Restorative benefits of transplanting human mesenchymal stromal cells overexpressing arginine decarboxylase genes after spinal cord injury

Cytotherapy. 2015 Jan;17(1):25-37. doi: 10.1016/j.jcyt.2014.08.006. Epub 2014 Oct 22.

Abstract

Background aims: Mesenchymal stromal cells (MSCs) promote functional recovery in central nervous system (CNS) injury. Neuroprotective effects of MSCs are being tested in clinical trials for the treatment of CNS injury; however, the underlying mechanisms remain unclear. Arginine decarboxylase (ADC) is a rate-limiting enzyme of agmatine synthesis and is known to exist in the CNS of mammals. The present study investigated whether transplantation of ADC-overexpressing human MSCs (ADC-hMSCs) after spinal cord injury (SCI) could increase the production of neurotrophic factors and promote cell survival, differentiation, axonal regeneration and the restoration of functional recovery.

Methods: Retroviral human ADC was constructed with the use of an LXSN vector. After compression injury in thoracic level 9, PKH26-labeled ADC-hMSCs were transplanted into the dorsolateral funiculus 1 mm rostral and caudal to the lesion site. The tissues were sampled at 2, 4 and 10 weeks after SCI.

Results: Behavioral analysis revealed that locomotor functions of the ADC-hMSC group were significantly restored. Histological analysis showed that the fibrotic scar volume was smaller in the ADC-hMSC-injected group than in any other group. Brain-derived neurotrophic factor level was significantly higher in the ADC-hMSC-injected group than in any other group throughout 10 weeks. Terminal deoxynucleotidyl transferase-mediated nick-end labeling assay showed decreased cell death, and co-localization analysis showed significant increase in the number of neurons and oligodendrocytes originating from transplanted hMSCs when they had been transduced with the ADC gene.

Conclusions: The results suggested that ADC-hMSCs are a more suitable candidate than hMSCs for stem cell therapy after SCI.

Keywords: arginine decarboxylase; mesenchymal stromal cells; spinal cord injury; transplantation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carboxy-Lyases / genetics*
  • Cell Differentiation / physiology
  • Cells, Cultured
  • Gene Expression Regulation, Enzymologic
  • Humans
  • Male
  • Mesenchymal Stem Cell Transplantation* / methods
  • Mesenchymal Stem Cells / cytology*
  • Mice
  • Nerve Regeneration / physiology*
  • Neurons / cytology
  • Recovery of Function / physiology*
  • Spinal Cord Injuries / pathology
  • Spinal Cord Injuries / therapy*

Substances

  • Carboxy-Lyases
  • arginine decarboxylase