Article

Systemic signals regulate ageing and rejuvenation of blood stem cell niches

Department of Stem Cell and Regenerative Biology, Harvard University, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Joslin Diabetes Center, One Joslin Place, Boston, Massachusetts 02115, USA.
Nature (Impact Factor: 42.35). 10/2010; 467(7317):872. DOI: 10.1038/nature09474
Source: PubMed

ABSTRACT Ageing in multicellular organisms typically involves a progressive decline in cell replacement and repair processes, resulting in several physiological deficiencies, including inefficient muscle repair, reduced bone mass, and dysregulation of blood formation (haematopoiesis). Although defects in tissue-resident stem cells clearly contribute to these phenotypes, it is unclear to what extent they reflect stem cell intrinsic alterations or age-related changes in the stem cell supportive microenvironment, or niche. Here, using complementary in vivo and in vitro heterochronic models, we show that age-associated changes in stem cell supportive niche cells deregulate normal haematopoiesis by causing haematopoietic stem cell dysfunction. Furthermore, we find that age-dependent defects in niche cells are systemically regulated and can be reversed by exposure to a young circulation or by neutralization of the conserved longevity regulator, insulin-like growth factor-1, in the marrow microenvironment. Together, these results show a new and critical role for local and systemic factors in signalling age-related haematopoietic decline, and highlight a new model in which blood-borne factors in aged animals act through local niche cells to induce age-dependent disruption of stem cell function.

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    • "These results are remarkable given that the cells were delivered into the systemic vasculature and not directly into the brain. However, few surviving HUCB-derived cells were found in the brain of animals that received transplants [101] [102] [103] and fewer of these surviving cells expressed neural markers, indicating that replacement of lost neurons was not the primary mechanism inducing brain repair. In addition to producing growth/trophic factors, the HUCB mononuclear cells also produce a number of cytokines and chemokines.Indeed, we have consistently found that HUCB administration interrupts the inflammatory cascade observed in the aged brain reduces apoptotic cell death [104] and enhances neurogenesis and angiogenesis [105]. "
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    • "On the contrary, the identification of critical extracellular factors that may have an impact on stem cell function could be addressed more easily. This approach has been successfully experimented both in the skeletal muscle, through the systemic delivery of a TGF-b receptor kinase inhibitor (Carlson et al., 2009), and in the hematopoietic system, by neutralization of the insulin-like growth factor-1 in the marrow microenvironment (Mayack et al., 2010). The positive impact of rosiglitazone on endothelial progenitor cells exposed to AGEs may be an additional example in this direction (Liang et al., 2009). "
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    • "A criticism of this approach has been that transplantation requires 'conditioning' of the recipient (e.g., through wholebody irradiation) and therefore necessarily entails damage to the niche. The question of HSC aging has now been further pursued by the Wagers laboratory using parabiosis, which does not require conditioning (Mayack et al., 2010). As is the case with muscle stem cell function, the authors showed that a considerable component of HSC aging results from an aged stem cell niche. "
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