Stem Cells and Human Mesodermal Organogenesis
Key human organs and tissues including the heart, blood, fat, muscle, and vessels are derived from the embryonic germ layer called mesoderm. The fascinating journey from early mesodermal precursors to functioning organs is not well understood, and in particular not for human development and disease. Our group is using stem cells to decipher the molecular control of human mesodermal organogenesis and pathogenesis. Based on molecular and developmental insights, our aim is to generate and study functional mesodermal tissues and organ-like structures in a dish.
Pluripotent stem cells have revolutionised human developmental biology and opened new avenues to regenerative medicine. Their extraordinary qualities include self-renewal in culture, amenability to genetic modifications and the potential to differentiate into specialised cell types, including mesodermal tissues (Figure 1). This makes them a powerful tool for the purpose of a) study the molecular control of human mesodermal development and disease, b) discover and testing drugs, and c) using them in transplantation therapy. We are employing pluripotent stem cells to investigate the following questions:
How do molecular interactions control cardiac and somitic mesoderm specification?
Human congenital disorders and other pathologies arise early in embryonic development due to mutations and deregulation of key genes. Many of these genes operate in regulatory networks that control mesoderm induction, patterning ?and specification of mesodermal subtypes (e.g. cardiac, lateral plate and somitic) into distinct progenitors and tissues (Figure 2). We can mimic mesodermal gene regulatory networks in vitro by using defined signals and specific timing to differentiate pluripotent stem cells into therapeutically relevant cells including cardiomyocytes, vascular cells, chondrocytes and adipocytes.
Our aim is to explore the interactions between signalling, epigenetic, RNA and transcription factor networks that drive cardiac and somitic mesoderm specification. We use powerful genetic (mutagenesis, tagging and fluorescent reporters), imaging (3D and live), proteomic (interaction and phospho mass spectrometry) and computational methods (regulatory networks analysis) to elucidate how specification works and how it goes wrong in disease. Finding answers to these fundamental questions will greatly enhance our understanding of human development and disclose new avenues of clinical application.
How do tissue interactions drive cardiac and somitic organogenesis?
In the vertebrate embryo, signalling and interactions between different progenitor tissues drive organogenesis. For instance, the heart is developing from interacting lateral plate mesoderm tissues that give rise to cardiac muscle, vasculature and pacemaker cells. Similarly, growing fat depots depend on interactions between (pre)-adipocytes and vascular cells. The crosstalk between different cell types is vital for the derivation, self-organisation and growth of organ-like structures in vitro and during organ regeneration in vivo.
Our aim is to understand how tissues communicate and thereby control human organ morphogenesis, growth and functional maturation. Our approach is to combine distinct lateral plate and somitic progenitors that express fluorescent reporters, thus permitting the imaging, physical separation and molecular analysis of interacting tissues (Figure 3). We also explore how perturbed signalling interactions between tissues result in defective organogenesis when mutant tissues are combined. Our key goal is to mimic human cardiac and somitic congenital defects in a dish and understand the biochemistry connecting mutant genotypes to clinically relevant phenotypes. Functional and molecularly defined human mesodermal organ-like structures will be invaluable for effective disease modelling and drug discovery.