Efficacy and dose-dependent safety of intra-arterial delivery of mesenchymal stem cells in a rodent stroke model

Dileep R Yavagal, Baowan Lin, Ami Raval, Philip S. Garza, Chuanhui Dong, Weizhao Zhao, Erika B. Rangel, Ian McNiece, Tatjana Rundek, Ralph L Sacco, Miguel Perez-Pinzon, Joshua Hare

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Abstract

Intra-arterial (IA) delivery of mesenchymal stem cells (MSCs) for acute ischemic stroke is attractive for clinical translation. However, studies using rat model of stroke have demonstrated that IA MSCs delivery can decrease middle cerebral artery (MCA) flow, which may limit its clinical translation. The goal of this study is to identify a dose of IA MSCs (maximum tolerated dose; MTD) that does not compromise MCA flow and evaluate its efficacy and optimal timing in a rat model of reversible middle cerebral artery occlusion (rMCAo). We sought to determine if there is a difference in efficacy of acute (1 h) versus sub-acute (24 h) IA MSCs treatment after rMCAo. Adult female Sprague-Dawley rats underwent rMCAo (90 min) and an hour later a single dose of MSCs (at de-escalating doses 1×106, 5×105, 2×105, 1×105 and 5×104) was given using IA route. MSCs were suspended in phosphate buffered saline (PBS) and PBS alone was used for control experiments. We measured the percent change in mean laser Doppler flow signal over the ipsilateral MCA in de-escalating doses groups to determine MTD. The results demonstrated that the lowering of IA MSC dose to 1×105 and below did not compromise MCA flow and hence an IA MSC dose of 16105 considered as MTD. Subsequently, 1 h and 24 h after rMCAo, rats were treated with IA MSCs or PBS. The 24 h delivery of IA MSCs significantly improved neurodeficit score and reduced the mean infarct volume at one month as compared to control, but not the 1 h delivery. Overall, this study suggests that the IA delivery of MSCs can be performed safely and efficaciously at the MTD of 1×105 delivered at 24 hours in rodent model of stroke.

Original languageEnglish
Article numbere93735
JournalPLoS One
Volume9
Issue number5
DOIs
StatePublished - May 7 2014

Fingerprint

Stem cells
Mesenchymal Stromal Cells
stroke
stem cells
Rodentia
rodents
Stroke
arteries
Safety
dosage
Middle Cerebral Artery Infarction
Middle Cerebral Artery
Rats
Phosphates
phosphates
translation (genetics)
animal models
Maximum Tolerated Dose
infarction
rats

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

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title = "Efficacy and dose-dependent safety of intra-arterial delivery of mesenchymal stem cells in a rodent stroke model",
abstract = "Intra-arterial (IA) delivery of mesenchymal stem cells (MSCs) for acute ischemic stroke is attractive for clinical translation. However, studies using rat model of stroke have demonstrated that IA MSCs delivery can decrease middle cerebral artery (MCA) flow, which may limit its clinical translation. The goal of this study is to identify a dose of IA MSCs (maximum tolerated dose; MTD) that does not compromise MCA flow and evaluate its efficacy and optimal timing in a rat model of reversible middle cerebral artery occlusion (rMCAo). We sought to determine if there is a difference in efficacy of acute (1 h) versus sub-acute (24 h) IA MSCs treatment after rMCAo. Adult female Sprague-Dawley rats underwent rMCAo (90 min) and an hour later a single dose of MSCs (at de-escalating doses 1×106, 5×105, 2×105, 1×105 and 5×104) was given using IA route. MSCs were suspended in phosphate buffered saline (PBS) and PBS alone was used for control experiments. We measured the percent change in mean laser Doppler flow signal over the ipsilateral MCA in de-escalating doses groups to determine MTD. The results demonstrated that the lowering of IA MSC dose to 1×105 and below did not compromise MCA flow and hence an IA MSC dose of 16105 considered as MTD. Subsequently, 1 h and 24 h after rMCAo, rats were treated with IA MSCs or PBS. The 24 h delivery of IA MSCs significantly improved neurodeficit score and reduced the mean infarct volume at one month as compared to control, but not the 1 h delivery. Overall, this study suggests that the IA delivery of MSCs can be performed safely and efficaciously at the MTD of 1×105 delivered at 24 hours in rodent model of stroke.",
author = "Yavagal, {Dileep R} and Baowan Lin and Ami Raval and Garza, {Philip S.} and Chuanhui Dong and Weizhao Zhao and Rangel, {Erika B.} and Ian McNiece and Tatjana Rundek and Sacco, {Ralph L} and Miguel Perez-Pinzon and Joshua Hare",
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AU - Yavagal, Dileep R

AU - Lin, Baowan

AU - Raval, Ami

AU - Garza, Philip S.

AU - Dong, Chuanhui

AU - Zhao, Weizhao

AU - Rangel, Erika B.

AU - McNiece, Ian

AU - Rundek, Tatjana

AU - Sacco, Ralph L

AU - Perez-Pinzon, Miguel

AU - Hare, Joshua

PY - 2014/5/7

Y1 - 2014/5/7

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