Hypoxic-preconditioned bone marrow stem cell mediumsignificantly improves outcome after retinal ischemia in rats

Steven Roth*, John C. Dreixler, Biji Mathew, Irina V Balyasnikova, Jacob R. Mann, Venkat Boddapati, Lai Xue, Maciej S Lesniak

*Corresponding author for this work

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

PURPOSE. We have previously demonstrated the protective effect of bone marrow stem cell (BMSC)-conditioned medium in retinal ischemic injury. We hypothesized here that hypoxic preconditioning of stem cells significantly enhances the neuroprotective effect of the conditioned medium and thereby augments the protective effect in ischemic retina. METHODS. Rats were subjected to retinal ischemia by increasing intraocular pressure to 130 to 135 mm Hg for 55 minutes. Hypoxic-preconditioned, hypoxic unconditioned, or normoxic medium was injected into the vitreous 24 hours after ischemia ended. Recovery was assessed 7 days after injections by comparing electroretinography measurements, histologic examination, and apoptosis (TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay). To compare proteins secreted into the medium in the groups and the effect of hypoxic exposure, we used rat cytokine arrays. RESULTS. Eyes injected with hypoxic BMSC-conditioned medium 24 hours after ischemia demonstrated significantly enhanced return of retinal function, decreased retinal ganglion cell layer loss, and attenuated apoptosis compared to those administered normoxic or hypoxic unconditioned medium. Hypoxic-preconditioned medium had 21 significantly increased protein levels compared to normoxic medium. CONCLUSIONS. The medium from hypoxic-preconditioned BMSCs robustly restored retinal function and prevented cell loss after ischemia when injected 24 hours after ischemia. The protective effect was even more pronounced than in our previous studies of normoxic conditioned medium. Prosurvival signals triggered by the secretome may play a role in this neuroprotective effect.

Original languageEnglish (US)
Pages (from-to)3522-3532
Number of pages11
JournalInvestigative Ophthalmology and Visual Science
Volume57
Issue number7
DOIs
StatePublished - Jun 1 2016

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Bone Marrow Cells
Conditioned Culture Medium
Stem Cells
Ischemia
Neuroprotective Agents
Apoptosis
Electroretinography
DNA Nucleotidylexotransferase
Retinal Ganglion Cells
In Situ Nick-End Labeling
Intraocular Pressure
Retina
Proteins
Cytokines
Injections
Wounds and Injuries

Keywords

  • Conditioned medium
  • Hypoxia
  • Neuroprotection
  • Retina
  • Stem cells

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Roth, Steven ; Dreixler, John C. ; Mathew, Biji ; Balyasnikova, Irina V ; Mann, Jacob R. ; Boddapati, Venkat ; Xue, Lai ; Lesniak, Maciej S. / Hypoxic-preconditioned bone marrow stem cell mediumsignificantly improves outcome after retinal ischemia in rats. In: Investigative Ophthalmology and Visual Science. 2016 ; Vol. 57, No. 7. pp. 3522-3532.
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abstract = "PURPOSE. We have previously demonstrated the protective effect of bone marrow stem cell (BMSC)-conditioned medium in retinal ischemic injury. We hypothesized here that hypoxic preconditioning of stem cells significantly enhances the neuroprotective effect of the conditioned medium and thereby augments the protective effect in ischemic retina. METHODS. Rats were subjected to retinal ischemia by increasing intraocular pressure to 130 to 135 mm Hg for 55 minutes. Hypoxic-preconditioned, hypoxic unconditioned, or normoxic medium was injected into the vitreous 24 hours after ischemia ended. Recovery was assessed 7 days after injections by comparing electroretinography measurements, histologic examination, and apoptosis (TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay). To compare proteins secreted into the medium in the groups and the effect of hypoxic exposure, we used rat cytokine arrays. RESULTS. Eyes injected with hypoxic BMSC-conditioned medium 24 hours after ischemia demonstrated significantly enhanced return of retinal function, decreased retinal ganglion cell layer loss, and attenuated apoptosis compared to those administered normoxic or hypoxic unconditioned medium. Hypoxic-preconditioned medium had 21 significantly increased protein levels compared to normoxic medium. CONCLUSIONS. The medium from hypoxic-preconditioned BMSCs robustly restored retinal function and prevented cell loss after ischemia when injected 24 hours after ischemia. The protective effect was even more pronounced than in our previous studies of normoxic conditioned medium. Prosurvival signals triggered by the secretome may play a role in this neuroprotective effect.",
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Hypoxic-preconditioned bone marrow stem cell mediumsignificantly improves outcome after retinal ischemia in rats. / Roth, Steven; Dreixler, John C.; Mathew, Biji; Balyasnikova, Irina V; Mann, Jacob R.; Boddapati, Venkat; Xue, Lai; Lesniak, Maciej S.

