Axon Degeneration Is Rescued with Human Umbilical Cord Perivascular Cells: A Potential Candidate for Neuroprotection After Traumatic Brain Injury

Stem Cells Dev. 2020 Feb 15;29(4):198-211. doi: 10.1089/scd.2019.0135. Epub 2019 Dec 10.

Abstract

Traumatic brain injury (TBI) leads to delayed secondary injury events consisting of cellular and molecular cascades that exacerbate the initial injury. Human umbilical cord perivascular cells (HUCPVCs) secrete neurotrophic and prosurvival factors. In this study, we examined the effects of HUCPVC in sympathetic axon and cortical axon survival models and sought to determine whether HUCPVC provide axonal survival cues. We then examined the effects of the HUCPVC in an in vivo fluid percussion injury model of TBI. Our data indicate that HUCPVCs express neurotrophic and neural survival factors. They also express and secrete relevant growth and survival proteins when cultured alone, or in the presence of injured axons. Coculture experiments indicate that HUCPVCs interact preferentially with axons when cocultured with sympathetic neurons and reduce axonal degeneration. Nerve growth factor withdrawal in axonal compartments resulted in 66 ± 3% axon degeneration, whereas HUCPVC coculture rescued axon degeneration to 35 ± 3%. Inhibition of Akt (LY294002) resulted in a significant increase in degeneration compared with HUCPVC cocultures (48 ± 7% degeneration). Under normoxic conditions, control cultures showed 39 ± 5% degeneration. Oxygen glucose deprivation (OGD) resulted in 58 ± 3% degeneration and OGD HUCPVC cocultures reduced degeneration to 34 ± 5% (p < 0.05). In an in vivo model of TBI, immunohistochemical analysis of NF200 showed improved axon morphology in HUCPVC-treated animals compared with injured animals. These data presented in this study indicate an important role for perivascular cells in protecting axons from injury and a potential cell-based therapy to treat secondary injury after TBI.

Keywords: cortical neurons; human umbilical cord perivascular cells (HUCPVCs); nerve growth factor (NGF); oxygen glucose deprivation (OGD); sympathetic cervical ganglia (SCGs); traumatic brain injury (TBI).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / drug effects
  • Axons / metabolism*
  • Axons / pathology
  • Brain Injuries, Traumatic / genetics
  • Brain Injuries, Traumatic / pathology
  • Brain Injuries, Traumatic / therapy*
  • Cell- and Tissue-Based Therapy / methods*
  • Chromones / pharmacology
  • Coculture Techniques
  • Disease Models, Animal
  • Embryo, Mammalian
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Gene Expression Regulation
  • Glucose / deficiency
  • Glucose / pharmacology
  • Humans
  • Morpholines / pharmacology
  • Nerve Growth Factor / pharmacology
  • Neurofilament Proteins / genetics
  • Neurofilament Proteins / metabolism
  • Neurons / drug effects
  • Neurons / metabolism*
  • Neurons / ultrastructure
  • Oxygen / pharmacology
  • Pericytes / drug effects
  • Pericytes / metabolism
  • Pericytes / transplantation*
  • Primary Cell Culture
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Superior Cervical Ganglion / cytology
  • Superior Cervical Ganglion / metabolism
  • Umbilical Cord / cytology
  • Umbilical Cord / metabolism

Substances

  • Chromones
  • Morpholines
  • Neurofilament Proteins
  • neurofilament protein H
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Nerve Growth Factor
  • Proto-Oncogene Proteins c-akt
  • Glucose
  • Oxygen