Inflammation and infection acutely suppress HSC function however, the long-term ramifications of such challenges are unclear. In this study HI-STEM researchers demonstrate that murine HSCs fail to recover functional potency up to 1 year post inflammatory/infection challenge, meaning that such events can have accumulative effect over a lifetime∞ this promotes acquisition of the aged state.

The artwork depicts bacteria, representative of infection and inflammation, driving the process of hematopoietic stem cell aging. The signage conveys several key points from the manuscript: namely that hematopoietic stem cells progressively and irreversibly lose their functionality as a result of infection/inflammatory challenge; that self-renewal is absent or extremely rare, both during and after such challenge; and that this ultimately acts to accelerate stem cells towards the destination of old age. The tunnel walls illustrate the progressive shift of the bone marrow from being densely packed with hematopoietic cells, to the adipocyte-dominated white marrow characteristic of aging in humans. Artwork generated by DrawImpacts (www.drawimpacts.com).

Ruzhica Bogeska, Ana-Matea Mikecin, Paul Kaschutnig, Malak Fawaz, Marleen Büchler-Schäff, Duy Le, Miguel Ganuza, Angelika Vollmer, Stella V. Paffenholz, Noboru Asada, Esther Rodriguez-Correa, Felix Frauhammer, Florian Buettner, Melanie Ball, Julia Knoch, Sina Stäble, Dagmar Walter, Amelie Petri, Martha J. Carreño-Gonzalez, Vinona Wagner, Benedikt Brors, Simon Haas, Daniel B. Lipka, Marieke A.G. Essers, Vivienn Weru, Tim Holland-Letz, Jan-Philipp Mallm, Karsten Rippe, Stephan Krämer, Matthias Schlesner, Shannon McKinney Freeman, Maria Carolina Florian, Katherine Y. King, Paul S. Frenette, Michael A. Rieger, Michael D. Milsom.

Inflammatory exposure drives long-lived impairment of hematopoietic stem cell self-renewal activity and accelerated aging, Cell Stem Cell. 2022 Jul 12:S1934-5909(22)00261-2. doi: 10.1016/j.stem.2022.06.012.

Free access: https://authors.elsevier.com/a/1fRPY6tu0CiH2q

Big congratulations to Marleen; our latest PhD student to graduate from the lab. Marleen did a great job at her virtual defense and we were able to celebrate afterwards with a virtual celebration. Special mention to the fantastic Harry Potter themed PhD graduation video that was made by the talented filmmakers in the group. Watch out for it making an appearance at the Oscars! Marleen’s special graduation hat is shown in the attached picture.

Congratulations to Jeyan Jayarajan, who has been granted a travel award to fund his attendance at this year’s Annual Meeting of the European Hematology Association in Vienna. He will present work from his PhD studies which examine the effect of co-housing “wildling” mice with laboratory mice on the hematopoietic system. This results in the horizontal transfer of microorganisms and multicellular pathogens that are normally found in wild mice to the experimental mice and represents what we believe is a more physiologic model of infection/colonisation than the direct injection of purified virus/bacteria particles.

Congratulations to Jeyan Jayarajan and Ana-Matea Mikecin, who were both awarded oral presentations at the 2021 Annual Meeting of the European Hematology Association, which takes place on a virtual platform this year. Jeyan will talk about his work on myeloproliferative neoplasms, with a specific focus on the role of Jak2-mutant dormant stem cells in mediating therapy resistance. Matea’s talk will focus on her investigation into the comparative analysis of the functional consequences of hematopoietic stem cell activation from dormancy in response to different external stimuli. In addition, Mick will give an invited talk on the mechanisms of leukemic transformation in the setting of Fanconi anemia.

He has been awarded a DKFZ International Graduate School fellowship to fund his PhD studies within the lab. Ian will join the group from Italy in the summer of 2021 and will study the effect of interferon therapy on dormant malignant stem cells in the setting of JAK2-mutated myeloproliferative neoplasms.

Congratulations to Megan, our latest PhD student to graduate from the lab. After an outstanding performance at her virtual defense, we had a virtual celebration spanning three continents (taking social distancing to a new level). Megan studied the mechanisms through which hematopoietic stem cells acquire genomic mutations during aging, and during the course of her studies presented her work at several international symposia.

