contractile cardiac tissue - High content drug screening with contractile cardiac tissue

From 01-11-2010 to 31-10-2011

Description

Tissue engineering for in vitro drug-screening applications based on tissue function is anactive area of translational research. Compared to targeted high-throughput drug-screeningmethods that rapidly analyze hundreds of thousands of compounds affecting a single biochemicalreaction or gene expression, high-content screening (HCS) with engineered tissues is morecomplex and based on the cumulative positive and negative effects of a compound on the multiplepathways altering tissue function. It may therefore serve as better predictor of in vivo activity andserve as a bridge between high-throughput drug screening and in vivo animal studies [1].The technology of creating force-generating constructs from skeletal muscle cells waspioneered by prof. Herman Vandenburgh (Brown University). It is based on the use of humanmuscle biopsies, from which new muscle tissue is grown in vitro. Miniaturized muscles areattached to flexible posts, of which the deflection indicates the force generated by the muscle. Anarray of these muscles is used to incubate with different drugs and thus a physiological parameter(muscle strength) can be determined in a high-throughput fashion [1-3]. The technology wassuccessfully used to identify compounds with negative (statins) and positive (IGF1) effects onskeletal muscle force generation [1]. Moreover, the muscle patches can be made for specificdiseases eg. Duchenne muscular dystrophy [3]. To date, this technology has beencommercialized by a spin-off company called Myomics Inc.A similar application with cardiac muscle tissue could be highly valuable. The issue so farhas been that it is hard to obtain cardiac muscle biopsies from a patient and moreover, adultcardiomyocytes are difficult to isolate and expand [4] and not readily amenable for tissueengineering (H. Vandenburgh, personal communication). However with the very recentdevelopments in stem cell technology, it becomes feasible to use a piece of skin (fibroblasts), dedifferentiateto induced pluripotent stem cells and re-differentiate to cardiomyocytes. Screeningfor drug side-effect on heart muscle is an important aspect of drug screening and except for usinganimals, little alternatives are available to assess cardiac muscle force. Ultimately, the potential ofgenerating cardiomyocytes from skin cells can allow for the development of personalizedmedicine in the field of cardiomyopathies.

Team

• Yves Moreau, Co-promoter
• Maumrilio Sampaolesi, Promoter (External)
• Lieven Thorrez, Team member

Financing

Funding: KU Leuven - Internal Funding KU Leuven

Program/Grant Type: IOF - IOF-mandaten: Postdoctoral Fellowships