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Transplantation of human umbilical cord blood cells mediated beneficial effects on apoptosis, angiogenesis and neuronal survival after hypoxic-ischemic brain injury in rats

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Abstract

Transplantation of human umbilical cord blood (hucb) cells in a model of hypoxic-ischemic brain injury led to the amelioration of lesion-impaired neurological and motor functions. However, the mechanisms by which transplanted cells mediate functional recovery after brain injury are largely unknown. In this study, the effects of hucb cell transplantation were investigated in this experimental paradigm at the cellular and molecular level. As the pathological cascade in hypoxic-ischemic brain injury includes inflammation, reduced blood flow, and neuronal cell death, we analyzed the effects of peripherally administered hucb cells on these detrimental processes, investigating the expression of characteristic marker proteins. Application of hucb cells after perinatal hypoxic-ischemic brain injury correlated with an increased expression of the proteins Tie-2 and occludin, which are associated with angiogenesis. Lesion-induced apoptosis, determined by expression of cleaved caspase-3, decreased, whereas the number of vital neurons, identified by counting of NeuN-positive cells, increased. In addition, we observed an increase in the expression of neurotrophic and pro-angiogenic growth factors, namely BDNF and VEGF, in the lesioned brain upon hucb cell transplantation. The release of neurotrophic factors mediated by transplanted hucb cells might cause a lower number of neurons to undergo apoptosis and result in a higher number of living neurons. In parallel, the increase of VEGF might cause growth of blood vessels. Thus, hucb transplantation might contribute to functional recovery after brain injury mediated by systemic or local effects.

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Acknowledgements

The authors would like to thank Janet Moers, Lidia Janota, Heike Groth and Jennifer Heinz for their excellent technical assistance and Helga Schulze for expert drawing.

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Authors and Affiliations

  1. Department of Functional Proteomics, Ruhr-University Bochum, Bochum, Germany

    Katja Rosenkranz & Katrin Marcus

  2. Department of Neuroanatomy and Molecular Brain Research, Ruhr-University Bochum, Bochum, Germany

    Sandra Kumbruch & Rolf Dermietzel

  3. Department of Molecular and Medical Virology, Ruhr-University Bochum, Bochum, Germany

    Matthias Tenbusch

  4. Department of Gynecology and Obstetrics, St. Elisabeth-Hospital Bochum, Bochum, Germany

    Katrin Marschner

  5. Department of Anatomy and Cell Biology, Saarland University, Building 61, Kirrberger Strasse 1, 66421, Homburg/Saar, Germany

    Carola Meier

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  1. Katja Rosenkranz
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  2. Sandra Kumbruch
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  3. Matthias Tenbusch
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  4. Katrin Marcus
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  5. Katrin Marschner
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  6. Rolf Dermietzel
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  7. Carola Meier
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Corresponding author

Correspondence to Carola Meier.

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Funding: This study was supported by a grant of the Stem Cell Network North Rhine Westphalia, Germany (to C.M.), and by the Medical Faculty of Ruhr-University Bochum, Germany (FoRUM)

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Fig. S1

Expression of occludin in rat brains assessed by immunohistochemistry. Representative images of immunhistochemical staining of occludin (green), on P21 rat brains of animals of the following groups a sham, b lesion and c lesion+hucb (lesion plus additional application of hucb cells). Nuclei are labeled in blue (Hoechst staining a–c). Scale bar in (a) for (a–c) 50 μm (PDF 2484 kb)

Fig. S2

Quantitative real time PCR analysis of rat VEGF mRNA expression. For determination of species origin of VEGF, quantitative real time PCR was performed with primers specific for rat VEGF. Analysis was performed at P9 and P21 in left hemispheres of rat brains of the following experimental groups: sham, sham+hucb, lesion and lesion+hucb. Significant differences of p < 0.05 are indicated by *** (PDF 5 kb)

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Rosenkranz, K., Kumbruch, S., Tenbusch, M. et al. Transplantation of human umbilical cord blood cells mediated beneficial effects on apoptosis, angiogenesis and neuronal survival after hypoxic-ischemic brain injury in rats. Cell Tissue Res 348, 429–438 (2012). https://doi.org/10.1007/s00441-012-1401-0

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