Congratulations to Dr. Susi Lux, whose abstract "Genetic rescue of of Fanca-/- HSPCs with Evi-1 overexpression suggests a mechanistic link with DNA damage response" has been accepted as an oral presentation at the forthcoming European School of Hematology Translational Research Conference: "Bone Marrow Failure Disorders - from the cell to the cure of the disease". The conference will take place on a virtual platform from the 13th to the 15th of November.

https://www.esh.org/conference/1st-translational-research-conference-on-bone-marrow-failure-disorders/

Congratulations to Esther Rodriguez, who has been awarded a DKFZ International Graduate School fellowship to fund the duration of her PhD research project in the group. Esther's PhD. project will be focused on assessing HSC functional potential using single cell transplantations in combination with mathematical modeling, which forms part of a collaboration with the group of Prof. Thomas Höfer, also at the DKFZ.

New work from the Milsom lab now available on bioRxiv "Hematopoietic stem cells fail to regenerate following inflammatory challenge."

Citation:

Ruzhica Bogeska, Paul Kaschutnig, Malak Fawaz, Ana-Matea Mikecin, Marleen Buechler-Schaeff, Stella Paffenholz, Noboru Asada, Felix Frauhammer, Florian Buettner, Melanie Ball, Julia Knoch, Sina Staeble, Dagmar Walter, Amelie Petri, Martha J Carreno-Gonzalez, Vinona Wagner, Benedikt Brors, Simon Haas, Daniel B Lipka, Marieke A.G. Essers, Tim Holland-Letz, Jan-Philipp Mallm, Karsten Rippe, Paul S Frenette, Michael A Rieger, Michael D Milsom
Hematopoietic stem cells fail to regenerate following inflammatory challenge.

bioRxiv 2020.08.01.230433; doi: 10.1101/2020.08.01.230433

Abstract:

Hematopoietic stem cells (HSCs) are canonically defined by their capacity to maintain the HSC pool via self-renewal divisions. However, accumulating evidence suggests that HSC function is instead preserved by sustaining long-term quiescence. Here, we study the kinetics of HSC recovery in mice, following an inflammatory challenge that induces HSCs to exit dormancy. Repeated inflammatory challenge resulted in a progressive depletion of functional HSCs, with no sign of later recovery. Underlying this observation, label retention experiments demonstrated that self-renewal divisions were absent or extremely rare during challenge, as well as during any subsequent recovery period. While depletion of functional HSCs held no immediate consequences, young mice exposed to inflammatory challenge developed blood and bone marrow hypocellularity in old age, similar to elderly humans. The progressive, irreversible attrition of HSC function demonstrates that discreet instances of inflammatory stress can have an irreversible and therefore cumulative impact on HSC function, even when separated by several months. These findings have important implications for our understanding of the role of inflammation as a mediator of dysfunctional tissue maintenance and regeneration during ageing.

Three scientists from the Division of Experimental Hematology will present their work at the annual meeting of the European Hematology Association, which will take place in June as a virtual conference due to the Covid-19 pandemic.

Sina Stäble will record an oral presentation on "COMBINED SINGLE-CELL DNA METHYLOME AND TRANSCRIPTOME ANALYSIS FACILITATES DECONVOLUTION OF HEMATOPOIETIC COMMITMENT DECISIONS” that will be available to stream during the meeting, and up to the end of October. She will also participate in a live question and answer panel discussion during the meeting.

Megan Druce will present an ePoster with audio narrative on "ASSESSMENT OF MUTATION BURDEN IN HEMATOPOIETIC STEM CELL CLONES AS A RESULT OF AGING AND INFLAMMATORY STRESS” which is a collaboration between the Division of Experimental Hematology and the group of Inigo Martincorena at the Wellcome Sanger Institute in Cambridge. Megan will also record an oral presentation that will be broadcast as part of the Young EHA Workshop that takes place before the main meeting. 