In: Investigative Ophthalmology and Visual Science, Vol. 57, No. 7, 01.06.2016, p. 3522-3532.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Hypoxic-preconditioned bone marrow stem cell mediumsignificantly improves outcome after retinal ischemia in rats

AU - Roth, Steven

AU - Dreixler, John C.

AU - Mathew, Biji

AU - Balyasnikova, Irina V

AU - Mann, Jacob R.

AU - Boddapati, Venkat

AU - Xue, Lai

AU - Lesniak, Maciej S

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N2 - PURPOSE. We have previously demonstrated the protective effect of bone marrow stem cell (BMSC)-conditioned medium in retinal ischemic injury. We hypothesized here that hypoxic preconditioning of stem cells significantly enhances the neuroprotective effect of the conditioned medium and thereby augments the protective effect in ischemic retina. METHODS. Rats were subjected to retinal ischemia by increasing intraocular pressure to 130 to 135 mm Hg for 55 minutes. Hypoxic-preconditioned, hypoxic unconditioned, or normoxic medium was injected into the vitreous 24 hours after ischemia ended. Recovery was assessed 7 days after injections by comparing electroretinography measurements, histologic examination, and apoptosis (TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay). To compare proteins secreted into the medium in the groups and the effect of hypoxic exposure, we used rat cytokine arrays. RESULTS. Eyes injected with hypoxic BMSC-conditioned medium 24 hours after ischemia demonstrated significantly enhanced return of retinal function, decreased retinal ganglion cell layer loss, and attenuated apoptosis compared to those administered normoxic or hypoxic unconditioned medium. Hypoxic-preconditioned medium had 21 significantly increased protein levels compared to normoxic medium. CONCLUSIONS. The medium from hypoxic-preconditioned BMSCs robustly restored retinal function and prevented cell loss after ischemia when injected 24 hours after ischemia. The protective effect was even more pronounced than in our previous studies of normoxic conditioned medium. Prosurvival signals triggered by the secretome may play a role in this neuroprotective effect.

AB - PURPOSE. We have previously demonstrated the protective effect of bone marrow stem cell (BMSC)-conditioned medium in retinal ischemic injury. We hypothesized here that hypoxic preconditioning of stem cells significantly enhances the neuroprotective effect of the conditioned medium and thereby augments the protective effect in ischemic retina. METHODS. Rats were subjected to retinal ischemia by increasing intraocular pressure to 130 to 135 mm Hg for 55 minutes. Hypoxic-preconditioned, hypoxic unconditioned, or normoxic medium was injected into the vitreous 24 hours after ischemia ended. Recovery was assessed 7 days after injections by comparing electroretinography measurements, histologic examination, and apoptosis (TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay). To compare proteins secreted into the medium in the groups and the effect of hypoxic exposure, we used rat cytokine arrays. RESULTS. Eyes injected with hypoxic BMSC-conditioned medium 24 hours after ischemia demonstrated significantly enhanced return of retinal function, decreased retinal ganglion cell layer loss, and attenuated apoptosis compared to those administered normoxic or hypoxic unconditioned medium. Hypoxic-preconditioned medium had 21 significantly increased protein levels compared to normoxic medium. CONCLUSIONS. The medium from hypoxic-preconditioned BMSCs robustly restored retinal function and prevented cell loss after ischemia when injected 24 hours after ischemia. The protective effect was even more pronounced than in our previous studies of normoxic conditioned medium. Prosurvival signals triggered by the secretome may play a role in this neuroprotective effect.

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