Jon-Paul Pepper1, Tiffany V Wang1, Valerie Hennes2, Soo Yeon Sun3, Justin K Ichida2. 1. USC (University of Southern California) Caruso Department of Otolaryngology-Head and Neck Surgery, Keck School of Medicine, USC, Los Angeles. 2. Department of Regenerative Medicine and Stem Cell Biology, Broad CIRM (California Institute for Regenerative Medicine) Center, Keck School of Medicine, USC, Los Angeles. 3. Division of Biokinesiology and Physical Therapy, Herman Ostrow School of Dentistry, USC, Los Angeles.
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.
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.
Authors: Melody N Craff; Jose L Zeballos; Timothy S Johnson; Milan P Ranka; Robert Howard; Pejman Motarjem; Mark A Randolph; Jonathan M Winograd Journal: Plast Reconstr Surg Date: 2007-01 Impact factor: 4.730
Authors: Mackenzie W Amoroso; Gist F Croft; Damian J Williams; Sean O'Keeffe; Monica A Carrasco; Anne R Davis; Laurent Roybon; Derek H Oakley; Tom Maniatis; Christopher E Henderson; Hynek Wichterle Journal: J Neurosci Date: 2013-01-09 Impact factor: 6.167
Authors: Nicholas A Sachs; Eli L Chang; Neha Vyas; Brandon N Sorensen; James D Weiland Journal: IEEE Trans Neural Syst Rehabil Eng Date: 2007-03 Impact factor: 3.802
Authors: Thomas Scholz; Alisa Krichevsky; Andrew Sumarto; Daniel Jaffurs; Garrett A Wirth; Keyianoosh Paydar; Gregory R D Evans Journal: J Reconstr Microsurg Date: 2009-03-19 Impact factor: 2.873
Authors: Athurva Gore; Zhe Li; Ho-Lim Fung; Jessica E Young; Suneet Agarwal; Jessica Antosiewicz-Bourget; Isabel Canto; Alessandra Giorgetti; Mason A Israel; Evangelos Kiskinis; Je-Hyuk Lee; Yuin-Han Loh; Philip D Manos; Nuria Montserrat; Athanasia D Panopoulos; Sergio Ruiz; Melissa L Wilbert; Junying Yu; Ewen F Kirkness; Juan Carlos Izpisua Belmonte; Derrick J Rossi; James A Thomson; Kevin Eggan; George Q Daley; Lawrence S B Goldstein; Kun Zhang Journal: Nature Date: 2011-03-03 Impact factor: 49.962
Authors: Justin K Ichida; Kim A Staats; Brandi N Davis-Dusenbery; Kendell Clement; Kate E Galloway; Kimberly N Babos; Yingxiao Shi; Esther Y Son; Evangelos Kiskinis; Nicholas Atwater; Hongcang Gu; Andreas Gnirke; Alexander Meissner; Kevin Eggan Journal: Development Date: 2018-11-21 Impact factor: 6.868