Fellows Lecture in Pairs: ‘Macrophage function in the regenerating heart’ and ‘Transposons diversify the wired- and wireless neural network of a complex brain’

Dr Filipa Simões: ‘Macrophage function in the regenerating heart’

The damage caused by myocardial infarction (MI) leads to a permanent loss of cardiac tissue in adult mammals. Following MI, large numbers of monocyte-derived macrophages are recruited to the injured heart. Macrophages are integral to both repair by scar formation and tissue regeneration; however, the local environmental cues and cell-cell interactions that control distinct macrophage functions across the damaged heart are largely unknown. I will describe recent findings where we reveal that macrophages directly contribute collagen to the forming post-injury scar. Unbiased transcriptomics shows an upregulation of collagens in both zebrafish and mouse macrophages following heart injury. Adoptive transfer of macrophages, from either collagen-tagged zebrafish or adult mouse GFPtpz-collagen donors, enhances scar formation via cell autonomous production of collagen. In zebrafish, the majority of tagged collagen localises proximal to the injury, within the overlying epicardial region, suggesting a possible distinction between macrophage-deposited collagen and that predominantly laid-down by myofibroblasts. Our findings contrast with the current model of scarring, whereby collagen deposition is exclusively attributed to myofibroblasts, and implicate macrophages as direct contributors to fibrosis during heart repair. A comprehensive understanding of the regenerative microenvironment in which the innate immune response persists but is permissible for regeneration, alongside targeting of macrophage-induced pro-fibrotic pathways, may ultimately contribute to the development of therapeutic strategies aimed at harnessing pro-regenerative responses within the injured mammalian heart.

Dr Simões Biography:

Filipa Simões is a Group Leader and British Heart Foundation Research Fellow at the Institute of Developmental and Regenerative Medicine, DPAG, and a Hugh Price Fellow at Jesus College, University of Oxford, UK. Her research is focused on understanding how immune cells, in particular macrophages, can be programmed by their neighbouring cells to repair the damage caused by a heart attack. Her team uses genomics, spatial transcriptomics and functional in vivo and in vitro assays to dissect the spatiotemporal dynamics of cellular microenvironments, identify intercellular signalling networks and decipher how these converge to define macrophage identity, plasticity and function in the healthy and diseased heart.

Dr Christoph Treiber: ‘Transposons diversify the wired- and wireless neural network of a complex brain’

A large part of our genome is made up of mobile genetic elements called transposons. We know that every person harbours their own, unique set of transposons, including within genes that determine the structure and function of our brain. This leads to an intriguing hypothesis: transposons might change brain functions and contribute to behavioural individuality.

The fruit fly is a well-established model organism that enables us to link gene functions with complex behaviours. I generated the first single-cell transcriptomic atlas of the fruit fly brain and revealed tight interactions between the transposons and neural genes. I found that transposons in introns of genes are frequently captured by alternative splicing and become part of neural mRNAs.

To link these molecular changes with complex behaviours, it will be necessary to understand how all ~100.000 neurons of the fly brain interact with each other. This requires knowledge about (a) the synaptic connections between neurons, the “wired network”, and (b) modulatory chemical interactions that occur throughout the brain, the “wireless network”.

In my talk I will present how we are working towards linking these two neural networks, and how we use new sequencing technologies to place transposon-gene fusions into these neural networks. My aim will be to convince you that transposons play an important role in the brain of animals and humans, and that our work on the fruit fly brain will provide valuable insights into the fundamental principles that link transposons with behavioural individuality.

Dr Treiber Biography:

Christoph Treiber completed a Master’s degree at the University of Vienna, where he joined the lab of Prof. David Keays at the IMP and investigated the neural basis of magnetoreception.

He found that contrary to the long-standing theory at the time, pigeons do not contain magnetic material in their beaks.

He then moved to Oxford for a DPhil in Genomic Medicine and Statistics and joined Scott Waddell’s lab, where his work focuses on the role of transposon mobilization in the brain. In addition, in 2017 he pioneered single-cell transcriptomics of the fruit fly brain.

He is currently a post-doctoral researcher in Scott’s lab, and he was recently awarded a 5-year ERC Starting grant to establish his own, independent research group at the new Biology Department in Oxford.

In his lab he will combine transcriptomics, in-vivo imaging and behavioural testing of fruit flies to investigate the impact of genomic variations on brain functions and behaviours.