Human stem cells transplanted into the rat stroke brain migrate to the spleen via lymphatic and inflammation pathways

Kaya Xu, Jea Young Lee, Yuji Kaneko, Julian P. Tuazon, Fernando Vale Diaz, Harry van Loveren, Cesario V. Borlongan

Research output: Contribution to journalArticle

Abstract

Despite mounting evidence of a massive peripheral inflammatory response accompanying stroke, the ability of intracerebrally transplanted cells to migrate to the periphery and sequester systemic inflammation remains unexamined. Here, we tested the hypothesis that human bone marrow mesenchymal stromal cells intracerebrally transplanted in the brain of adult rats subjected to experimental stroke can migrate to the spleen, a vital organ that confers peripheral inflammation after stroke. Sham or experimental stroke was induced in adult Sprague-Dawley rats by a 1 hour middle cerebral artery occlusion model. One hour after surgery, rats were intracerebrally injected with human bone marrow mesenchymal stromal cells (3×105/9 mL), then euthanized on day 1, 3, or 7 for immunohistochemical assays. Cell migration assays were performed for human bone marrow mesenchymal stromal cells using Boyden chambers with the bottom plate consisting of microglia, lymphatic endothelial cells, or both, and treated with different doses of tumor necrosis factor-a. Plates were processed in a fluorescence reader at different time points. Immunofluorescence microscopy on different days after the stroke revealed that stem cells engrafted in the stroke brain but, interestingly, homed to the spleen via lymphatic vessels, and were propelled by inflammatory signals. Experiments using human bone marrow mesenchymal stromal cells co-cultured with lymphatic endothelial cells or microglia, and treated with tumor necrosis factor-a, further indicated the key roles of the lymphatic system and inflammation in directing stem cell migration. This study is the first to demonstrate brain-to-periphery migration of stem cells, advancing the novel concept of harnessing the lymphatic system in mobilizing stem cells to sequester peripheral inflammation as a brain repair strategy.

Original languageEnglish (US)
Pages (from-to)1062-1073
Number of pages12
JournalHaematologica
Volume104
Issue number5
DOIs
StatePublished - Apr 30 2019

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Mesenchymal Stromal Cells
Stem Cells
Spleen
Stroke
Inflammation
Brain
Lymphatic System
Microglia
Endothelial Cells
Tumor Necrosis Factor-alpha
Cell Migration Assays
Lymphatic Vessels
Middle Cerebral Artery Infarction
Fluorescence Microscopy
Cell Movement
Sprague Dawley Rats
Fluorescence

ASJC Scopus subject areas

  • Hematology

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Human stem cells transplanted into the rat stroke brain migrate to the spleen via lymphatic and inflammation pathways. / Xu, Kaya; Lee, Jea Young; Kaneko, Yuji; Tuazon, Julian P.; Vale Diaz, Fernando; van Loveren, Harry; Borlongan, Cesario V.

In: Haematologica, Vol. 104, No. 5, 30.04.2019, p. 1062-1073.

Research output: Contribution to journalArticle

Xu, Kaya ; Lee, Jea Young ; Kaneko, Yuji ; Tuazon, Julian P. ; Vale Diaz, Fernando ; van Loveren, Harry ; Borlongan, Cesario V. / Human stem cells transplanted into the rat stroke brain migrate to the spleen via lymphatic and inflammation pathways. In: Haematologica. 2019 ; Vol. 104, No. 5. pp. 1062-1073.
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