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

Bachstetter AD, Pabon MM, Cole MJ, Hudson CE, Sanberg PR, Willing AE, Bickford PC, Gemma C - BMC Neurosci (2008)

Bottom Line: 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.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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Molecular Pharmacology and Physiology, University of South Florida, College of Medicine, Tampa, FL 33612, USA. abachste@health.usf.edu

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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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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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)

Mentions: Using the optical fractionator method of design based stereology, we counted the number of OX-6+ cells in the dentate gyrus 15 days after a single UCBMC injection; this was at the same time point that we observed an increase in DCX+ cells and BrdU+ cells. OX-6 is a marker for MHCII and presumably stains for microglia in an activated, proinflammatory state. In aged rats, we found that 15 days after the UCBMC treatment there was a significant decrease (t(12) = 2.699; p < 0.05) in the total number of activated OX-6+ microglia in the UCBMC group (678.7 ± 155.3 n = 7) compared to the media control (1217 ± 128.0 n = 8) (Figure 3A). The decrease in OX-6+ microglia negatively correlated with the number of DCX+ cells (Spearman r(15) = -- 0.6429; p < 0.01) (Figure 3E).


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

Bachstetter AD, Pabon MM, Cole MJ, Hudson CE, Sanberg PR, Willing AE, Bickford PC, Gemma C - BMC Neurosci (2008)

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)
© Copyright Policy - open-access
Related In: Results  -  Collection

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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)
Mentions: Using the optical fractionator method of design based stereology, we counted the number of OX-6+ cells in the dentate gyrus 15 days after a single UCBMC injection; this was at the same time point that we observed an increase in DCX+ cells and BrdU+ cells. OX-6 is a marker for MHCII and presumably stains for microglia in an activated, proinflammatory state. In aged rats, we found that 15 days after the UCBMC treatment there was a significant decrease (t(12) = 2.699; p < 0.05) in the total number of activated OX-6+ microglia in the UCBMC group (678.7 ± 155.3 n = 7) compared to the media control (1217 ± 128.0 n = 8) (Figure 3A). The decrease in OX-6+ microglia negatively correlated with the number of DCX+ cells (Spearman r(15) = -- 0.6429; p < 0.01) (Figure 3E).

Bottom Line: 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.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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Molecular Pharmacology and Physiology, University of South Florida, College of Medicine, Tampa, FL 33612, USA. abachste@health.usf.edu

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.

Show MeSH
Related in: MedlinePlus