Cardiovascular disease (CVD) is the most common cause of death worldwide in the adult population, with a ~21% increase in the last decade. In Europe, CVDs remain the most common cause of death despite the decline in age-standardized death rates, causing ~4 Million deaths/ year. In addition, congenital cardiac disease is the most prevalent organ malformation. However, the development of potential breakthrough drugs for CVDs is shockingly low (2%), in comparison to those for cancer (45%). The key reasons include a limited molecular understanding of human cardiac development and homeostasis along with its substantial molecular and functional differences in comparison to popular animal models and the currently declining number of druggable molecular targets. Thus a systematic understanding of molecular regulation of cardiac fate and identity is essential to understand the fundamental principles of self-organization of the human heart, investigating the etiology of cardiovascular diseases, and to develop therapeutic interventions for congenital and adult-onset cardiac disorders. The current understanding of the molecular regulation of cardiac cell fate and identity is mainly based on signal transduction, epigenetic, and transcriptional mechanisms. However, RNA is the primary language of communication from the genome. We are only beginning to understand the RNA regulatory principles that govern cell fate decisions and cellular identity. For instance, mutations in RNA binding proteins (RBPs) are among the most common causes of genetic disorders, while the molecular and functional role of majority of the RBPs is unknown. Our lab is focused on understanding the fundamental RNA-centric processes (controlled by RNA binding proteins, non-coding RNAs, and regulatory motifs embedded in primary transcripts and mRNAs) and their regulatory logic that program cardiac cell fate and identity during human embryogenesis. In close collaboration with the industry, we are developing non-immunogenic, next-generation RNA therapeutics for congenital cardiac diseases. We employ pluripotent stem cells based cell fate engineering (2D differentiation and organoid models)  in combination with systems biology and genome editing approaches to reconstruct and investigate human cardiac development and disease.

Our long-term mission  is to gain a systems level understanding of the RNA regulatory principles that shape the self-organization and homeostasis of the cardiovascular system in humans in order to develop therapeutic solutions for tissue/ organ regeneration.

1. Translational specialization of cellular identity in cardiovascular development and disease (Funded by ERC Consolidator Grant):
   
   The human heart is the first functional organ formed in an embryo. Impaired embryonic cardiovascular cell fate decisions and morphogenesis are among the most prevalent causes of congenital cardiac disease. While the cell type diversity and their developmental trajectories are mapped to single-cell levels in the developing heart, the regulatory programs defining cardiac lineages and diversity remain largely restricted to the epigenetic, transcriptome, and signal transduction layers. However, the success of developmental cell fate decisions requires timely, specific, accurate, and efficient rewiring of the regulatory proteome to support rapid cellular identity changes, a process controlled spatiotemporally by mRNA translation machinery. Emerging evidence, including from our lab, reveals the central role of selective mRNA translation in presetting developmental trajectories and defining cardiac identity. In support, we discovered that protein levels of WNT signaling components, key cardiac morphogen signaling machinery, are programmed spatiotemporally by a specialized mRNA translation circuit. Yet, a systematic systems-wide understanding of the principles and regulatory mechanisms by which the developmental transcriptome is differentially translated in time and space to authorize cardiac cell fate decisions, and cardiomyocyte diversity remains elusive. In this project, we are investigating the mediators and mechanisms by which developmental transcriptome is differentially translated to enable embryonic cell fate decisions during cardiogenesis, cardiac homeostasis, and disease. To this end, we use hiPSC-based differentiation models, organoids, and RNA biology approaches such as eCLiP-seq & Ribo-seq in combination with CRISPR-Cas9-based targeted screens to understand the principles of human cardiogenesis, cardiac homeostasis, and disease.
   
   Science Advances 2023 
   
   Nature 2011 
   
   Nature communications 2017
   
   

   

   Abstract illustration summarizing the findings of the study: Bartsch et al. reveal that a specialized mRNA translation circuit (depicted by the ribosome in the center) presets the future cardiac commitment competence of human embryonic stem cells (illustrated by crucial stages of human cardiac development around the ribosome). Progression in embryonic cardiac development is highlighted by the surrealistic representation of the growing seedling. The prioritization of cardiac commitment over other germ layers by this mRNA translation circuit is represented by the highlight over the heart (bottom left corner) compared to the brain and lungs in the shadow (representing the other key lineages). (Image credit: DrawImpacts (Emma Vidal) and Kurianlab, Inspiration: Salvador Dali’s ‘La Gare de Perpignan’ situated at Museum Ludwig, Cologne)
   
   
   

2. Long non-coding RNA mediated regulation of cell-fate decisions during development and homeostasis:
   
   The human body is composed of about hundreds of different cell types. The identity and function of these distinct cell types are precisely programmed by the regulatory networks encoded in the 3 billion base pairs of DNA that constitute the human genome. While 60% of our genome is transcribed, less than 2% of it is translated to proteins. In contrast to previous assumptions, this suggests that a significant majority of the regulatory information from the genome functions as RNAs, termed non-coding RNAs. Emerging evidences suggest that a substantial portion of these non-coding transcripts control myriad biological processes ranging from development to disease, establishing the vital role played by these RNA regulatory elements.
   
   Cell Stem Cell 2019
   
   Cancer Cell 2018
   
   Circulation 2015
   
   Press release
   
   
   
3. Conserved metabolic mediators of tissue-specific aging:
   
   A temporal decline in the functional and molecular integrity of an organism defines its ageing process. While multiple hallmarks of ageing have recently been enumerated, our understanding of their functional, molecular and temporal hierarchy remains incomplete. The significance of these hallmarks in the ageing process vary in a tissue/ cell type specific manner. Considering the physiological differences between organs, it is conceivable that their susceptibility to these distinct triggers of ageing can differ. Therefore, it is important to delineate those mechanisms that influence the ageing process of specific organs to better understand organismal ageing. We investigate evolutionarily conserved mechanisms that leads to aging of the heart.(EMBO Reports 2019)
   
   
   
4. RNA-regulons mediating cell-fate decisions during cardiac regeneration:
   
   Heart failure is a leading cause of mortality and morbidity in the developed world, partly because of the minimal regenerative ability of the mammalian heart. However, several fish and amphibians do possess dramatic ability to regenerate damaged organs, including heart. We use a combinatorial approach including regeneration competent models, state-of-the art stem cell-based models and systems biology approaches to understand the hidden regulatory layers enabling organ/ tissue regeneration.
   
   Cell Stem 
   
   Cell 2014