Stem Cell
Physiology

Arbeitsgruppe Apl. Prof. Dr. Robert A.J. Oostendorp

Research Interests

Our research group studies the interactions of normal and malignant hematopoietic stem cells (HSCs) and their microenvironment, also called the niche. We are particularly interested in unraveling the underlying molecular mechanisms of these interactions and their feedback loops and how these affect the biological behavior of HSCs and leukemia-initiating cells (LICs).

Our main focus is the study of how functional changes in niche cells contribute to HSC maintenance and leukemogenesis in vivo. In our studies, we utilize a diverse toolbox of in-vitro and in-vivo genetic and other molecular models currently focused on the study of factors secreted by stromal cells of the microenvironment, such as the canonical Wnt-signaling inhibitors (SFRP1, SFRP2, and WNT5A) and stress-induced stromal factors such as CTGF. We are particularly interested how stromal cells signal to HSCs and LICs, and which intracellular processes are affected by these signals. For instance, we have found that stromal cells regulate actin assembly in HSCs and LICs. Actin assembly is important for diverse cellular functions, such as migratory responses, vesicle formation (endocytosis, exocytosis, autophagy), and cell division.

One of the main goals of these studies is to ascertain the relevance of the niche-regulated signaling pathways, and how these can be used as possible targets to improve HSC engraftment, as well as in the therapy of malignant myeloid disease.

Selected Publications

2019
Müller T, Pennisi S, Zwick A, Decker S, Klein C, Rister B, Rudorf A, Kissel S, Follo M, Wäsch R, Illert A, Pfeifer D, Oostendorp RAJ, Waskow C, Duyster J. PIM1 inhibition effectively enhances plerixafor-induced HSC moblization by counteracting CXCR4 upregulation and blocking CXCL12 secretion. Leukemia. Accepted for publication (February 7th, 2019).

2018
Wenk C, Garz AK, Grath S, Huberle C, Witham D, Weickert M, Malinverni R, Niggemeyer J, Kyncl M, Hecker J, Pagel C, Mulholland CB, Müller-Thomas C, Leonhardt H, Bassermann F, Oostendorp RAJ, Metzeler KH, Buschbeck M, Götze KS. Direct modulation of the bone marrow mesenchymal stromal cell compartment by azacitidine enhances healthy hematopoiesis.(link is external) Blood Adv. 2018 Dec 11;2(23):3447-3461. doi: 10.1182/bloodadvances.2018022053.

Mangolini M, Götte F, Moore A, Ammon T, Oelsner M, Lutzny-Geier G, Klein-Hitpass L, Williamson JC, Lehner PJ, Dürig J, Möllmann M, Rásó-Barnett L, Hughes K, Santoro A, Méndez-Ferrer S, Oostendorp RAJ, Zimber-Strobl U, Peschel C, Hodson DJ, Schmidt-Supprian M, Ringshausen I. Notch2 controls non-autonomous Wnt-signalling in chronic lymphocytic leukaemia.(link is external) Nat Commun. 2018 Sep 21;9(1):3839. doi: 10.1038/s41467-018-06069-5.

Habringer S, Lapa C, Herhaus P, Schottelius M, Istvanffy R, Steiger K, Slotta-Huspenina J, Schirbel A, Hänscheid H, Kircher S, Buck AK, Götze K, Vick B, Jeremias I, Peschel C, Oostendorp R, Wester HJ, Grigoleit GU, Keller U. Dual Targeting of Acute Leukemia and Supporting Niche by CXCR4-Directed Theranostics. Theranostics. 2018; 8: 369-383. doi: 10.7150/thno.21397.

2017
Garz AK, Wolf S, Grath S, Gaidzik V, Habringer S, Vick B, Rudelius M, Ziegenhain C, Herold S, Weickert MT, Smets M, Peschel C, Oostendorp R, Bultmann S, Jeremias I, Thiede C, Döhner K, Keller U, Götze K. Azacitidine combined with the selective FLT3 kinase inhibitor crenolanib disrupts stromal protection and inhibits expansion of residual leukemia-initiating cells in FLT3-ITD AML with concurrent epigenetic mutations. Oncotarget. 2017; 8: 108738-108759. doi: 10.18632/oncotarget.21877.

