Anne-Claude Gavin and Anthony D. Ho
Anne-Claude Gavin and Anthony D. Ho
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.
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.
- 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).
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.
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.
The orchestra of lipid-transfer proteins at the crossroads between metabolism and signaling. Chiapparino A, Maeda K, Turei D, Saez-Rodriguez J, Gavin AC.
Prog Lipid Res. 2016 Jan;61:30-9. doi: 10.1016/j.plipres.2015.10.004. Epub 2015 Dec 1. Review.PMID:26658141
The systematic analysis of protein-lipid interactions comes of age.
Saliba AE, Vonkova I, Gavin AC.
Nat Rev Mol Cell Biol. 2015 Dec;16(12):753-61. doi: 10.1038/nrm4080. Epub 2015 Oct 28. PMID: 26507169
Pre-transplant weight loss predicts inferior outcome after allogeneic stem cell transplantation in patients with myelodysplastic syndrome.
Radujkovic A, Becker N, Benner A, Penack O, Platzbecker U, Stölzel F, Bornhäuser M, Hegenbart U, Ho AD, Dreger P, Luft T.
Oncotarget. 2015 Oct 27;6(33):35095-106. doi: 10.18632/oncotarget.4805.
Lipid Cooperativity as a General Membrane-Recruitment Principle for PH Domains.
Vonkova I, Saliba AE, Deghou S, Anand K, Ceschia S, Doerks T, Galih A, Kugler KG, Maeda K, Rybin V, van Noort V, Ellenberg J, Bork P, Gavin AC.
Cell Rep. 2015 Sep 1;12(9):1519-30. doi: 10.1016/j.celrep.2015.07.054. Epub 2015 Aug 20. PMID: 26299969
A Conserved Circular Network of Coregulated Lipids Modulates Innate Immune Responses.
Köberlin MS, Snijder B, Heinz LX, Baumann CL, Fauster A, Vladimer GI, Gavin AC, Superti-Furga G.
Cell. 2015 Jul 2;162(1):170-83. doi: 10.1016/j.cell.2015.05.051. Epub 2015 Jun 18. PMID:26095250
Functional fingerprinting of human mesenchymal stem cells using high-throughput RNAi screening.
Erdmann G, Suchanek M, Horn P, Graf F, Volz C, Horn T, Zhang X, Wagner W, Ho AD, Boutros M.
Genome Med. 2015 May 17;7(1):46. doi: 10.1186/s13073-015-0170-2. eCollection 2015. PMID: 26120366
Quantitative mass spectrometry of posttranslational modifications: keys to confidence.
Hennrich ML, Gavin AC.
Sci Signal. 2015 Apr 7;8(371):re5. doi: 10.1126/scisignal.aaa6466. Review. PMID:25852188
Modules, networks and systems medicine for understanding disease and aiding diagnosis.
Gustafsson M, Nestor CE, Zhang H, Barabási AL, Baranzini S, Brunak S, Chung KF, Federoff HJ, Gavin AC, Meehan RR, Picotti P, Pujana MÀ, Rajewsky N, Smith KG, Sterk PJ, Villoslada P, Benson M.
Genome Med. 2014 Oct 17;6(10):82. doi: 10.1186/s13073-014-0082-6. eCollection 2014.
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