Research in detail
This research group focuses on understanding the mechanisms that control cell fate decisions in the early mammalian embryo. For this we study how lineage specific differentiation and cell survival are coordinated during mammalian embryogenesis using genetically manipulated embryos and embryonic stem cells.
During the first stages of pluripotent stem cell differentiation, when the precursors of all organs and tissues are formed, embryonic cells undergo a dramatic series of changes, that include changes in their transcriptional and epigenetic landscape, changes in the signalling environment that they are exposed to, and metabolic changes. The coordination of all these events requires not only very careful orchestration in the developing tissues, but also relies on the existence of very stringent controls to ensure the elimination of abnormal or aberrant cells. Our laboratory studies the signalling pathways, transcriptional events, cellular metabolic pathways and the epigenetic mechanisms that regulate differentiation. By integrating this information into the context of the developing embryo we hope to achieve an understanding of how multiple cellular and molecular inputs are coordinated during the differentiation process and to apply the knowledge we obtain to regenerative medicine.
Our studies have helped elucidate the signals that initiate anterior pattern in the early embryo (e.g. Di Gregorio et al., Development 2007; Clements et al., Current Biology 2011; Stuckey et al., Development 2011 and PloS One 2011; Trichas et al., PLoS Biology 2011 & 2012) and allowed us to apply this knowledge to direct the differentiation of pluripotent cells into neuronal subtypes which are relevant to regenerative medicine, and that had previously been refractory to isolation in vitro (Cambray et al., Nature Communications 2012). Furthermore, our work on the checkpoints that ensure cell fitness during embryonic differentiation have identified a key role for microRNAs in establishing the apoptotic threshold of primed pluripotent stem cells (Spruce et al., Developmental Cell 2011; Pernaute et al., Genes & Dev 2014).Additionally we have identified a conserved role in mammals for cell competition, a general fitness sensor mechanism that controls cell fate in a wide variety of contexts. These studies demonstrated that during early development, cell competition monitors the fitness of pluripotent stem cells, and therefore acts as a quality control for the fitness of he pluripotent stem cell pool (Sancho et al., Developmental Cell 2013).
Our laboratory focuses on regenerative biology, a rapidly growing branch of science that explores the mechanisms employed by different organisms to replace lost or damaged tissues and organs. The regeneration of organs and appendages after injury occurs in diverse animal species but appears to be a remote and exceptional attribute in mammalian organs. One of the major problems in mammalian tissue regeneration is the paucity of damaged tissue to support cell survival and proliferation. Inflammatory responses leading to fibrous tissue formation and production of oxidative stress species generate a non-permissive environment for cell migration and proliferation/differentiation, reducing the possibility of stem cell progenitors, as well as circulating stem cells, to properly benefit the injured organ. Mammalian cardiac tissue has a particularly limited regenerative capacity. Reversal of cardiac damage entails remodeling of scar tissue, generation of new contractile myocytes and formation of a capillary network able to support the greater demands of the new regenerating myocardium.
Cardiac Myogenesis, Death and Regeneration
Professor Schneider's research concerns the problem of cardiac muscle cell number, in its fundamental and applied dimensions. The capacity of mammals' heart tissue to undergo self-repair is quite meagre by comparison to newts or certain fish, virtually thwarting functional recovery from heart attacks and other forms of human heart disease. Consequently, one theme in Professor Schneider's lab has been to dissect genetic circuits that impose the irreversible block to cell cycling in “post-mitotic” ventricular muscle. By developing Cre/lox systems that delete genes exclusively in cardiomyocytes, he was able to prove that growth arrest in cardiac muscle specifically required the “pocket protein” Rb, acting in concert with the related protein p130.
A second aspect concerns the drivers of cardiac muscle cell formation in the embryo, such as the Wnt and bone morphogenetic protein families and their downstream effectors. Using genome-wide expression profiling and RNA interference, Professor Schneider demonstrated in mouse embryonic stem cells an essential role for Sox17 in cardiac myogenesis driven by these signals. Sox17 acts largely by controlling Hex, a transcription factor required for endodermal cells to make the heart-inducing factors that pattern primitive mesoderm.
Third, an inverse approach to rescuing cardiac muscle cell number is to alleviate cell death. Professor Schneider showed that forced expression of Bcl-2 or telomerase reverse transcriptase in mouse myocardium reduces infarct size. These are good days to have a heart attack, if you are a mouse.
Fourth, he has identified multiple protein kinases that are activated by cardiac stress pathways, promote cardiac myocyte apoptosis, and are potential nodal control points for cardiac cell death.
In short, the goal is not just fundamental discoveries in cardiac biology, but also their conversion, over time, into testable theories of cardiac pathogenesis and workable therapies. Basic research projects are available for the many proteins studied (Cdk9, Cdk7, MAT1, TAK1, MAP4K4, Sox17, Hhex). Basic and applied projects are available on heart-derived progenitor cells for cardiac repair, directed differentiation, and cardiomyocyte apoptosis as therapeutic targets.