Ana-Matea Mikecin will also present an ePoster at the meeting, focussed on her study of the effect of different forms of stress on hematopoietic stem cell biology: "HEMATOPOIETIC STEM CELLS SUSTAIN MATURE BLOOD CELL PRODUCTION DURING STRESS HEMATOPOIESIS ON THE EXPENSE OF SELF-RENEWAL."

Congratulations to Megan Druce. Her abstract, “Assessment of mutation burden in hematopoietic stem cell clones as a result of ageing and inflammatory stress” has been selected for a short talk at the forthcoming EMBL conference on Advances in Stem Cells and Regenerative Medicine, in March. The group will also be represented with poster presentations from Marleen Büchler, Ana-Matea Mikecin and Stephan Krämer (collaboration with the Lipka group).

Mick Milsom has recently been elected as a chair of the Molecular Hematopiesis Workshop of the European Hematology Association (EHA) and also as a member of the Scientific Committee on Bone Marrow Failure of the American Society of Hematology (ASH). Both roles involve the organisation of content for the annual scientific meetings of each society.

Congratulations to Ruzhica Bogeska and Sina Stäble, whose abstracts have both been selected for presentation at the annual meeting of the American Society of Hematology, which will be held in Orlando, Florida, in December. Both Ruzhica and Sina have been given prestigious Abstract Achievement Awards to help offset the costs of travel to the meeting in Orlando.

Ruzhica’s abstract, "No Evidence for Hematopoietic Stem Cell Self-Renewal in-Vivo Following Inflammatory Challenge” has been awarded an oral presentation, while Sina’s abstract, "Deconvolution of Hematopoietic Commitment Decisions By Genome-Wide Analysis of Progressive DNA Methylation Changes”, will be presented at a poster.

Susi has been awarded a DKFZ Postdoctoral Fellowship to support her time working in the lab.

Congratulations to Sina Stäble. Her abstract, “Deconvolution of hematopoietic commitment decisions by genome-wide analysis of progressive DNA methylation changes”, has been selected for oral presentation at the annual meeting of the European Hematology Association (EHA), which will take place from June 13th-16th in Amsterdam. Sina’s project forms part of a long-standing collaboration between the laboratories of Mick Milsom and Daniel Lipka, from the Division of Cancer Epigenomics at the DKFZ.

Following an annual appraisal of our progress, we are happy to announce that the MPN Foundation has decided to renew our project funding for one additional year. The funding supports a collaborative research project between the HI-STEM Experimental Hematology Group, and the groups of Dr. Steven Lane at the Queensland Institute for Medical Research in Brisbane, Australia, and Ann Mullally at the Dana-Faber Cancer Institute/Brigham and Women’s Hospital in Boston, USA.

Dr. Ruzhica Bogeska has been selected to give a talk at the European School of Hematology’s 3rd Scientific Workshop on "The Hematological Microenvironment and its Therapeutic Targeting", which will be held at the Francis Crick Institute in London on February 24-26th 2019. The Workshop features talks from internationally renowned experts in normal and malignant hematology and will be a great opportunity for Ruzhica to showcase her work on the impact of inflammatory stress on hematopoietic stem cell function.

Further details at www.esh.org/conference/3rd-scientific-workshop-tumour-microenvironment-in-the-haematological-malignancies-and-its-therapeutic-targeting/

Congratulations to Sina Stäble on being awarded a talk at the forthcoming annual conference of the German Stem Cell Network, which will take place in September.

Ms. Stäbles abstract titled "Unidirectional and progressive DNA methylation changes define hematopoietic lineage commitment" has been selected for an oral presentation at the 6th GSCN Conference in Heidelberg (19.-21.9.2018), Session Computational Stem Cell Biology on Wednesday, 19 Sept. 14:30 - 16:00 h.

Further details at http://www.gscn.org/conferences/2018/home.aspx

Julius was selected to present at the International Behr-Symposium on Stem Cells and Cancer (Heidelberg, Sept. 16-19), which is organized by HI-STEM.

Further details at www.scc2018.de

Congratulations to Julius Gräsel, who has just been awarded an oral presentation at the 30th Annual International Scientific Symposium of the Fanconi Anemia Research Foundation, which will take place in Newport Beach California in September. Based on the evaluation of Julius’ submitted abstract, his travel costs will be reimbursed by the Research Foundation.