Demetz G, Oostendorp RAJ, Boxberg AM, Sitz W, Farrell E, Steppich B, Steinsiek AL, Rudelius M, Ott I. Overexpression of Insulin-Like Growth Factor-2 in Expanded Endothelial Progenitor Cells Improves Left Ventricular Function in Experimental Myocardial Infarction. J Vasc Res. 2017; 54: 321-328. doi: 10.1159/000479872.

Steinhoff G, Nesteruk J, Wolfien M, Kundt G; PERFECT Trial Investigators Group, Börgermann J, David R, Garbade J, Große J, Haverich A, Hennig H, Kaminski A, Lotz J, Mohr FW, Müller P, Oostendorp R, Ruch U, Sarikouch S, Skorska A, Stamm C, Tiedemann G, Wagner FM, Wolkenhauer O. Cardiac Function Improvement and Bone Marrow Response -: Outcome Analysis of the Randomized PERFECT Phase III Clinical Trial of Intramyocardial CD133+ Application After Myocardial Infarction. EBioMedicine. 2017; 22: 208-224. doi: 10.1016/j.ebiom.2017.07.022.

Klar K, Perchermeier S, Bhattacharjee S, Harb H, Adler T, Istvanffy R, Loffredo-Verde E, Oostendorp RAJ, Renz H, Prazeres da Costa C. Chronic schistosomiasis during pregnancy epigenetically reprograms T cell differentiation in offspring of infected mothers.(link is external) Eur J Immunol. 2017; 47: 841-847. doi: 10.1002/eji.201646836.

Schreck C, Istvánffy R, Ziegenhain C, Sippenauer T, Ruf F, Henkel L, Gärtner F, Vieth B, Florian MC, Mende N, Taubenberger A, Prendergast Á, Wagner A, Pagel C, Grziwok S, Götze KS, Guck J, Dean DC, Massberg S, Essers M, Waskow C, Geiger H, Schiemann M, Peschel C, Enard W, Oostendorp RAJ. Niche WNT5A regulates the actin cytoskeleton during regeneration of hematopoietic stem cells.(link is external) J Exp Med. 2017; 214: 165-181. doi: 10.1084/jem.20151414.

2016
Ruf F, Schreck C, Wagner A, Grziwok S, Pagel C, Romero S, Kieslinger M, Shimono A, Peschel C, Götze KS, Istvanffy R*, Oostendorp RAJ*. Loss of Sfrp2 in the niche amplifies stress-induced cellular responses, and impairs the in vivo regeneration of the hematopoietic stem cell pool. Stem Cells. 2016; 34: 2381-92. doi: 10.1002/stem.2416. (*: joint senior authors)

Müller TA, Grundler R, Istvanffy R, Rudelius M, Hennighausen L, Illert AL, Duyster J. Lineage-specific STAT5 target gene activation in hematopoietic progenitor cells predicts the FLT3(+)-mediated leukemic phenotype.(link is external) Leukemia. 2016 Aug;30(8):1725-33. doi: 10.1038/leu.2016.72.

Klein C, Zwick A, Kissel S, Forster CU, Pfeifer D, Follo M, Illert AL, Decker S, Benkler T, Pahl H, Oostendorp RAJ, Aumann K, Duyster J, Dierks C. Ptch2 loss drives myeloproliferation and MPN progression. J Exp Med. 2016, 213: 273-290 doi: 10.1084/ jem.20150556.

Jilg S, Reidel V, Müller-Thomas C, König J, Schauwecker J, Höckendorf U, Huberle C, Gorka O, Schmidt B, Burgkart R, Ruland J, Kolb HJ, Peschel C, Oostendorp RAJ, Götze KS, Jost PJ. Blockade of BCL-2 proteins efficiently induces apoptosis in progenitor cells of high-risk myelodysplastic syndromes patients.(link is external) Leukemia. 2016; 30: 112-23. doi: 10.1038/leu.2015.179.

2015
Istvánffy R, Vilne B, Schreck C, Ruf F, Pagel C, Grziwok S, Henkel L, Prazeras da Costa O, Berndt J, Stümpflen V, Götze KS, Schiemann M, Peschel C, Mewes HW, Oostendorp RAJ. Stroma-derived connective tissue growth factor maintains cell cycle progression and repopulation activity of hematopoietic stem cells in vitro. Stem Cell Reports. 2015; 5: 702-715. doi: 10.1016/ j.stemcr.2015.09.018.

