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Transplantation dose alters the dynamics of human neural stem cell engraftment, proliferation and migration after spinal cord injury.

ABSTRACT: The effect of transplantation dose on the spatiotemporal dynamics of human neural stem cell (hNSC) engraftment has not been quantitatively evaluated in the central nervous system. We investigated changes over time in engraftment/survival, proliferation, and migration of multipotent human central nervous system-derived neural stem cells (hCNS-SCns) transplanted at doses ranging from 10,000 to 500,000 cells in spinal cord injured immunodeficient mice. Transplant dose was inversely correlated with measures of donor cell proliferation at 2 weeks post-transplant (WPT) and dose-normalized engraftment at 16 WPT. Critically, mice receiving the highest cell dose exhibited an engraftment plateau, in which the total number of engrafted human cells never exceeded the initial dose. These data suggest that donor cell expansion was inversely regulated by target niche parameters and/or transplantation density. Investigation of the response of donor cells to the host microenvironment should be a key variable in defining target cell dose in pre-clinical models of CNS disease and injury.

SUBMITTER: Piltti KM

PROVIDER: S-EPMC4600655 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Transplantation dose alters the dynamics of human neural stem cell engraftment, proliferation and migration after spinal cord injury.

Piltti Katja M KM Avakian Sabrina N SN Funes Gabriella M GM Hu Antoinette A Uchida Nobuko N Anderson Aileen J AJ Cummings Brian J BJ

Stem cell research 20150726 2

The effect of transplantation dose on the spatiotemporal dynamics of human neural stem cell (hNSC) engraftment has not been quantitatively evaluated in the central nervous system. We investigated changes over time in engraftment/survival, proliferation, and migration of multipotent human central nervous system-derived neural stem cells (hCNS-SCns) transplanted at doses ranging from 10,000 to 500,000 cells in spinal cord injured immunodeficient mice. Transplant dose was inversely correlated with ...[more]

PMID: 26298025

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Project description:BackgroundLimited progress in terms of an effective treatment for spinal cord injury (SCI) emphasizes the urgent need for novel therapies. As a vital central nervous system component, the resident astrocytes play crucial roles in regulating recovery after SCI. In this study, recovery after SCI was compared following the transplantation of either A1 or A2 astrocytes. A1 astrocytes are harmful as they upregulate the neurotoxic classical complement cascade genes. Conversely, A2 astrocytes are characterized as neuroprotective as they upregulate the production of many neurotrophic factors.MethodsWe used different supernatant obtained from microglia stimulated with lipopolysaccharide or interleukin-4 to generate A1 and A2 astrocytes. We detected the influence of astrocytes on neurons by co-culturing A1 and A2 astrocytes with neurons. We transplanted astrocytes into the lesion site of the spinal cord and assessed lesion progression, neural restoration, glia formation and locomotor recovery.ResultsAstrocytes were polarized into A1 and A2 phenotypes following culture in the supernatant obtained from microglia stimulated with lipopolysaccharide or interleukin-4, respectively. Furthermore, co-culturing A2 astrocytes with neurons significantly suppressed glutamate-induced neuronal apoptosis and promoted the degree of neuron arborization. Transplantation of these A2 astrocytes into the lesion site of the spinal cord of mice significantly improved motor function recovery, preserved spared supraspinal pathways, decreased glia scar deposition, and increased neurofilament formation at the site of injury compared to the transplantation of A1 astrocytes. Additionally, enhanced A2 astrocytes with potentially beneficial A2-like genes were also detected in the A2 group. Moreover, luxol fast blue staining and electron microscopy indicated increased preservation of myelin with organized structure after transplantation of A2 astrocytes than of A1 astrocytes.ConclusionsA2 astrocyte transplantation could be a promising potential therapy for SCI. Video abstract.

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Transplantation dose alters the dynamics of human neural stem cell engraftment, proliferation and migration after spinal cord injury.

Publications

Transplantation dose alters the dynamics of human neural stem cell engraftment, proliferation and migration after spinal cord injury.

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