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Conor McCann's Research Group


Gut Development and Repair Group

Image of Tuj-nNOS McCann
My research interests focus on the development and physiology of the gastrointestinal tract with particular reference to the genetic and microenvironmental factors responsible for cellular fate

determination in both normal and pathophysiological conditions. We have a particular focus on investigating the underlying molecular and genetic mechanisms of gut disease to improve diagnosis and develop novel therapeutic approaches, including stem cells and gut tissue engineering, for their treatment.

Normal gastrointestinal (GI) function requires the coordinated interaction of the enteric neurons and glial cells that comprise the enteric nervous system (ENS), interstitial cells of Cajal, and smooth muscle cells. Defects in the development of these cell types results in a range of commonly occurring gut disorders/diseases including Hirschsprung disease (aganglionic megacolon), intestinal pseudo-obstruction, and other motility defects.

Understanding how the gut develops and how molecular and cellular pathogenesis lead to neuromuscular diseases drives our research in developing regenerative medicine approaches to better treat gut disorders.

Image of Tuj-nNOS McCann
Image of ENS montage McCann

We take a number of approaches, in collaboration with groups locally, nationally and internationally to:

  • Investigate the mechanisms underlying enteric nervous system (ENS) and interstitial cells of Cajal (ICC) development
  • Explore how coordinated activity in the gut develops 
  • Better understand the underlying pathophysiology of gut motility disorders
  • Develop novel stem cell-based therapies for gut disorders such as Hirschsprung disease
  • Use tissue engineering approaches to manufacture replacements for diseased gut
Lab Members

Ben Cairns

Projects

Developing a human pluripotent stem cell-based strategy for treating Hirschsprung disease

Together with Dr. Anestis Tsakiridis and Prof. Peter Andrews (University of Sheffield), we are currently establishing the preclinical basis for regenerative medicine approaches for the treatment of Hirschsprung disease.

Hirschsprung disease is a life-threatening intestinal disorder caused by an absence of intrinsic nerve cells (aganglionosis) in the most distal GI tract. It occurs in approximately 1 in 5000 live births, making it one of the most common congenital diseases affecting the gut. Given that intrinsic gut nerve cells (enteric neurons) mediate the contractions necessary for normal gut function, their absence in Hirschsprung patients causes severe constipation or intestinal obstruction. The only treatment available is surgical removal of the affected part of the bowel combined with a 'pull through' procedure, which entails connecting the healthy part of the gut to the anus. However, the surgery necessitates retention of part of the abnormal gut including the anal sphincter, which is likely to account in part for the long-term, often life-long, gastrointestinal problems and poor quality of life suffered by the majority of patients. Surgery, readmission and outpatient hospital appointments which are required for the management of this condition present a significant burden for the healthcare system.

Recent advances in the understanding of development of the gut's intrinsic (enteric) nervous system and pathogenesis of the disease, as well as considerable progress in regenerative medicine, have highlighted potential for alternative treatments, such as cell replacement therapy. Although preclinical testing has demonstrated that cell therapy should be a viable option for treating Hirschsprung disease, the availability of human enteric neurons from post-natal gut remains a bottleneck for the development of cell-based therapies. An attractive alternative source is offered by pluripotent stem cells, where there is significant potential to generate appropriate cells for therapy, both in terms of numbers and the ability to tailor cell properties. We have recently developed efficient protocols to generate human neural crest cells and enteric nervous system progenitors from human pluripotent stem cells. In this project, we will test the ability of these progenitors to correct for the lack of enteric neurons in models of Hirschsprung disease following transplantation. We will also optimise the current methods of generating and purifying human enteric nervous system progenitors, from pluripotent stem cells, and will develop new transplantation protocols and models of Hirschsprung disease.

Using ex vivo organotypic cultures to investigate donor cell integration in the gut

INtestinal Tissue ENgineering Solution

Teaching

I currently co-lead the Molecular Aspects of Cell and Gene Therapy module, at UCL, which forms a core part of the UCL Great Ormond Street Institute of Child Health MSc. Cell and Gene Therapy

For more information on the Programme please click here.

Publications

Hamilton, N. J. I., Lee, D. D. H., Gowers, K. H. C., Butler, C. R., Maughan, E. F., Jevans, B., . . . Janes, S. M. (2020). Bioengineered airway epithelial grafts with mucociliary function based on collagen IV- and laminin-containing extracellular matrix scaffoldsEur Respir J. doi:10.1183/13993003.01200-2019

Navoly, G., Chapman, C., & McCann, C. J. (2020). Enteric neural stem cell integration in ex vivo organotypic colon cultures.

