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Klump Lab

Generation of somatic stem and progenitor cells, in vitro

In all organisms, the constant replenishment of cells lost due to aging and tissue damage is guaranteed by somatic, tissue-resident stem cells. Because of their regenerative potential, these multipotent stem cells are prime targets for the treatment of a plethora of disorders.
Our lab tries to understand how such cells can be generated, in vitro, for future tailored cell- and gene therapy of patients.


Development of hematopoietic stem- and progenitor cells from pluripotent stem cells, in vitro
Pluripotent stem cells, such as embryonic stem (ES-) or `reprogrammed´, induced pluripotent stem (iPS-) cells, are defined by their capability to develop towards cells of all three germ layers, ecto-, meso- and endoderm. In contrast to the mesodermal, multipotent HSCs, these cells can be stably propagated in culture and are relatively easily amenable to genetic intervention by homologous recombination. Hence, patient-specific `autologous´ iPS-cells are especially attractive for gene repair and subsequent directed differentiation towards HSCs, in vitro. Because  differentiation of pluripotent stem cells appears to autonomously recapitulate many aspects of the developing embryo, this model is also very useful for studying the control of cell fate decisions crucial for blood stem cell development, in vitro. We are studying in vitro hematopoiesis using pluripotent stem cells from mice and humans.

Funded by the Deutsche Forschungsgemeinschaft (DFG)

The homeodomain transcription factor HOXB4 and its impact on
early hematopoietic progenitor development

To generate multipotent hematopoietic stem- and progenitor cells (HSPCs), in vitro, we take advantage of the homeodomain transcription factor HOXB4, which supports hematopoietic development of differentiating pluripotent stem cells (such as ES- or iPS-cells) when expressed ectopically and also mediates expansion of adult HSPCs, in vitro and in vivo. A deeper understanding of the molecular pathways influenced by HOXB4 during pluripotent stem cell differentation will help us to substantially improve protocols for the in vitro generation of HSPCs and, thus, allow us to omit ectopically expressed supportive transcription factors in future.

Deciphering the mechanism(s) of HOXB4 action during hematopoetic development and expansion of HSPCs
The molecular mechanisms how homeodomain transcription factors control self renewal and differentiation of hematopoietic stem and progenitor cells is still far from being clear. Although constitutive ectopic HOXB4 expression biases hematopoietic differentiation towards myelopoiesis and away from lymphopoiesis, it mediates a `benign´ HSC expansion without leading to leukemia, as observed with other HOX proteins, such as HOXB3 or HOXA10.
We have demonstrated that HOXB4 alters the sensitivity of many signaling pathways by changing the regulation of key genes involved in these processes. In turn, the activity of HOXB4 (i.e. transcriptional activation or repression of its target genes) appears to depend on the cell type itself and its context, the (micro)environment.
To gain a better understanding of the activities of this versatile transcription factor on HSC formation, self renewal and differentiation, we are identifying and studying its posttranslational modifications, protein interaction partners and their influence on target gene binding and expression.

Limbal Stem Cells of the Human Cornea
Limbal epithelial stem cells (LESC) of the human cornea are essential for constant regeneration of the eye surface. They reside in the outer rim of the cornea, termed `limbus´. Their loss ultimately leads to blindness. Thus, they are a prime target cell for the treatment of disease- or accident-related vision loss.
Our main goals are:
- the enrichment and in depth characterization of this ill-defined
stem cell population.
- the de novo generation of patient-specific, autologous limbal epithelial stem cells from induced pluripotent stem cells (iPSCs) for generating transplantable corneal epithelium tissue, in vitro.

in cooperation with Prof. Daniel Meller, M.D.
Clinics for Ophtalmology, University Hospital Jena

Funded by the Deutsche Forschungsgemeinschaft (DFG)

Disease modeling based on induced Pluripotent Stem Cells (iPSCs):
generation of iPSC-derived neurons for understanding
Angelman Syndrome, in vitro

in cooperation with Laura Steenpass, Ph.D.
Institute for Human Genetics, University Hospital Essen.

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latest update: February 17, 2018