title: Grafted murine induced pluripotent stem cells prevent death of injured rat motoneurons otherwise destined to die.
abstract: Human plexus injuries often include the avulsion of one or more ventral roots, resulting in debilitating conditions. In this study the effects of undifferentiated murine iPSCs on damaged motoneurons were investigated following avulsion of the lumbar 4 (L4) ventral root, an injury known to induce the death of the majority of the affected motoneurons. Avulsion and reimplantation of the L4 ventral root (AR procedure) were accompanied by the transplantation of murine iPSCs into the injured spinal cord segment in rats. Control animals underwent ventral root avulsion and reimplantation, but did not receive iPSCs. The grafted iPSCs induced an improved reinnervation of the reimplanted ventral root by the host motoneurons as compared with the controls (number of retrogradely labeled motoneurons: 503 ± 38 [AR+iPSCs group] vs 48 ± 6 [controls, AR group]). Morphological reinnervation resulted in a functional recovery, i.e. the grafted animals exhibited more motor units in their reinnervated hind limb muscles, which produced a greater force than that in the controls (50 ± 2.1% vs 11.9 ± 4.2% maximal tetanic tension [% ratio of operated/intact side]). Grafting of undifferentiated iPSCs downregulated the astroglial activation within the L4 segment. The grafted cells differentiated into neurons and astrocytes in the injured cord. The grafted iPSCs, host neurons and glia were found to produce the cytokines and neurotrophic factors MIP-1a, IL-10, GDNF and NT-4. These findings suggest that, following ventral root avulsion injury, iPSCs are able to induce motoneuron survival and regeneration through combined neurotrophic and cytokine modulatory effects.
authors.affiliation: Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Szeged, Szeged, Hungary.
authors.forename: Krisztián
authors.initials: K
authors.lastname: Pajer
authors.affiliation: Biotalentum Ltd., Gödöllő, Hungary.
authors.forename: Csilla
authors.initials: C
authors.lastname: Nemes
authors.affiliation: Biotalentum Ltd., Gödöllő, Hungary.
authors.forename: Sára
authors.initials: S
authors.lastname: Berzsenyi
authors.affiliation: Biotalentum Ltd., Gödöllő, Hungary.
authors.forename: Krisztián A
authors.initials: KA
authors.lastname: Kovács
authors.affiliation: Biotalentum Ltd., Gödöllő, Hungary.
authors.forename: Melinda K
authors.initials: MK
authors.lastname: Pirity
authors.affiliation: Department for Trauma Surgery, Medical University Vienna, Vienna, Austria.
authors.forename: Gholam
authors.initials: G
authors.lastname: Pajenda
authors.affiliation: Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Szeged, Szeged, Hungary. Electronic address: nogradi.antal@med.u-szeged.hu.
authors.forename: Antal
authors.initials: A
authors.lastname: Nógrádi
authors.affiliation: Biotalentum Ltd., Gödöllő, Hungary; Molecular Animal Biotechnology Laboratory, Szent István University, Gödöllő, Hungary. Electronic address: andras.dinnyes@biotalentum.hu.
authors.forename: András
authors.initials: A
authors.lastname: Dinnyés
mesh_terms: D000818:Animals; D016923:Cell Death; D002470:Cell Survival / Q000502:physiology; D064987:Cell- and Tissue-Based Therapy / Q000379:methods; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D051379:Mice; D009046:Motor Neurons / Q000166:cytology*; D009414:Nerve Growth Factors / Q000378:metabolism; D009416:Nerve Regeneration / Q000502:physiology*; D051381:Rats; D020127:Recovery of Function / Q000502:physiology; D013116:Spinal Cord / Q000166:cytology; D013126:Spinal Nerve Roots / Q000293:injuries*
chemical_list: D009414:Nerve Growth Factors