Kirschner Lab

Cell Cycle Analysis of Embryonic Stem Cells During Renewal and Differentiation

Introduction

ES cells have the capacity to differentiate in vitro in any type of cells and obtaining “ES-like” cells from adult tissues will offer the opportunity to create patient-tailored cells to use in the therapy of many different diseases. Yet, to reach that stage we need a greater understanding of the mechanisms underlying the cell cycle of ES cells and of the processes occurring during their differentiation.

Embryonic stem (ES) cells have atypical cell cycle features including very short gap phases and short generation times. It has also been reported that, in contrast to other cell types, the levels of the APC/C substrates and other cell cycle regulators are constant along their cell cycle. Furthermore, it has been shown that the pocket proteins pRb and p107 are constantly phosphorylated and inactivated. Because in many embryonic systems differentiation and proliferation are often closely correlated, the unusual properties of the ES cell cycle may be associated with the ability to preserve the undifferentiated state.

Ongoing Research

I am studying the regulation of Cdk and APC/C activities in murine embryonic stem cells (mESC) and how their perturbation affects pluripotency and cell cycle regulation.

Moreover, I am performing a screen (together with Sean Irwin) to identify and characterize the molecular processes occurring during differentiation.

The studies proposed here have the potential to greatly increase our understanding of stem cell biology and to unravel the interaction between cell cycle control, differentiation and maintenance of pluripotency. This will ease the task of achieving high quality standards in the derivation of ES-like cells from adult stem cells and in the derivation of a plethora of cell types to use for treatments of many different diseases.

Collaboration

We are collaborating with George Daley’s lab at Children Hospital (Boston) , in particular with post-doc fellow In-Hyun Park.

My Scientific Background

I graduated at the University of Parma, in Italy, with a 5 year-college degree in Molecular Biology and Biochemistry, under the supervision of Prof. Ottonello and Prof. Rossi. I defended a dissertation on the biochemical analysis of eukaryotic transcription factors. Following my graduation, I won a fellowship awarded by the National Eye Institute (US National Institute of Health) for studying the role of nutritional supplements on the onset of age-related cataract. During that period, I progressively became interested in human disease biology, especially the molecular mechanisms of cancer

I then started a Ph.D. program in the laboratory of Dr. Kristian Helin at the European Institute of Oncology (EIO) in Milan, a renowned research center in basic and clinical cancer biology. I worked under the co-supervisions of both Dr Helin and Dr Gordon Peters (Cancer Research UK) and the degree-granting institution was the Open University in the United Kingdom, affiliated to EIO. My project in Dr. Helin’s lab focused on the molecular mechanisms regulating human DNA replication and cell cycle progression in cancer cells. While at EIO, I was also awarded a fellowship of the Italian Foundation for Cancer Research. I defended my dissertation in front of a committee chaired by Prof. Julian Blow. I completed my PhD program with three peer-reviewed papers. In two of these papers we described the roles of the human protein Geminin in assuring only one round of replication per cell cycle and in maintaining genomic stability.

In October 2005 I started my postdoctoral training in the laboratory of Prof. Marc Kirschner.