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Stem cells and cardiac regeneration
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CD133+ - Hematopoietic stem cells

It has been claimed in many publications that the CD133+ sub-population plays a key role in neoangiogenesis (growth of new blood vessels). At the RTC we were able to demonstrate in studies with mice that an intramyocardial application of bone marrow- and umbilical blood-derived cells after ischemic damage had a positive effect on the neoangiogenesis and the survival of the animal in a myocardial infarction model. At this point, we are following up new research directions to unravel the underlying regulation mechanisms.
Stem cell products have to possess a significant functional stability for their clinical application.  Therefore, we conducted appropriate investigations with CD133+ stem cells. A storage period of up to 30 hours did not impact the quality and function of the cell product at all. However, a storage period of 72 hours caused a significant loss of stem cell function. Obviously, these results are important for the therapeutic application of these stem cell products.

It is of critical importance for the efficacy of stem cells that they migrate effectively into the damaged tissue. In this context we established models which can be used for investigations of human CD133+ cell migration: in vitro by the measurement of the impact of SDF-1 in the Boyden-Chamber and in vivo with the help of a xenogenic transplantation model by means of injection into the circulation of the dissected mouse cremaster muscle. At present, these in vitro- and in vivo-models are being further standardized and will be available for investigations of patient samples at the RTC shortly.
 

 
 

CD271+ - Mesenchymal stem cells

Mesenchymal stem cells (MSC) are considered as promising cells for regeneration of heart tissue. Our studies showed that the injection of bone marrow-derived MSC (BM-MSC) in immune-deficient mice undergoing LAD  ligature induced MI revealed significantly improved heart function, reduced cardiac remodeling, and increased survival rate. The mice injected in the same manner with umbilical blood-derived MSC (CD-MSC)  did not show any improvement at all. This is the reason why we con tinue focusing on bone marrow –derived stem cells. The identification of their mode of action is one of the main focuses at the RTC.
Until now, it has been impossible to effectively isolate MSC freshly from bone marrow for the therapeutic application using specific surface markers and their adhesion and differentiation capacity. For the first time, we managed to isolate and to characterize all mesenchymal progenitor cells of a single population from human bone marrow by means of immuno-magnetic methods with help of the surface protein CD271. Furthermore, we were able to identify further mesenchymal markers expressed on freshly isolated CD271+ cells using a multiple staining and we were able to establish this verification procedure as a standardized method. These novel findings may lead to new approaches for the development of optimized therapies.

 
 

Mesp1+ progenitor cells

The direct programming of pluripotent stem cells (also called as „forward programming”) for an effective differentiation to specific cells is a further aim of our group. For this purpose, the decoding  of cardiovascular stem cell differentiation is an essential requirement. In this context the transcription factor Mesp1 has been identified as a central regulatory element for the induction of cardiovasculogenesis. In a comparative analysis of MesP1 and Nkx2.5, we were recently able to manage a cardiovascular programming of murine ES-cells into various different myocardial cell subtypes for the first time. Most recently, we established the Mesp1 promoter for the isolation of common cardiovascular progenitor cells. The next step is to continue decoding the Mesp1-dependent signaling cascades.

 
 

Pacemaker cells

The “Sick-Sinus-Syndrome” is used as a collective term to describe a series of diseases of pacemaker cells in the sinus node of the heart. Besides extensive medicinal and electrophysiological therapies pacemakers are being implanted for the prevention and treatment of cardiac arrhythmia. Although the latter method is well established, pacemakers have weak points, such as their insensibility towards the autonomous nervous system as well as increased risk of infections and injuries of vessels and myocardium.

Furthermore, maintenance of battery and electrodes of these devices must be considered. With the help of cell-based pacemakers (biological pacemaker), which autonomously induce a stable rhythm of heart, some of the mentioned problems could possibly be avoided. In a recently published study we were able to show for the first time that stem cell programming by means of the transcription factor Tbx3 combined with MHC promotor-based selection leads to high-purity pacemaker cell aggregates generated from murine ES cells whose functionality could be proven both in vitro and ex vivo. Our goal is to identify new factors and cell surface molecules with which cell programming and purification approaches can be optimized such that clinical translation can be prepared.

 
   

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Legal The RTC is supported by the BMBF and the State Mecklenburg-Western Pomerania using EU Structural Funds.