Division of Stem Cell Biology and Cellular Engineering

Research Focus

Our research focusses on molecular mechanisms that regulate human stem cells, particularly hematopoietic stem cells, mesenchymal stem cells, and induced pluripotent stem cells. We characterize how epigenetic changes are acquired during differentiation and how cell fate is regulated by external stimuli. We are particularly interested in the following aspects:

Mesenchymal stem cells are precursors for osteocytes, chondrocytes and adipocytes. These cells are currently tested in a broad range of clinical trials for tissue engineering.  We are working on optimized culture conditions and definition of molecular markers for quality control of mesenchymal stem cells. Alternatively these cells can be derived from induced pluripotent stem cells, which may result in more standardized cell preparations.

Mesenchymal stem cells that were differentiated towards (A) chondrocytes, (B) adipocytes and (C) osteocytes (Franzen et al., 2017). Scale bar: 100 µm.

It is fascinating that even individual cells can sense and respond to mechanical stimuli. In cooperation with various institutes for material research we are investigating how biomaterials, surface topography, and elasticity impact on growth and differentiation of stem cells. We want to understand how cell-material and cell-cell interactions influence self-organization, pluripotency and specification of cells in culture.

(A) Generation of nanostructures with a laser beam. (B) Induced pluripotent stem cells grow along the nanostructures (Abagnale et al., 2017).

Aging of the organism as well as replicative senescence during culture expansion of stem cells is associated with various functional and molecular changes. Methylation of cytosines in the DNA can be used to reliably track the state of cellular aging. We want to understand the molecular mechanisms and the functional relevance of this “epigenetic clock”.

(A) Donor age of blood samples was predicted based on DNA methylation patterns and the predictions correlate well with the chronological age (Lin et al., 2016). (B) Mesenchymal stem cells of early passage display longer telomeres than those of late passage (Hänzelmann et al., 2015).

Hematopoietic stem cells have been successfully transplanted for more than 50 years. We are analyzing how culture expansion and hematopoietic engraftment impact on the epigenetic makeup. Furthermore, we differentiate induced pluripotent stem cells towards hematopoietic lineages that may be used for disease modeling and address the relevance of specific genes and splice variants (e.g. by CRISPR-Cas9n technology).

(A) Culture expansion of hematopoietic stem and progenitor cells (CD34+ cells, HSCs) on plastic or mesenchymal stromal cells (MSCs). (B) HSCs maintain a stem cell like phenotype for a higher number of cell divisions when co-cultured with MSCs (adapted from Weidner et al., 2013).

Cancer initiating cells are often derived from stem and progenitor cells. We investigate how this process is associated with specific epigenetic changes – particularly in different types of leukemia. Furthermore, we investigate epigenetic characteristics of the non-malignant cancer-associated fibroblasts, which play a crucial role for tumor development.

(A) Bone marrow smear of a leukemia patient. (B) Acute myeloid leukemia patients can be stratified by the DNAm level of only a single CpG site (Božić et al., 2015).

Cellular differentiation is governed by epigenetic changes – and hence the epigenetic makeup is ideally suited to characterize cells. We have developed DNA methylation signatures to define cell populations, e.g. pluripotent cells (Epi-Pluri-Score), mesenchymal stromal cells (Epi-MSC-Score), blood counts (Epi-Blood-Count), or prognostic biomarkers in various diseases. We can also provide service for these assays with a spin-off company Cygenia (www.cygenia.com).

(A) The potential of iPSCs can be validated by the Epi-Pluri-Score (Lenz et al., 2015). (B) The blood cell composition can be estimated based on DNA methylation of 6 CpG sites (Frobel et al., 2017).