplant for Neuromuscular Atrophy in a Mouse Model of Sciatic Nerve Injury

Author Affiliations
  • 1USC (University of Southern California) Caruso Department of Otolaryngology–Head and Neck Surgery, Keck School of Medicine, USC, Los Angeles
  • 2Department of Regenerative Medicine and Stem Cell Biology, Broad CIRM (California Institute for Regenerative Medicine) Center, Keck School of Medicine, USC, Los Angeles
  • 3Division of Biokinesiology and Physical Therapy, Herman Ostrow School of Dentistry, USC, Los Angeles
JAMA Facial Plast Surg. Published online December 15, 2016. doi:10.1001/jamafacial.2016.1544
Key Points

Question  Are human induced pluripotent stem cells a potential source of replacement motor neurons in the setting of peripheral motor nerve injury?

Findings  In this experimental study, motor neurons derived from human induced pluripotent stem cells successfully engrafted and extended neurites to target denervated muscle in 13 mmunodeficient mice with sciatic nerve injury. These motor neurons reduced denervation-induced muscular atrophy compared with negative controls.

Meaning  Motor neurons derived from human induced pluripotent stem cells may have future use in the treatment of peripheral motor nerve injury, including facial paralysis.

Abstract

Importance  Human motor neurons may be reliably derived from induced pluripotent stem cells (iPSCs). In vivo transplant studies of human iPSCs and their cellular derivatives are essential to gauging their clinical utility.

Objective  To determine whether human iPSC-derived motor neurons can engraft in an immunodeficient mouse model of sciatic nerve injury.

Design, Setting, and Subjects  This nonblinded interventional study with negative controls was performed at a biomedical research institute using an immunodeficient, transgenic mouse model. Induced pluripotent stem cell–derived motor neurons were cultured and differentiated. Cells were transplanted into 32 immunodeficient mice with sciatic nerve injury aged 6 to 15 weeks. Tissue analysis was performed at predetermined points after the mice were killed humanely. Animal experiments were performed from February 24, 2015, to May 2, 2016, and data were analyzed from April 7, 2015, to May 27, 2016.

Interventions  Human iPSCs were used to derive motor neurons in vitro before transplant.

Main Outcomes and Measures  Evidence of engraftment based on immunohistochemical analysis (primary outcome measure); evidence of neurite outgrowth and neuromuscular junction formation (secondary outcome measure); therapeutic effect based on wet muscle mass preservation and/or electrophysiological evidence of nerve and muscle function (exploratory end point).

Results  In 13 of the 32 mice undergoing the experiment, human iPSC-derived motor neurons successfully engrafted and extended neurites to target denervated muscle. Human iPSC-derived motor neurons reduced denervation-induced muscular atrophy (mean [SD] muscle mass preservation, 54.2% [4.0%]) compared with negative controls (mean [SD] muscle mass preservation, 33.4% [2.3%]) (P = .04). No electrophysiological evidence of muscle recovery was found.

Conclusions and Relevance  Human iPSC-derived motor neurons may have future use in the treatment of peripheral motor nerve injury, including facial paralysis.

Level of Evidence  NA.

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