Peripheral injection of human umbilical cord blood stimulates neurogenesis in the aged rat brain - PubMed (original) (raw)

Peripheral injection of human umbilical cord blood stimulates neurogenesis in the aged rat brain

Adam D Bachstetter et al. BMC Neurosci. 2008.

Abstract

Background: Neurogenesis continues to occur throughout life but dramatically decreases with increasing age. This decrease is mostly related to a decline in proliferative activity as a result of an impoverishment of the microenvironment of the aged brain, including a reduction in trophic factors and increased inflammation.

Results: We determined that human umbilical cord blood mononuclear cells (UCBMC) given peripherally, by an intravenous injection, could rejuvenate the proliferative activity of the aged neural stem/progenitor cells. This increase in proliferation lasted for at least 15 days after the delivery of the UCBMC. Along with the increase in proliferation following UCBMC treatment, an increase in neurogenesis was also found in the aged animals. The increase in neurogenesis as a result of UCBMC treatment seemed to be due to a decrease in inflammation, as a decrease in the number of activated microglia was found and this decrease correlated with the increase in neurogenesis.

Conclusion: The results demonstrate that a single intravenous injection of UCBMC in aged rats can significantly improve the microenvironment of the aged hippocampus and rejuvenate the aged neural stem/progenitor cells. Our results raise the possibility of a peripherally administered cell therapy as an effective approach to improve the microenvironment of the aged brain.

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Figures

Figure 1

Figure 1

Proliferation is increased in aged rats following UCBMC treatment. To determine if UCBMC could stimulate proliferation of the hippocampal neural progenitor/stem cells rats received two i.p. injections of BrdU (50 mg/kg) and were sacrifice the following day. (A) Quantification of the BrdU immunoreactive cell in the SGZ/GCL in aged rats 2 days after the UCBMC treatment showed that there was a significant (p < 0.005) increase in the number of BrdU immunoreactive cells. (B, C) Photomicrographs of the dentate gyrus of a media-treated rat (B) and a UCBMC-treated rat (C) shows the BrdU staining in those animals sacrificed 2 days after the treatment. (D)The arrow in C points to a cluster of BrdU immunoreactive cells from the UCBMC-treated rat shown in D at higher magnification. (E) To determine how long proliferation might remain elevated injections of BrdU (50 mg/kg) began 14 days after the treatment. Quantification of the BrdU immunoreactive cells determine that the UCBMC-treated group had significantly (p < 0.01) more cells in the SGZ/GCL then the animals that received media alone. (F, G) BrdU staining of the media-treated (F) and the UCBMC-treated (G) animals in the dentate gyrus of the hippocampus 15 days after the treatment. (H) Arrow in G points to cells shown at higher magnification in H. (scale bar for B, C, F, G is 100 μm; scale bar for D, H is 25 μm)

Figure 2

Figure 2

15 days after a UCBMC treatment neurogenesis is increase in aged rats. To determine if UCBMC treatment could stimulate neurogenesis aged F344 rats were sacrificed and immunohistochemical stained for DCX and BrdU. (A) A significant increase (p < 0.05) in the number of DCX+ cells, quantified in the SGZ/GCL, was found in the UCBMC treated rats. (B, C) Photomicrographs show the dentate gyrus demonstrating the DCX immunohistochemistry in the media-treated (B) and UCBMC-treated (C) rats. (D) A higher magnification photomicrograph of area indicated in C shows a number of DCX+ cells showing the different morphologies of the cells. (E) The results obtained with DCX were confirmed by BrdU. BrdU was injected i.p. for five consecutive days after the single injection of UCBMC. 10 days after the last injection of BrdU the animals were sacrificed. Compare to both a media control as well as an human adult peripheral blood (PBMC) control the UCBMC treated animals had significantly more BrdU+ cells (p < 0.01). (F, G, H) Photomicorgaphs of dentate gyrus shows BrdU immunohistochemistry in the media-treated (F), PBMC-treated (G) and UCBMC-treated (H) rats. (I, J) Immunofluorescence was conducted to determine the phenotype of the BrdU+ cells. (I) An example of the cells double labeled with BrdU+/NeuN+ (I; shown in orthogonal projection) and BrdU+/TUJ1+ (J; shown using maximum projection). (scale bar for B, C, F, G, H is 100 μm; scale bar for D is 25 μm)

Figure 3

Figure 3

The decrease in microglia activation correlates with neurogenesis. 15 days after the UCBMC treatment a significant reduction (p < 0.05) was found in the number of OX-6+ cells in the dentate gyrus of the aged rats (A). (B, C) Photomicrographs are shown of the hippocampus of media-treated (C) and UCBMC-treated (C) rats. (D) A higher magnification photomicrograph of area indicated by arrow in B. (E) A significant negative correlation (p < 0.01) was found between the number of OX-6+ cells and the amount of neurogenesis as determine by the number of DCX+ cells. (F) The OX-6+ were further characterized based on morphology. The cell on the left represents a typical 'Type 1' cell the cell on the right represents a typical 'Type 2' cell. Both 'Type 1' (p < 0.05; G) and 'Type 2' (p < 0.01; H) OX-6+ cells were significantly reduced in the aged animals following UCBMC treatment, but there was a greater reduction in 'Type 2' cells amounting to a four fold change. (scale bar for B, C is 200 μm; scale bar for D is 25 μm)

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