Investigating monogenic and complex diseases with pluripotent stem cells

Key Points Human genetic studies have revealed the molecular basis of countless monogenic diseases but have been less successful in dissecting complex multigenic conditions. Embryonic stem cells and induced pluripotent stem cells are new tools that offer promise for determining the functional consequences of genetic variation. Pluripotent stem cells (PSCs) are inexhaustible, scalable and physiologically native material for experimentation. Robust and efficient differentiation towards selected cell and tissue types is one of the largest barriers to studying diseases in specific tissues, but progress is being made at a rapid pace. We review selected PSC disease models that have been successfully applied to the study of more complex diseases. We describe the multiple ways in which the challenge of studying non-cell-autonomous phenotypes might be addressed, such as through the use of co-culture experiments, organoids and human–mouse chimaeras. The advent of genomic and sequencing technology will prove useful in describing the genetic profile of large sets of patient-derived cells. The contribution of environmental and epigenetic factors to complex diseases may be equal to or greater than the contribution of genetics. PSCs can be used to probe the contribution of these factors. It is difficult to perform targeted genetic modifications in human PSCs; the use of less-sophisticated genetic reagents and naturally occurring mutations from patient-derived cells are thus required. Low-penetrance, modest and late-onset phenotypes are major challenges when studying complex or polygenic factors in any setting, including stem cells. Thanks to improved functional assays and more effective protocols for directed tissue differentiation, pluripotent stem cells are proving increasingly useful for uncovering the genetic and epigenetic basis of monogenic and complex diseases, and for investigating the functional consequences of genetic variation. Human genetic studies have revealed the molecular basis of countless monogenic diseases but have been less successful in associating phenotype to genotype in complex multigenic conditions. Pluripotent stem cells (PSCs), which can differentiate into any cell type, offer promise for defining the functional effects of genetic variation. Here, we recount the advantages and practical limitations of coupling PSCs to genome-wide analyses to probe complex genetics and discuss the ability to investigate epigenetic contributions to disease states