Shane is a Principal Investigator and Senior Fellow in the Division of Developmental Biology and Medicine within the Faculty of Biology, Medicine and Health. Shane studied for his PhD at the University of Leeds in 2006 and was then awarded a Wellcome Trust Sir Henry Wellcome Fellowship in 2007 to support postdoctoral work in the laboratory of Didier Stainier at the University of California, San Francisco (UCSF). In 2011, Shane was awarded a Wellcome Trust Research Career Development Fellowship and moved to the University of Manchester to establish his own laboratory. More recently, in 2020 Shane became a Wellcome Trust Senior Research Fellow.

The vertebrate vasculature consists of an extensive branched network of blood vessels that supplies all tissues with essential nutrients and oxygen. As such, new blood vessel morphogenesis (or angiogenesis) is critical for the development, growth and repair of almost all organs and tissues. Moreover, imbalances in angiogenesis contribute to numerous disease states, including blindness, arthritis, ischaemic disorders and cancer. Thus, manipulation of angiogenesis has clear therapeutic potential, yet, we are just beginning to decipher the complex mechanisms underpinning new blood vessel growth.

Like any newly forming or regenerating tissue, in angiogenesis cells must precisely coordinate a diverse suite of cellular behaviours (e.g. cell migration, proliferation, polarity and differentiation) to collectively build functional organs. To do this, endothelial cells employ a core toolkit of morphogenetic mechanisms (e.g. collective cell migration, competitive cell fate decisions, tissue branching, patterning/guidance mechanisms and tubulogenesis), processes that are broadly conserved across many tissue systems. Thus, by defining the basic mechanisms of angiogenesis, we aim to both reveal fundamental principles underpinning tissue building relevant to many tissue contexts, as well as define putative therapeutic approaches to tackling pathological angiogenesis.

Of note, our recent research interests include:

Coordination of collective cell migration by asymmetric cell divisions:

Angiogenesis is coordinated by the collective migration of specialised leading “tip” and trailing “stalk” endothelial cells. The molecular determinants of tip versus stalk identity are well known, namely VEGFR and Notch signalling, respectively. However, the importance of endothelial cell division in coordinating tip-stalk specification in angiogenesis was only recently revealed by my lab. Using an interdisciplinary approach combining in silico computational modelling studies with in vivo live single-cell imaging approaches in the zebrafish model, we demonstrated that tip cell divisions are asymmetric and elegantly coordinate the collective migration of branching endothelial cells by self-generating the tip-stalk hierarchies that drive angiogenesis (Costa et. al., 2016. Nat. Cell Biol.; Costa et. al., 2017. Cell Cycle). We find that asymmetric positioning of the mitotic spindle in dividing tip cells generates daughter cell size asymmetries, differential Vegfr signal levels, and establishes the post-mitotic leader-follower hierarchies that coordinate collective cell behaviour in angiogenesis. Likewise, our collaborator (Claudia linker, KCL) uncovered functional conservation of such asymmetric division in the coordination of trunk neural crest cell morphogenesis (Richardson et. al., 2016. Cell Rep.). Thus, we have defined asymmetric division as a novel mechanism for the coordination of communal cell identity decisions in collective cell migration that likely directs tissues morphogenesis in many cellular contexts. Studies probing how these asymmetric divisions are controlled, how they regulate post-mitotic cell fate and their conserved function in the control of other morphogenetic tissue systems are all active areas of research in my lab.

Spatial control of tissue morphogenesis via mRNA compartmentalisation:

The polarised targeting of diverse mRNAs to the front of motile cells is a hallmark of cell migration, yet, precise functional roles for such targeting of mRNAs has long remained unknown. Likewise, their relevance to modulation of tissue dynamics in vivo is unclear (Herbert et. al., 2019. Essays in Biochem.). Using single-molecule analysis, endogenous gene-edited mRNAs and zebrafish in vivo live-cell imaging, my lab has recently shown that this compartmentalisation of mRNAs uniquely acts as a molecular compass that orients motile cell polarity to spatially direct tissue movement (Costa et. al., 2019. BioRxiv). Using cell fractionation to isolate motile cell protrusions and RNAseq we defined distinct clusters of mRNAs that have unique spatial distributions in migrating endothelial cells, both in vitro and in vivo. For example, the mRNA for RAB13 is universally spatially targeted to motile processes of diverse cell types. Importantly, we find that the targeting of certain mRNAs to the front of motile cells leads to precise local control of subsequent protein expression, which drives regional remodelling of key cytoskeletal structures in cells that orient cell and tissue movement. Hence, disruption of this mRNA compartmentalisation depolarises motile cells and disrupts the guidance of newly forming blood vessels during vascular development in vivo in zebrafish embryos. What’s more, considering we have identified numerous mRNAs that exhibit this polarised subcellular localisation (as well as possessing putative motile functions), spatial compartmentalisation of numerous mRNAs likely coordinates diverse aspects of motile cell behaviour. Studies investigating the mechanisms triggering such polarised targeting of certain mRNAs (but not others), the function of compartmentalised mRNAs in directing motile cell behaviour and if this phenomenon can be hijacked to predictably direct cell and tissue movement are currently ongoing.

