Prof. Roger Pedersen
Mechanics of Mesoderm Differentiation in Mammalian Pluripotent Stem Cells
Anne McLaren Laboratory for Regenerative Medicine
Department of Surgery, University of Cambridge, Pedersen Group Members
Roger Pedersen is Director of Research in Regenerative Medicine in the Department of Surgery and the Anne McLaren Laboratory for Regenerative Medicine. After receiving a PhD in biology from Yale University in 1970, he specialised in mammalian embryology. From 1971, he headed a research programme at the University of California, San Francisco, exploring developmental potency and cell fate in early mouse development. That work, together with clinical service in assisted reproductive therapies, led him to studies on human embryos and stem cells. In 2001, confronting federal funding restrictions for this work, he relocated to the University of Cambridge, where he heads a team of researchers devoted to delivering human embryonic stem cells to clinical use.
Tel: 01223 763236
Our current research focuses on understanding how pluripotent mammalian stem cells maintain their undifferentiated state and undergo differentiation into mesoderm, reflecting an enduring interest in the emergence of diversity during mammalian 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 signaling 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 BRACHYURY and CDX2 genes as key mediators of embryonic and extraembryonic lineage differentiation in hESCs and EpiSCs.
Our focus on mesoderm led us to molecular pathways for early human cardiomyocyte differentiation, with a goal of understanding the transcriptional networks responsible for a left ventricular cardiomyocyte identity and using this to generate more homogeneous cardiomyocyte populations for therapeutic applications and drug discovery. We also study epigenetic status as a property that distinguishes mouse ESCs or induced pluripotent stem cells (which lose genomic imprints during culture) from EpiSCs and hESCs (which maintain genomic imprints). Thus, we emphasise both developmental genetic and epigenetic studies as instruments for understanding lineage-specific regulation of gene expression. Taken together, these studies should significantly accelerate the progression from basic stem cell research to clinical applications.
Plain EnglishWe are studying the differentiation of pluripotent stem cells into mesoderm. Our main experimental focus is on human embryonic stem cells, though we also study human induced pluripotent stem cells and mouse epiblast-derived stem cells. We hope to understand how unspecialised cells take their first steps and whether this can set them in the direction of their ultimate specialisation, especially blood and cardiac cell types. Potential applications of our work include blood cells for transplantation and improved yields of defined cardiac cell types.
- Bernardo AS, Faial T, Niakan KK, Ortmann D, Gardner L, Senner CE, Callery EM, Trotter MW, Hemberger M, Smith JC, Moffett A, Bardwell L and Pedersen RA. (2011) BRACHYURY and CDX2 mediate BMP-induced differentiation of human and mouse pluripotent stem cells into embryonic and extraembryonic lineages. Cell Stem Cell 9: 144-155.
- Chng Z, Teo A, Pedersen RA, Vallier L. (2010) SIP1 blocks mesendoderm differentiation induced by Activin/Nodal signaling in human embryonic stem cells. Cell Stem Cell, 6: 59-70.
- Vallier L, Mendjan S, Brown S, Chng Z, Teo A, Smithers LE, Trotter MW, Cho CH, Martinez A, Rugg-Gunn P, Brons G, Pedersen RA. (2009) Activin/Nodal signalling maintains pluripotency by controlling Nanog expression. Development 136: 1339-1349.
- Smith JR, Maguire S, Davis LA, Alexander M, Yang F, Chandran S, ffrench-Constant C, Pedersen RA. (2008). Robust, persistent transgene expression in human embryonic stem cells is achieved with AAVS1-targeted integration. Stem Cells. 26: 496-504.
- Brons, IGM, Smithers LE, Trotter MW, Rugg-Gunn P, Sun B, Chuva de Sousa Lopes SM, Howlett SK, Clarkson A, Ahrlund-Richter L, Pedersen RA and Vallier L. (2007) Derivation of pluripotent epiblast stem cells from mammalian embryos. Nature 448: 191-195.