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Molecular Medicine Partnership UnitResearch Groups

Early warning signals of aging in human stem cells

gavin_ho

Anne-Claude Gavin and Anthony D. Ho

Anne-Claude Gavin and Anthony D. Ho

Project Summary

The regenerative power of a living organism is linked to the potential of its stem cells to replace the corresponding damaged tissue. A living organism is therefore as old as its stem cells. Surprisingly little is known about the impact of time and age on the basic units of life, the stem cells. Using hematopoietic stem cells (HSC) and their microenvironment as a model, our long-term goal is to define the molecular mechanisms of ageing in somatic stem cells and means to correct these age-related alterations. The experimental approaches are (1) identification of candidate genes and proteins by expression analyses of HSC as well as mesenchymal stromal cells (MSC) derived from different age groups, (2) correlation of cell biological characteristics with ageing specific alterations in genomes and proteomes; (3) analysis of acetylation, phosphorylation of candidate genes associated with aging; (4) relationship of these alterations to development of myelodysplastic syndromes (MDS) as a model for a typical age specific disease.

Background

Besides loss of functions, reduced capacity to regenerate tissues or organs upon injury and a propensity to infections and cancers are the most prominent hallmarks of senescence. The regenerative prowess of a living organism is linked to the ability and potential of its stem cells to replace the corresponding damaged tissue. Whereas the vulnerability to infectious disease and cancer is associated with a decline of the immune system, the latter is in turn a sum product of interactions among hematopoietic stem cells (HSC), the microenvironments in the bone marrow, among others. Hence both phenomena can be interpreted as signs of aging at the level of somatic stem cells. HSC are ideal models for studies on the influence of time, age and environment on somatic stem cells.

Goals

  • To define the fundamental molecular and cell biological mechanisms of ageing in HSC.
  • To understand the roles of genetic and proteomic alterations on the process of ageing.
  • To determine the molecular and cellular alterations of MSC with ageing, and their impact on supportive function for HSC.
  • To combine the cell biological, proteomic, and genetic studies for a better understanding of age-related diseases such as MDS

Research Focus 1: To define the fundamental molecular and cell biological mechanisms of aging of HSC

An understanding of the cellular and molecular mechanisms that regulate self-renewal and differentiation of HSC, as well as their alterations with ageing will provide a basis for prevention and treatment of diseases associated with old age such as myelodysplastic syndromes (MDS).
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Research Focus 2: To determine the molecular and cellular alterations of MSC upon ageing, and their impact on supportive function for HSC

There is growing evidence that the stem cell niche is important for the regulation of cellular ageing in adult stem cells.
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Research Focus 3: FP7 Project SyStemAge
SyStemAge is uniquely positioned to bridge the gap between the clinical, biomedical and natural sciences and immediately contribute to bio-gerontology.
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Selected Publications

SnapShot: protein-protein interaction networks.
Seebacher J. and Gavin A.C.
Cell 2011 March 18;144, 1000

DNA methylation pattern changes upon long-term culture and aging of human mesenchymal stromal cells.
Bork S, Pfister S, Witt H, Horn P, Korn B, Ho AD, Wagner W.
Aging Cell 2010 Feb;9(1):54-63.

Co-Culture with Mesenchymal Stromal Cells Increases Proliferation and Maintenance of Hematopoietic Progenitor Cells.
Walenda T, Bork S, Horn P, Wein F, Saffrich R, Diehlmann A, Eckstein V, Ho AD, Wagner W.
J Cell Mol Med. 2010 Jan;14(1-2):337-50.

Transcriptome complexity in a genome-reduced bacterium.
Güell M., van Noort V., Yus E., Chen W.-H., Leigh-Bell J., Michalodimitrakis K., Yamada T., Arumugam M., Doerks T., Kühner S., Rode M., Suyama M., Gavin A.C., Bork P. and Serrano L.
Science 2009 326, 1268-1271.

Aging and replicative senescence have related effects on human stem and progenitor cells.
Wagner W, Bork S, Horn P, Krunic D, Walenda T, Diehlmann A, Benes V, Blake J, Huber FX, Eckstein V, Boukamp P, Ho AD.
PLoS One 2009 Jun 9;4(6):e5846.


Research group's MMPU link to University Hospital web page