Spagnoli Lab

Spagnoli Lab

Molecular and Cellular Basis of Embryonic Development

Profile

Understanding the establishment of cellular identity is a major goal in stem cell biology and regenerative medicine. The aim of our research is to elucidate the mechanisms regulating cellular identity and plasticity of key metabolic organs, such as the liver and the pancreas.

Our group is interested in understanding the interplay between extrinsic signals and intrinsic determinants in establishing and maintaining cell identities. We use a combination of genetic approaches with genomic strategies and imaging in mouse embryos and stem cells to study how distinct cell types, such as liver and pancreas, arise from common progenitors and acquire specialized shape to form functional organs.

What is the gene regulatory network upstream of this fate decision between liver and pancreas? Is the establishment of distinct cellular identities and morphogenetic programs interdependent? How plastic are these cellular states? Can we harness cell plasticity between liver and pancreas towards novel regenerative therapies for diabetes?

Ultimately, the long-term goal of our research is to establish a paradigm for engineering cell identity in regenerative medicine, bridging basic science and clinical research.

Research

A fundamental question in developmental biology is how a specialized tissue originates from a pluripotent precursor cell in the embryo. The endoderm germ layer gives rise to a number of vital organs in our body, including the lungs, liver, pancreas and intestine.

This remarkable diversity derives from a homogenous and multipotent precursor cell population. We are interested in understanding the mechanisms that pattern and establish competence within anterior embryonic endoderm in order to progressively specify the pancreatic organ domain.

In addition, we focus on spatio-temporal mechanisms that restrict specification of the pancreas versus neighboring tissues, such as the liver. A complete understanding of these early events will provide insights into the development of these organs. Finally, this information might be crucial for advances in regenerative medicine strategies for the treatment of incurable diseases, such as diabetes.

In vivo lineage analysis of pancreatic and hepatic precursor cells

 

One main focus of our laboratory is to investigate how pancreatic versus hepatic fate decision occurs in the endoderm at both the cellular and molecular level. To conduct a comprehensive in vivo analysis of the hepatic-pancreatic lineage in the mouse embryo, we use transgenic reporter models that express fluorescent proteins under the control of lineage-specific promoters. We are using these new genetic tools to: i. address in vivo and in vitro if the liver and pancreas arise from a common bipotent precursor; and ii. trace and molecularly profile the presumptive precursor cell and its descendants in the mouse embryo. All together, these experiments will determine how the hepatic-pancreatic lineage is established in vivo, whether a bipotent endodermal precursor exists, and provide us with its molecular signature.

Pdx1 E9.5 mouse in situ

 

Molecular mechanisms controlling pancreas versus liver fate decision

 

Hepatic and pancreatic endoderm share a common set of intrinsic regulatory factors, such as the FoxA and GATA transcription factors, and are exposed to the same extrinsic signals, FGF and BMP. However, it remains unclear how the same factors can activate pancreatic genes, such as Pdx1 and Ptf1a, in the future pancreas, without inducing them in hepatic progenitors; and analogously, they enable liver development, but not pancreatic development in the hepatic endoderm. Both intrinsic and extrinsic regulators of this cell fate decision are under study in our laboratory. All together, these experiments will define developmental regulators that are able not only to specify one fate, but also antagonize the other (eg. pancreatic versus hepatic). This knowledge will be crucial for defining lineage reprogramming strategies of liver to pancreas toward a new cure for diabetes.

Novel signals guiding endodermal progenitors toward pancreatic fate

 

In another line of research, we are investigating molecular players that act as morphogenetic factors during early pancreatic development. In the developing pancreas, the branching epithelium is organized in discrete domains, delineating one specific domain of progenitor cells at the tip of the branches. Ongoing projects in the lab aim at understanding how morphogenesis controls progenitor cell proliferation and different cell types specification.

Branching pancreatic epithelium

Publications

Dr. Francesca Spagnoli
Dr. Francesca Spagnoli
Contact
Phone: 9406-2519
Max-Delbrück-Centrum für Molekulare Medizin (MDC)
Robert-Rössle-Str. 10
13092 Berlin, Deutschland
Building 31.1, Room 1061