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Molecular Medicine Partnership Unit

The MMPU is a joint venture between the Medical Faculty of the University of Heidelberg and the European Molecular Biology Laboratory (EMBL).

Stem Cells and Ageing

Anne-Claude Gavin and Anthony D. Ho

MMPU Group 2011 – 2018

Our research interest

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 as signatures of ageing at the level of somatic stem cells. HSC and the bone marrow niche 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 systems understanding of age-related diseases such as MDS

Research Focus 1:

To define the fundamental molecular and cell biological mechanisms of ageing 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 overwhelming evidence that the stem cell niche plays a significant role for the ageing process in adult stem cells.

Research Focus 3:

SyStemAge

SyStemAge is uniquely positioned to bridge the gap between the clinical, biomedical and natural sciences and immediately contribute to bio-gerontology.

Selected publications

Coupling proteomics and metabolomics for the unsupervised identification of protein-metabolite interactions in Chaetomium thermophilum.
Li Y, Kuhn M, Zukowska-Kasprzyk J, Hennrich ML, Kastritis PL, O’Reilly FJ, Phapale P, Beck M, Gavin AC, Bork P.
PLoS One. 2021 Jul 9;16(7):e0254429. doi: 10.1371/journal.pone.0254429. eCollection 2021. PMID: 34242379 Free PMC article.

Cell metabolism regulates integrin mechanosensing via an SLC3A2-dependent sphingolipid biosynthesis pathway.
Boulter E, Estrach S, Tissot FS, Hennrich ML, Tosello L, Cailleteau L, de la Ballina LR, Pisano S, Gavin AC, Féral CC.
Nat Commun. 2018 Nov 19;9(1):4862. doi: 10.1038/s41467-018-07268-w. PMID:30451822

Cell-specific proteome analyses of human bone marrow reveal molecular features of age-dependent functional decline.
Hennrich ML, Romanov N, Horn P, Jaeger S, Eckstein V, Steeples V, Ye F, Ding X, Poisa-Beiro L, Lai MC, Lang B, Boultwood J, Luft T, Zaugg JB, Pellagatti A, Bork P, Aloy P, Gavin AC, Ho AD.
Nat Commun. 2018 Oct 1;9(1):4004. doi: 10.1038/s41467-018-06353-4. PMID:30275468

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.

Group members

in alphabetical order

Evgenia Belyaeva, Scientific Project Officer

Karina Borowski, FACS Operator

Ximing Ding, PhD Student (EMBL International PhD Programme – EIPP)

Volker Eckstein, FACS Operator

Luciana Egolf, Technician

Anne-Claude Gavin, PhD, Group Leader

Marco Hennrich, Mass Spectrometrist

Anthony D. Ho, MD, FRCPC, Group Leader

Patrick Horn, PhD, Scientist

Noorie Karimbocus, PhD Student (EMBL International PhD Programme – EIPP)

Petra Lindemann, Scientific Project Officer

Christoph Lutz, MD, Senior Physician

Linda Manta, PhD, Postdoc

Laura Poisa Beiro, PhD, Postdoc

Tobias Roider, MD, Postdoc

Jan Seebacher, PhD, Scientist

Fei Ye, PhD Student (EMBL International PhD Programme – EIPP)

Anne-Claude Gavin and Anthony D. Ho
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