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Rejuvenation of aged progenitor cells from muscle and liver after exposure to soluble factors from young animals

(Conboy et al, Nature 2005;433:760-764)
Summary by: Jaeyeaon Cho and Monique Johnson

LAY SUMMARY
Body tissue regenerates well in young people, but much less so in older individuals.  To discover whether this decline is irreversible, or influenced by circulatory factors, Conboy et al. joined together the circulatory systems of young and old rodents, as a parabiotic pair. Interestingly, aged muscle and liver regained their regenerative properties when exposed to sera from young animals.  Young molecular signatures, involving Notch signalling (in muscle), and cEBPa-mediated cell cycle regulation (in liver) were also restored.  This finding implies that the proliferative potential of stem and progenitor cells is retained even as aging progresses, and that young molecular signalling patterns can revitalize the regeneration of tissue.

SCIENTIFIC SUMMARY
The regenerative capacity of stem cells declines with age. Ion movement through membrane channel or activation of cell membrane receptors could be implicated in this decline, with changes in the expression of genes. The Notch pathway is essential for the activation, proliferation and myogenic lineage progression of satellite cells, which are thought to be muscle stem cells and are needed for muscle repair. The decline in the muscle repair in the aged partly occurs by failure of the Notch pathway. In the case of the liver, age-related decrease in hepatocyte proliferation is due to the formation of specific complexes involving cell cycle regulators and cEBP. Levels of the cEBP-α–Brm complex increase in the livers of old rodents, leading to a decline in hepatocyte proliferation.

This study addresses the influence of systemic factors on aged progenitor cells using parabiotic pairings. This system involved sharing of the circulatory system between two mice, through surgical intervention. The key utility of this technique is that it unites the vascular systems of the two animals, allowing exchange of blood-borne molecules. When old mice were paired with young mice (heterochronic parabiosis), old mice were exposed to factors present in young serum. The exposure of satellite cells from old mice to young serum enhanced the expression of the Notch ligand (Delta), which increased Notch activation, and improved the proliferation of the satellite cells. Furthermore, heterochronic parabiosis increased aged hepatocyte proliferation and restored the cEBPα complex to levels seen in young animals. Cells from young partners were distinguishable from cells of old mice and less than 0.1% of regenerated myotubes in aged muscle were from the parabiotic partner.
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                       Heterochronic                                           Isochronic

To determine if similar mechanisms were operative for other stem cells, the studies examined satellite cells. Parabiotic pairings (above diagram) between two young mice or two old mice (isochronic parabioses) served as controls. Five days after injury, muscles in young mice in both the isochronic and heterochronic groups experienced robust regeneration.  A slight reduction was shown in heterochronic groups when the number of new myocytes was compared between the two groups. In old isochronic mice groups, poor regenerative capacity was shown as predicted. There was reduced proliferation of satellite cells obtained from both young and old mice that were cultured with sera from young mice and in conditions where notch signaling was inhibited. The studies show that enhanced activation and proliferation of aged myogenic progenitor cells by sera from young mice was notch-dependent.

The cEBP- α–Brm protein complex was detected in liver extracts from old isochronic parabionts but not in young isochronic parabionts. Notably, the formation of the cEBP- α –Brm complex was diminished in liver extracts from old heterochronic parabionts. The complex was present at elevated levels in young heterochronic parabionts as compared to young controls. This was also consistent with the modest inhibition of hepatocyte proliferation in young heterochronic parabionts. A young systemic environment restores a young molecular signaling profile to aged progenitor cells in the liver and also appears to enhance their proliferation.

These results suggest that the of progenitor cell activity involved age-related systemic factors. These systemic factors appear to modulate the molecular signaling pathways critical to the activation of tissue-specific progenitor cells. The systemic environment of a young animal promotes successful regeneration, whereas that of older animals either fails to promote or actively inhibits successful tissue regeneration. The decline of tissue regenerative potential with age can be reversed through the modulation of systemic factors. This suggests that tissue specific stem and progenitor cells retain much of their intrinsic proliferative potential even when old. Clearly, further studied to identify the systemic factors critical to tissue regeneration will be of great interest for diseases linked age and also for regenerative medicine.