Klump Lab
Generation of somatic stem and progenitor cells, in vitro
Our lab tries to understand how blood-forming stem cells (hematopoietic stem cells, HSCs) can be generated, in vitro, for
future tailored cell- and gene therapy of patients.
RESEARCH TOPICS:
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.
RESEARCH TOPICS:
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
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 hematopoietic development and
expansion of HSPCs
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.
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.
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.
latest update: September 2nd, 2021