Transcriptional control of collective tissue behaviour:

To identify new determinants of the tip versus stalk cell identity that coordinates collective cell movement in angiogenesis, we have employed an integrated pharmacological and transcriptomic strategy for the detection of novel tip and stalk cell-associated genes in vivo (Herbert et. al., 2012. Current Biology). Upon incubation of zebrafish embryos with well-established pharmacological inhibitors Vegfr or Notch, both alone or in combination, we could either repress tip cell formation (Vegfr inhibition), induce ectopic tip cell formation (Notch inhibition) or recover ectopic tip cell formation (Notch + Vegfr inhibition). Subsequent FACS isolation of GFP-positive endothelial cells and multifactorial transcriptomic comparison with DMSO-treated controls identified previously unknown tip cell restricted genes that are tightly spatiote­­mporally associated with tip cell behavior in vivo. This previous work has allowed us to define key transcriptional switches that couple selection of tip versus stalk identity to induction of cell-type-specific behaviours. For example, we have previously shown that the tip cell restricted gene hlx1 coordinates stalk versus tip cell behaviour in vivo, although the mechanisms involved remain unclear (Herbert et. al., 2012. Curr. Biol.). Moreover, we revealed that tip cell-restricted expression of the tetraspanin gene, tm4sf18, drives positive-feedback modulation of Vegfr signalling and spatiotemporally regulates tip-stalk signalling dynamics and identity decisions in vivo (Page et. al., 2019. Cell Rep.). Work defining the localisation, regulation and function of other previously unidentified tip and stalk cell specific transcripts uncovered by these studies are currently in progress.

Communal coordination of cell behaviour underpinning organ formation

Research in my lab aims to address the fundamental question of “how do cells work together to collectively build complex tissues?”. In particular, how are groups of cells able to interpret a signal, accurately communicate this information to neighbouring cells and precisely coordinate their communal cell behaviour, morphology and identity to drive functional organ formation?

This question is core to understanding how all tissues form during embryonic development via the process of “morphogenesis” - whereby un-patterned cell populations elegantly reorganise into distinct organs and tissues. Moreover, such communal coordination of cell behaviour also critically underpins the repair or regeneration of tissues following damage, and these processes are frequently subverted in disease. As such, the ultimate aim of our work is to exploit knowledge of these mechanisms to realise novel therapeutic strategies tackling pathological tissue formation and/or repair in disease states as diverse as myocardial infarction, chronic wounds and cancer.

To tackle these questions, we focus on the vertebrate cardiovascular system and formation of the intricate blood vessel network that supplies all tissues with essential oxygen and nutrients. Blood vessel formation (or angiogenesis) is a paradigm model for investigating the core mechanisms by which cells communally coordinate their behaviour during tissue formation; including broadly conserved processes such as collective cell migration, competitive cell fate decisions, tissue branching morphogenesis, tissue patterning/guidance mechanisms and tubulogenesis. Moreover, dysregulation of angiogenesis underpins numerous pathological processes, including tumour growth and metastasis, retinopathy and blindness, arthritis, limb ischemia and atherosclerosis. Hence, not only do studies of angiogenesis shed light on the fundamental principles of tissue building, novel insights have clear therapeutic potential.

To define the core molecular and cellular mechanisms coordinating cell behaviour in angiogenesis, my lab adopts an interdisciplinary multiscale approach integrating genetic studies (e.g. CRIPSR gene editing and/or transgenic tools) in vertebrate models (e.g. zebrafish embryos) and primary human cells with single cell-resolution in-vivo time-lapse microscopy, ‘Omics’ techniques (e.g. transcriptomics, proteomics) and computational modelling. In recent years we’ve exploited these approaches to reveal unexpected roles for cell division (Costa et. al., 2016. Nat. Cell Biol.), signal-induced positive-feedback (Page. et. al., 2019. Cell Rep.) and spatial compartmentalisation of mRNAs (Costa et. al., 2019. bioRxiv) in the communal coordination of cell interactions and behaviour driving angiogenesis and tissue formation.

- Shane Herbert (Principal Investigator and Senior Fellow)

- Holly Lovegrove (Wellcome Trust Sir Henry Wellcome Postdoctoral Fellow)

- Raphael Thuret (BHF Postdoctoral Researcher)

- Georgia Hulmes (Wellcome Trust Postdoctoral Fellow)

- Sabrina Ghadaouia (Wellcome Trust PhD Student)

- Joshua Bradbury (BBSRC PhD Student)

- Georgios Charalambous (BBSRC PhD Student)