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Abstract

Abstract

Our research focuses on understanding how pluripotent mammalian stem cells maintain their undifferentiated state and undergo differentiation in culture – this reflecting my enduring interest in the emergence of diversity during mouse gastrulation.

In recent studies we have examined the role of transforming growth factor family members in both pluripotency and differentiation. This involved analysis of the signalling cascade induced by treating hESCs with Activin or Nodal, determining how their response to these growth factors maintains hESC pluripotency. We started by developing chemically defined culture conditions in which the activities of specific growth factors could be identified and studied in a controlled manner. We then carried out a detailed analysis of the roles of Smad proteins (Smad2 and Smad3) as direct regulators of Nanog, which in turn blocks an hESC default differentiation into neuroectoderm. These studies led to our discovery of a novel type of pluripotent epiblast stem cell (EpiSC) from the late epiblast layer of mouse and rat embryos. EpiSCs share many features with hESCs, and subsequent work supports our hypothesis that hESCs are the human counterparts of EpiSCs, with similar responses to growth factors and mechanisms of pluripotency and differentiation.

In our most recent work we have focused on the role of bone morphogenetic protein (BMP)-4 in the cell fate decision between endoderm and mesoderm, demonstrating the similarity of BMP-induced hESC and EpiSC differentiation to mesoderm induction during mouse gastrulation. This work reveals the importance of BRACHYURY and CDX2 genes as key mediators of embryonic and extraembryonic lineage differentiation in hESCs and EpiSCs. Our focus on mesoderm leads us on to molecular pathways for early human cardiomyocyte differentiation, with a goal of understanding the transcriptional networks responsible for cardiomyocyte identity and using this to generate more homogeneous cardiomyocyte populations for therapeutic applications and drug discovery. Taken together, these studies should significantly accelerate the progression from basic stem cell research to clinical applications.

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/content/papers/10.5339/qproc.2012.stem.1.6
2012-02-01
2019-08-20
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http://instance.metastore.ingenta.com/content/papers/10.5339/qproc.2012.stem.1.6
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  • Received: 05 Mar 2012
  • Accepted: 28 Mar 2012
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