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Division of Experimental Hematology

Dr. Michael Milsom

Tracking stem cell fate decisions during in vitro culture using time-lapse video microscopy. A DNA repair-defective hematopoietic stem cell isolated from a Fanconi anemia knockout (Fanca-/-) mouse demonstrate post-mitotic apoptosis (frame with red border) compared to the normal cell division behavior illustrated by a wild type (WT) murine hematopoietic stem cell. Performed in collaboration with the group of Prof. Michael Rieger, University of Frankfurt.

In regenerating organs, the process of aging is likely driven by the progressive depletion of adult stem cell populations that are responsible for maintaining tissues throughout the lifetime of an organism. One mechanism thought to be a primary cause of progressive adult stem cell depletion with ongoing time, is the accumulation of DNA damage in the stem cell compartment and the subsequent response to this insult. As well as potentially driving the loss of adult stem cells, DNA damage in this cell population is the likely mechanism behind the sequential acquisition of transforming mutations that lead to malignant transformation. Critically, to date, no one has identified the universal physiologic source of DNA damage in adult stem cells that leads to age-associated functional decline and transformation. We have recently developed a model of DNA damage in hematopoietic stem cells (HSCs) in vivo, which is precipitated by exposure of mice to agonists that mimic physiologic stress such as infection and chronic blood loss. These stress agonists drive HSCs out of their homeostatic quiescent status, resulting in de novo DNA damage as a consequence of increased replicative stress associated with dynamic changes in HSC energy metabolism. Importantly, this stress-induced DNA damage results in a phenotype of cumulative HSC attrition and a myeloid differentiation bias, which is akin to accelerated aging. In the setting of a clinically relevant mouse model of defective DNA repair (Fanconi anemia), stress hematopoiesis leads to a premature collapse of the entire hematopoietic system, fully recapitulating the progression of this disease in Fanconi anemia patients.

FUTURE OUTLOOK: The model described above is an ideal platform to study the response of HSCs to physiologic DNA damage and will allow us to better understand how environmental stress stimuli such as infections can impact upon both the rate of aging of tissues and the incidence of malignant transformation. This may have important clinical implications relevant to the study of age-related hematopoietic defects in patients. Furthermore, by defining the mechanism via which transforming mutations are acquired in HSCs in response to stress, we will potentially gain a new perspective on environmental factors that influence carcinogenesis. Such knowledge could then be used to devise strategies which reduce the risk of developing cancer in the first place.

Dr. Milsom is also a group leader at the Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), a public-private partnership between the DKFZ and the Dietmar Hopp Foundation. Further detail can be found here.


Dr. Michael Milsom
Experimental Hematology (A012)

Deutsches Krebsforschungszentrum and Heidelberg Institut für Stammzelltechnologie und experimentelle Medizin (HI-STEM GmbH)
Im Neuenheimer Feld 280
69120 Heidelberg

Tel.: +49 6221 42 3901

Selected Publications

  • Walter D. et al. (2015). Exit from dormancy provokes DNA damage-induced attrition in haematopoietic stem cells. Nature, 520(7548), 549-552.
  • Cabezas-Wallscheid N. et al. (2014). Identification of regulatory networks in HSCs and their immediate progeny via integrated proteome, transcriptome and DNA methylome analysis. Cell Stem Cell, 15(4), 507-522. §Shared senior authorship.
  • Lipka D.B. et al. (2014). Identification of DNA methylation changes at cis-regulatory elements during early steps of HSC differentiation using tagmentation-based whole genome bisulphite sequencing. Cell Cycle, 13(22), 3476-3487. §Shared senior authorship.
  • Geiselhart A. et al. (2012). Disrupted signalling through the Fanconi anemia pathway leads to dysfunctional hematopoietic stem cell biology: underlying mechanisms and potential therapeutic strategies. Anemia, 2012, 265790.
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