Human pluripotent stem cells: an emerging model in developmental biology

Abstract

SummaryDevelopmental biology has long benefited from studies of classic model organisms. Recently, human pluripotent stem cells (hPSCs), including human embryonic stem cells and human induced pluripotent stem cells, have emerged as a new model system that offers unique advantages for developmental studies. Here, we discuss how studies of hPSCs can complement classic approaches using model organisms, and how hPSCs can be used to recapitulate aspects of human embryonic development 'in a dish'. We also summarize some of the recently developed genetic tools that greatly facilitate the interrogation of gene function during hPSC differentiation. With the development of high-throughput screening technologies, hPSCs have the potential to revolutionize gene discovery in mammalian development. Key words: Human pluripotent stem cells, Directed differentiation, Gene targeting, High-throughput screening IntroductionHuman pluripotent stem cells (hPSCs), which include human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), can self-renew indefinitely in culture while maintaining the ability to become almost any cell type in the human body (Takahashi et al., 2007;Thomson et al., 1998;Yu et al., 2007). The potential of using hPSCs for cell replacement therapy and disease modeling has been discussed extensively (Wu and Hochedlinger, 2011). This Review focuses on an equally important, yet often overlooked, aspect: using hPSCs to gain insights into human embryonic development. Although this potential has been long recognized (Keller, 2005;Pera and Trounson, 2004), it is only beginning to be realized, owing to advances in both in vitro differentiation approaches and genetic manipulation tools in hPSCs. In this Review, we summarize the latest progress in this nascent, yet rapidly advancing, field and discuss future prospects and potential challenges of using hPSCs for studies of developmental biology. First, the strengths and limitations of classic model organisms are discussed to highlight the need for a new model. Second, we illustrate how hPSCs can be used to recapitulate defined steps of embryogenesis, and we discuss how hPSC-based studies can lead to novel insights into human development. Next, we review new genetic tools that can be applied to interrogate gene function during the in vitro differentiation of hPSCs. Finally, the potential of using hPSCs for discovery-driven research is discussed.This Review focuses primarily on work performed using hPSCs, with occasional references to studies using mouse pluripotent stem cells when comparable studies are not yet available in human cells; work from both hiPSCs and hESCs is discussed, although more examples stem from hESCs, owing to their more-frequent use in differentiation experiments. Nonetheless, because of the high degree of similarity between hESCs and hiPSCs (Yamanaka, 2012), it is likely that the general strategies and most conclusions will apply to both hESCs and hiPSCs. The need for a new model systemA main challenge in biology is to understa...

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