Welcome to the Mendjan Lab
Our group explores the mechanisms that underlie tissue patterning, self-organisation and functional maturation in two models of mesodermal organogenesis – the embryonic heart and the adipose organ. The embryonic heart, the first functional organ to form in humans, develops from patterned endocardial, myocardial and epicardial progenitors of the mesoderm germ layer. These organ precursors crosstalk and co-differentiate resulting in a rapid succession of self-organising events (Figure 1). Similarly, the adipose organ emerges as precursors of adipocytes, vasculature and peripheral nerves interact and co-develop into functionally distinct white and brown adipose tissues (Figure 2). Despite insights about mesoderm, cardiac and adipose development, it remains a major challenge to molecularly discern how signalling and gene expression translate into patterning, structural self-organisation and functional maturation of mesodermal organs.
The most common human birth defects comprise aberrations during the interaction and co-specification of mesodermal precursors as cardiogenesis unfolds, resulting in congenital heart disease. Moreover, some of the most widespread disorders in adults are obesity, diabetes and cardiovascular complications, which arise from a shift in balance of adipose tissue type, changes in adipose tissue vascularisation and innervation, and the pathological crosstalk between the adipose organ and the cardiovascular system. Therefore, insights into the mechanisms underlying organogenesis in humans will advance the development of new treatment strategies for these disorders.
Pluripotent stem cell (PSC) differentiation and derivation of organoids have revolutionised human developmental biology and opened new avenues to regenerative medicine. However, we are still far from mimicking the fascinating complexity of organogenesis, and we understand little of the molecular mechanisms that drive it. While hPSC can be readily differentiated into multiple cell types of an embryonic organ like the heart, the key self-organising processes of heart tube formation, looping, trabeculation, ballooning, septation and functional maturation remain elusive. Further challenges are in vitro vascularisation and innervation of organ-like structures, which are essential hallmarks of organogenesis and functionality, as typified by white and brown adipose tissues.
Our guiding principle is that the only way to fully understand the molecular complexities of organogenesis in vivo is by recreating the steps of organ formation in vitro.
Our objective is to discover how signalling and gene expression drive patterning, self-organisation and functional maturation of mesodermal organ-like structures, and how mutations cause disorders of human organogenesis. To achieve these aims, we systematically apply principles of in vivo development and translate them in vitro.
Our lab philosophy is to tackle these challenges from multiple experimental and methodological angles. We combine 2D and 3D stem cell differentiation into multiple lineages (Figure 3, Movie), and perturbations by small molecules, CRISPR, shRNA and degrons, with quantitative imaging as well as with global epigenome, transcriptome and proteome analysis.
Bertero, A., Madrigal, P., Galli, A., Hubner, NC., Moreno, I., Burks, D., Brown, S., Pedersen, RA., Gaffney, D., Mendjan, S., Pauklin, S., Vallier, L. (2015). Activin/nodal signaling and NANOG orchestrate human embryonic stem cell fate decisions by controlling the H3K4me3 chromatin mark. Genes Dev. 29(7):702-17
Mendjan, S., Mascetti, VL., Ortmann, D., Ortiz, M., Karjosukarso, DW., Ng, Y., Moreau, T., Pedersen, RA. (2014). NANOG and CDX2 pattern distinct subtypes of human mesoderm during exit from pluripotency. Cell Stem Cell. 15(3):310-25
Pedersen, RA., Mascetti, V., Mendjan, S. (2012). Synthetic organs for regenerative medicine. Cell Stem Cell. 10(6):646-7
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(8):1339-49
Mendjan, S., Taipale, M., Kind, J., Holz, H., Gebhardt, P., Schelder, M., Vermeulen, M., Buscaino, A., Duncan, K., Mueller, J., Wilm, M., Stunnenberg, HG., Saumweber, H., Akhtar, A. (2006). Nuclear pore components are involved in the transcriptional regulation of dosage compensation in Drosophila. Mol Cell. 21(6):811-23