Alterung hämatopoetischer Stammzellen und epigenetische Veränderungen: ein Weg zur Stammzellverjüngung.
Zusammenfassung der Projektergebnisse
Stem cells were initially thought to be endowed with unlimited self-renewal capacity and thus assumed to be exempt from aging. It has been subsequently demonstrated though that there is a successive age-dependent functional decline in hematopoietic, intestinal and muscle stem cell activity, impairing tissue homeostasis and regeneration. Recent publications indicate that distinct undesirable phenotypes associated with aged stem cells can be improved by pharmacological approaches or dietary interventions, demonstrating that the functional decline of aged stem cells and tissues may be reversible9. In particular within the current project I focused on hematopoietic stem cells (HSCs), which are critical for the homeostasis of the hematopoietic system by continuously providing mature blood cells over the whole lifespan of an individual. It has been demonstrated that the functional decline in hematopoiesis in the elderly, which involves a progressive reduction in the immune response and an increased incidence of leukemia, is at least in part linked to changes in the function of HSCs upon aging. Indeed, young and aged HSCs show quantitative differences that are in part intrinsic to HSCs themselves like reduced self-renewal activity upon transplantation, decreased ability to support erythropoiesis and lymphopoiesis and skewing toward myeloid differentiation. Aging is also the major risk factor for developing clonal hematopoiesis, myelodysplastic syndromes and leukemia. During my post-doctoral training, I investigated the role of the small RhoGTPase Cdc42 in driving aging of HSCs. I demonstrated that elevated activity of Cdc42 is critical in regulating HSC aging and rejuvenation through cytosol (Cdc42 and tubulin localization) and nuclear (localization of the epigenetic mark acetylated Histone 4 on lysine 16 or H4K16ac) polarity establishment. The molecular mechanisms downstream of Cdc42 that establish the epigenetic polarity and play a role in HSC aging and rejuvenation were unknown. Based on my preliminary data I postulated that Cdc42 plays a critical role in regulating the symmetry/asymmetry of HSC division and hypothesized that by regulating Cdc42 activity/polarity it would have been possible to control and improve HSC differentiation/selfrenewal upon aging via regulation of epigenetic mechanisms (epigenetic polarity). Therefore, the novel hypothesis to test within the current DFG funded project was that the epigenetic architecture of H4K16ac is linked to the outcome of the stem cell division and to the transmission of epigenetic information to daughter cells and that ultimately it could relate to the daughter stem cell function in maintaining tissue homeostasis. The results demonstrated that indeed aging alters the epigenetic asymmetry of HSC division. This is measured as differences in inheritance of H4K16ac by daughter cells upon HSC division and also by a difference in open chromatin (by single daughter ATAC-seq). Furthermore, our data demonstrated that LaminA/C regulates epigenetic and chromatin architecture changes downstream of Cdc42 upon HSC aging. H4K16ac ChIP-seq dataset reveal alterations in H4K16ac deposition that correlate with changes in expression of critical hematopoietic and aging related genes. More importantly ChIP-seq data highlighted changes in chromatin architecture and chromosome 11 localization within HSCs upon aging and rejuvenation. Finally, we showed that Cdc42 activity can control chromatin architecture by affecting LaminA/C expression/distribution in HSCs.
Projektbezogene Publikationen (Auswahl)
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(2019) Hematopoietic Stem Cell Dynamics Are Regulated by Progenitor Demand: Lessons from a Quantitative Modeling Approach. Stem cells (Dayton, Ohio) 37 (7) 948–957
Klose, Markus; Florian, Maria Carolina; Gerbaulet, Alexander; Geiger, Hartmut; Glauche, Ingmar
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(2017) Expression and activity of the small RhoGTPase Cdc42 in blood cells of older adults are associated with age and cardiovascular disease. J. Gerontol. A. Biol. Sci. Med. Sci.
Florian, M. C., Klenk, J., Marka, G., Soller, K., Kiryakos, H., Peter, R., Herbolsheimer, F., Rothenbacher, D., Denkinger, M., and Geiger, H.
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(2017) Niche WNT5A regulates the actin cytoskeleton during regeneration of hematopoietic stem cells. J. Exp. Med. 214, 165-181
Schreck, C., Istvanffy, R., Ziegenhain, C., Sippenauer, T., Ruf, F., Henkel, L., Gartner, F., Vieth, B., Florian, M. C., Mende, N., Taubenberger, A., Prendergast, A., Wagner, A., Pagel, C., Grziwok, S., Gotze, K. S., Guck, J., Dean, D. C., Massberg, S., Essers, M., Waskow, C., Geiger, H., Schiemann, M., Peschel, C., Enard, W., and Oostendorp, R. A.
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(2017) Osteopontin attenuates aging-associated phenotypes of hematopoietic stem cells. EMBO J 36, 840-853
Guidi, N., Sacma, M., Standker, L., Soller, K., Marka, G., Eiwen, K., Weiss, J. M., Kirchhoff, F., Weil, T., Cancelas, J. A., Florian, M. C., and Geiger, H.
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(2017) Septin 6 regulates engraftment and lymphoid differentiation potential of murine longterm hematopoietic stem cells. Exp. Hematol.
Senger, K., Marka, G., Soller, K., Sakk, V., Florian, M. C., and Geiger, H.
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(2017) Vitamin A-Retinoic Acid Signaling Regulates Hematopoietic Stem Cell Dormancy. Cell 169, 807-823 e819
Cabezas-Wallscheid, N., Buettner, F., Sommerkamp, P., Klimmeck, D., Ladel, L., Thalheimer, F. B., Pastor-Flores, D., Roma, L. P., Renders, S., Zeisberger, P., Przybylla, A., Schonberger, K., Scognamiglio, R., Altamura, S., Florian, C. M., Fawaz, M., Vonficht, D., Tesio, M., Collier, P., Pavlinic, D., Geiger, H., Schroeder, T., Benes, V., Dick, T. P., Rieger, M. A., Stegle, O., and Trumpp, A.
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(2018) Aging alters the epigenetic asymmetry of HSC division. PLoS Biol 16, e2003389
Florian, M. C., Klose, M., Sacma, M., Jablanovic, J., Knudson, L., Nattamai, K. J., Marka, G., Vollmer, A., Soller, K., Sakk, V., Cabezas-Wallscheid, N., Zheng, Y., Mulaw, M. A., Glauche, I., and Geiger, H.
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(2018) LaminA/C regulates epigenetic and chromatin architecture changes upon aging of hematopoietic stem cells. Genome Biol 19, 189
Grigoryan, A., Guidi, N., Senger, K., Liehr, T., Soller, K., Marka, G., Vollmer, A., Markaki, Y., Leonhardt, H., Buske, C., Lipka, D. B., Plass, C., Zheng, Y., Mulaw, M. A., Geiger, H., and Florian, M. C.
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(2019) Rational identification of a Cdc42 inhibitor presents a new regimen for long-term hematopoietic stem cell mobilization. Leukemia 33: 749-761
Liu, W., Du, W., Shang, X., Wang, L., Evelyn, C., Florian, M. C., Ryan, M. A., Rayes, A., Zhao, X., Setchell, K., Meller, J., Guo, F., Nassar, N., Geiger, H., Pang, Q., and Zheng, Y.
