Pluripotent stem cell models of human heart disease

Abstract

Understanding the molecular basis of many cardiac diseases has been hampered by the lack of appropriate in vitro cell culture models that accurately reflect the human disease phenotypes. In the past few years, remarkable advances in stem cell biology have made possible this long-standing ambition-the generation of human and even patient-specific cellular models of diseases. Combined with other novel technologies in the fields of human genetics, tissue engineering, and gene-targeted manipulation, disease modeling with pluripotent stem cells has the promise to influence modern cardiovascular medicine on several fronts: molecular understanding of pathological mechanisms, early diagnosis, drug development, and effective treatment.

Figure 1.

Strategies for obtaining human disease-specific cardiac cells and their use in disease modeling and drug screening. Human embryonic stem cells (hESCs) can be derived from human normal blastocysts and then genetically targeted to introduce a disease-associated mutation by homologous recombination. Alternatively, patient-specific induced pluripotent stem cells (iPSCs) can be derived directly from patient somatic cells (e.g., skin fibroblasts or blood cells) by different reprogramming methods. Either type of disease-specific pluripotent stem cells can be differentiated in vitro into all kinds of cardiac cells (cardiac myocytes, cells of the conductive system, smooth muscle cells, and endothelial cells) through a cardiovascular progenitor population. Differentiated cardiac cells can then be used in disease modeling to understand the molecular mechanisms underlying disease phenotypes and in drug screening to determine the effects of candidate drugs or new compounds and identify target pathways. Examples of different cellular readouts are presented.

Figure 2.

Pathways and factors involved in cardiac differentiation of human pluripotent stem cells in vitro. Differentiation of human pluripotent stem cells (hPSCs) into the cardiovascular lineages (cardiomyocytes, smooth muscle cells, and endothelial cells) is a multistep process that involves initial epithelial to mesenchymal transition, mesoderm induction and specification, cardiac specification and differentiation, and functional maturation. Each of these steps is temporally controlled by specific signaling pathways and factors, and each cellular intermediate is characterized by the expression of different markers; surface markers are marked with an asterisk.

Figure 3.

The limitations of pluripotent stem cells in disease modeling and emerging solutions for identifying disease-related phenotypes.