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Pluripotent stem cells

We (the Stem Cell Biology Unit) do research on embryonic stem cells and induced pluripotent stem cells of the common marmoset monkey (Callithrix jacchus). In collaboration with our partners we work on the directed differentiation of these pluripotent stem cells into clinically relevant cell types. The long-term goal of our work is to develop and evaluate cell replacement therapies in a preclinically relevant non-human primate model.

Embryonic stem cells (ESC) can proliferate almost indefinitely and develop into any kind of cell – in other words: they are pluripotent. Mouse ESC were first published in the early 80s of the last century while the first monkey ESC were published in 1995 and the first human ESC in 1998. Although research with embryonic stem cells is extremely divers, basically three key aspects can be defined:

(1) Cell replacement therapy,
(2) Basic cell and developmental studies and
(3) Toxicity testing (partial replacement of animal studies by cell culture studies using pluripotent ESC).

(c) Debowski
Generation of a stem cell line. Left: An early embryo at the blastocyst stage. Middle: The so-called “outgrowth stage”: The primary cells of the embryo are cultured and propagated in vitro. Right: A colony of embryonic stem cells.

Primates and rodents significantly differ from each other with regard to many aspects: e.g. neurobiology, immunology, (patho-) physiology, reproductive biology, embryology and anatomy. Parts of these differences between rodents and primates are also reflected in the respective ESC cultures. In order to gain novel and clinically relevant insights, it is important to include non-human primates as model organisms in stem cell biology.

Induced pluripotent stem cells

An adult organism mainly is composed of so-called somatic cells. Unlike embryonic stem cells (see above), these cells are not pluripotent but restricted to fulfill specific functions in the respective tissue or organ they reside in (e.g. muscle cells or neurons). For a long time it was assumed that this specialization of a cell is irreversible. However, in 2006, when reprogramming of somatic cells succeeded, this concept was shown not to be valid any more. By introducing only four transcription factors into murine fibroblasts (fibroblasts are cells originating from the connective tissue present in skin or other organs), these cells could be reverted into a pluripotent state. Since these cells regained the ability to develop into any kind of specialized cell type, they were named induced pluripotent stem cells (iPSC). The suitablility of iPSC in cell replacement therapy has been demonstrated e.g. in a sickle-cell anemia mouse model.

(c) Debowski
Left: Cells of connective tissue (fibroblasts) in culture. Middle: Genetic elements which are introduced into fibroblasts and induce pluripotency. Right: Induced pluripotent stem cells resulting from fibroblasts.

With regard to clinical application of cell replacement therapy, ethical as well as technical problems arising from the isolation and usage of embryonic stem cells could be circumvented by using patient-specific iPSC. Stem Cell Biology Unit generates iPSC from the common marmoset monkey (Callithrix jacchus). We employ non-viral techniques and methods like the piggyBac system for reprogramming. In order to apply these iPSC in preclinical studies for cell replacement therapies, they are differentiated into various cell types in collaboration with different partners like the Deutsches Zentrum für Herz-Kreislaufforschung.

Warthemann R, Eildermann K, Debowski K, Behr R (2012):
False-positive antibody signals for the pluripotency factor OCT4A (POU5F1) in testis-derived cells may lead to erroneous data and misinterpretations.
Mol Hum Reprod 18(12): 605-612.

Müller T, Fleischmann G, Eildermann K, Mätz-Rensing K, Horn PA, Sasaki E, Behr R (2009):
A novel embryonic stem cell line derived from the common marmoset monkey (Callithrix jacchus) exhibiting germ cell-like characteristics.
Hum Reprod. Jun;24(6):1359-1372.

Behr R, Heneweer C, Viebahn C, Denker HW, Thie M (2005):
Epithelial-mesenchymal transition in colonies of rhesus monkey embryonic stem cells: a model for processes involved in gastrulation.
Stem Cells. Jun; 23(6): 805-816.