Our group explores the mechanisms underlying organogenesis, particularly the formation of the human heart. The embryonic heart, the first functional organ to form in humans, develops by patterning of endocardial, myocardial and epicardial progenitors from the mesoderm germ layer. These organ precursors crosstalk and co-specify resulting in a rapid succession of self-organising events. Despite our insights about mesoderm and cardiac development, it remains a major challenge to discern how signalling and gene expression translate into patterning, structural self-organisation and functional maturation of the heart.
The most common human birth defects originate from the faulty co-specification and aberrant self-organisation of mesodermal precursors during cardiogenesis. The resulting congenital heart disorders affect many pregnancies, children and a growing number of adults with life-long complications. Importantly, cardiac developmental genes and processes play also an important role in the aetiology of cardiovascular disease - the major cause of death in humans. Insights into the underlying mechanisms will advance our understanding of heart disease and lead to development of new treatment strategies.
Figure 1: DrJanaOfficial / CC BY-SA (https://creativecommons.org/licenses/by-sa/4.0)
Human pluripotent stem cell (hPSC) 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 differentiated into multiple cardiac cell types, the key self-organising processes of heart tube formation, looping, trabeculation, ballooning, septation, valve development and functional maturation remain elusive. Further challenges comprise modelling heart-specific vascularisation, innervation and interactions with adipose tissue, which have a major impact on cardiac development, function and disease.
Our guiding principle is that to understand the molecular control of organogenesis and pathogenesis in vivo, we must be able to recreate the key processes also in vitro.
Figure 2: Step-by-step in-vitro reconstitution of cardiogenesis
Our objective is to discover how signalling and gene expression drive patterning, self-organisation and functional maturation of cardiac structures, and how mutations cause disorders of cardiogenesis. To achieve these aims, we systematically apply principles of in vivodevelopment and translate them to in vitro models.
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, and perturbations by small molecules, CRISPR, shRNA and degrons, with quantitative imaging, as well as with global epigenome, transcriptome and proteome analysis.
Figure 3: Self-organising cardiac organoids form cavities
Video 1: Developing 3D cardiac organoid
Video 2: Contracting 3D cardiac organoid
Video 3: High-throughput development of 3D cardiac organoids
Pablo Hofbauer, Stefan Jahnel, Nora Papai, Magdalena Giesshammer, Mirjam Penc, Katherina Tavernini, Nastasja Grdseloff, Christy Meledeth, Alison Deyett, Clara Schmidt, Claudia Ctortecka, Šejla Šalic, Maria Novatchkova, Sasha Mendjan (2020). Cardioids reveal self-organizing principles of human cardiogenesis BioRxiv.
Bertero, A., Brown, S., Madrigal, P., Osnato, A., Ortmann, D., Yiangou, L., Kadiwala, J., Hubner, NC., de Los Mozos, IR., Sadée, C., Lenaerts, AS., Nakanoh, S., Grandy, R., Farnell, E., Ule, J., Stunnenberg, HG., Mendjan, S., Vallier, L. (2018). The SMAD2/3 interactome reveals that TGFβ controls m<sup>6</sup>A mRNA methylation in pluripotency. Nature. 555(7695):256-259
Haider, S., Meinhardt, G., Saleh, L., Kunihs, V., Gamperl, M., Kaindl, U., Ellinger, A., Burkard, TR., Fiala, C., Pollheimer, J., Mendjan, S., Latos, PA., Knöfler, M. (2018). Self-Renewing Trophoblast Organoids Recapitulate the Developmental Program of the Early Human Placenta. Stem Cell Reports. 11(2):537-551
Faial, T., Bernardo, AS., Mendjan, S., Diamanti, E., Ortmann, D., Gentsch, GE., Mascetti, VL., Trotter, MW., Smith, JC., Pedersen, RA. (2015). Brachyury and SMAD signalling collaboratively orchestrate distinct mesoderm and endoderm gene regulatory networks in differentiating human embryonic stem cells. Development. 142(12):2121-35
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
Sun, B., Ito, M., Mendjan, S., Ito, Y., Brons, IG., Murrell, A., Vallier, L., Ferguson-Smith, AC., Pedersen, RA. (2012). Status of genomic imprinting in epigenetically distinct pluripotent stem cells. Stem Cells. 30(2):161-8
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