Franke K, Vilne B, Prazeres da Costa O, Rudelius M, Peschel C, Oostendorp RAJ, Keller U. In vivo hematopoietic Myc activation directs a transcriptional signature in endothelial cells within the bone marrow microenvironment. Oncotarget. 2015; 6: 21827-21839. doi: 10.18632/ oncotarget.5217.

Ruppert R, Moser M, Sperandio M, Rognoni E, Orban M, Liu W-H, Schulz AS, Oostendorp RAJ, Massberg S, Fässler R. Kindlin-3-mediated integrin adhesion is dispensible for quiescent, but required for activated hematopoietic stem cells. J Exp Med. 2015 212(9):1415-32. doi: 10.1084/jem.20150269.

Tomiatti V, Istvanffy R, Pietschmann E, Kratzat S, Hoellein A, Quintinilla-Fend L, von Bubnoff N, Peschel C, Oostendorp RAJ*, Keller U*. Cks1 is a critical regulator of hematopoietic stem cell quiescence and cell cycling, operating upstream of Cdk inhibitors. Oncogene. 2015; 34: 4347-57. doi: 10.1038/onc.2014.364. *: joint senior authors.

2014

Vasold J, Wagner M, Drolle H, Deniffel C, Kütt A, Oostendorp R, Sironi S, Rieger C, Fiegl M. The bone marrow microenvironment is a critical player in the NK cell respon se against acute myeloid leukaemia in vitro.(link is external) Leuk Res. 2014; 39: 257-62. doi: 10.1016/j.leukres.2014.12.001.

Vong QP, Leung WH, Houston J, Li Y, Rooney B, Holladay M, Oostendorp RAJ, Leung W. TOX2 regulates human natural killer cell development by controlling T-BET expression.(link is external) Blood. 2014 Oct 28. pii: blood-2014-06-582965

Wöhrer S, Knapp DJ(link is external), Copley MR(link is external), Benz C(link is external), Kent DG(link is external), Rowe K(link is external), Babovic S(link is external), Mader H(link is external), Oostendorp RAJ, Eaves CJ(link is external). Distinct Stromal Cell Factor Combinations Can Separately Control Hematopoietic Stem Cell Survival, Proliferation, and Self-Renewal. Cell Rep.(link is external) 2014; 7: 1956-67. doi: 10.1016/j.celrep.2014.05.014.

Klar R, Schober S, Rami M, Mall S, Merl J, Hauck SM, Ueffing M, Admon A, Slotta-Huspenina J, Schwaiger M, Stevanović S, Oostendorp RAJ, Busch DH, Peschel C, Krackhardt AM. Therapeutic targeting of naturally presented myeloperoxidase-derived HLA peptide ligands on myeloid leukemia cells by TCR-transgenic T cells.(link is external) Leukemia. 2014; 28: 2355-66. doi: 10.1038/leu.2014.131.

Schreck C, Bock F, Grziwok S, Oostendorp RAJ, Istvánffy R. Regulation of hematopoiesis by activators and inhibitors of Wnt signaling from the niche.(link is external) Ann N Y Acad Sci. 2014; 1310: 32-43. doi: 10.1111/nyas.12384. Review.

2013
Florian MC, Kalpana J. Nattamai KJ, Dörr K, Marka G, Überle B, Vas V, Eckl C, Andrä I, Schiemann M, Oostendorp RAJ, Scharffetter-Kochanek K, Kestler HA, Zheng Y, Geiger H. A canonical to non-canonical Wnt signalling switch in haematopoietic stem-cell ageing. Nature, 2013; 503:3 92-396. doi: 10.1038/nature12631

Lutzny G, Kocher T, Schmidt-Supprian M, Rudelius M, Klein-Hitpass R, Finch AJ, Dürig J, Wagner M, Haferlach C, Kohlmann A, Schnittger S, Seifert M, Wanninger S, Zaborsky N, Oostendorp R, Ruland J, Leitges M, Kuhnt T, Schäfer Y, Lampl B, Peschel C, Egle A, Ringshausen I. Protein Kinase C-b-Dependent Activation of NF-kB in Stromal Cells Is Indispensable for the Survival of Chronic Lymphocytic Leukemia B Cells In Vivo. Cancer Cell, 2013; 23: 77-92. doi: 10.1016/j.ccr.2012.12.003