Ward, A. I., Lewis, M. D., Khan, A. A., McCann, C. J., Francisco, A. F., Jayawardhana, S., . . . Kelly, J. M. (2020). In Vivo Analysis of Trypanosoma cruzi Persistence Foci at Single-Cell ResolutionmBio, 11 (4). doi:10.1128/mBio.01242-20

Frith, T. J. R., Gogolou, A., Hackland, J. O. S., Hewitt, Z. A., Moore, H. D., Barbaric, I., . . . McCann, C. J. (2020). Retinoic Acid Accelerates the Specification of Enteric Neural Progenitors from In-Vitro-Derived Neural CrestStem Cell Reports, 15 (3), 557-565. doi:10.1016/j.stemcr.2020.07.024

McCann, C. J., Alves, M. M., Brosens, E., Natarajan, D., Perin, S., Chapman, C., . . . Thapar, N. (2019). Neuronal Development and Onset of Electrical Activity in the Human Enteric Nervous SystemGastroenterology. doi:10.1053/j.gastro.2018.12.020

Frith, T. J. R., Gogolou, A., Hackland, J. O. S., Barbaric, I., Thapar, N., Burns, A., . . . McCann, C. (2019). Retinoic acid accelerates the specification of enteric neural progenitors from in vitro-derived neural crest. doi:10.1101/819748

McCann, C., Goldstein, A., Hotta, R., Thapar, N., Hofstra, R., Burns, A., & McCann, C. (2019). Stem Cell Therapy for Enteric NeuropathiesHirschsprung's Disease and Allied Disorders. Springer. doi:10.1007/978-3-030-15647-3_8

Frith, T. J. R., McCann, C., Gogolou, A., Thapar, N., Tsakiridis, A., Burns, A., & Andrews, P. W. (2019). Transplantation of hPSC derived enteric neural progenitors as a basis to derive a preclinical cell therapy for Hirschsprung's disease. Presented at: Annual Conference of the British-Society-for-Gene-and-Cell-Therapy.

Vaes, N., Schonkeren, S. L., Brosens, E., Koch, A., McCann, C. J., Thapar, N., . . . Melotte, V. (2018). A combined literature and in silico analysis enlightens the role of the NDRG family in the gutBiochimica et Biophysica Acta - General Subjects, 1862 (10), 2140-2151. doi:10.1016/j.bbagen.2018.07.004

McCann, C., & Thapar, N. (2018). Enteric Neural Stem Cell Therapies for Enteric NeuropathiesNeurogastroenterology and Motility. doi:10.1111/nmo.13369

Perin, S., McCann, C. J., De Coppi, P., & Thapar, N. (2018). Isolation and characterisation of mouse intestinal mesoangioblastsPediatric Surgery International. doi:10.1007/s00383-018-4373-7

Urbani, L., Camilli, C., Phylactopoulos, D. E., Crowley, C., Natarajan, D., Scottoni, F., . . . De Coppi, P. (2018). Multi-stage bioengineering of a layered oesophagus with in vitro expanded muscle and epithelial adult progenitorsNature Communications. doi:10.1038/s41467-018-06385-w

McCann, C. J., Borrelli, O., & Thapar, N. (2018). Stem cell therapy in severe pediatric motility disordersCurrent Opinion in Pharmacology, 43, 145-149. doi:10.1016/j.coph.2018.09.004

Jevans, B., McCann, C., Thapar, N., & Burns, A. (2018). Transplanted enteric neural stem cells integrate within the developing chick spinal cord: implications for spinal cord repairJournal of Anatomy. doi:10.1111/joa.12880

McCann, C., Natarajan, D., Perin, S., Alves, M., Brosens, E., Hofstra, R., . . . Thapar, N. (2017). Development of coordinated electrical activity in the human foetal enteric nervous system.

Cooper, J. E., Natarajan, D., McCann, C. J., Choudhury, S., Godwin, H., Burns, A. J., & Thapar, N. (2017). In vivo transplantation of fetal human gut-derived enteric neural crest cellsNeurogastroenterology and Motility, 29 (1), 12900. doi:10.1111/nmo.12900

McCann, C. J., Cooper, J. E., Natarajan, D., Jevans, B., Burnett, L. E., Burns, A. J., & Thapar, N. (2017). Transplantation of enteric nervous system stem cells rescues nitric oxide synthase deficient mouse colonNATURE COMMUNICATIONS, 8, ARTN 15937. doi:10.1038/ncomms15937

Perin, S., McCann, C. J., Borrelli, O., De Coppi, P., & Thapar, N. (2017). Update on Foregut Molecular embryology and Role of Regenerative Medicine TherapiesFRONTIERS IN PEDIATRICS, 5, ARTN 91. doi:10.3389/fped.2017.00091

Williams, D. J., Archer, R., Archibald, P., Bantounas, I., Baptista, R., Barker, R., . . . Zimmerman, H. (2016). Comparability: manufacturing, characterization and controls, report of a UK Regenerative Medicine Platform Pluripotent Stem Cell Platform Workshop, Trinity Hall, Cambridge, 14-15 September 2015Regenerative medicine.

Cooper, J. E., McCann, C. J., Natarajan, D., Choudhury, S., Boesmans, W., Delalande, J. -. M., . . . Thapar, N. (2016). In Vivo Transplantation of Enteric Neural Crest Cells into Mouse Gut; Engraftment, Functional Integration and Long-Term SafetyPLOS ONE, 11 (1), ARTN e0147989. doi:10.1371/journal.pone.0147989

Burns, A. J., Goldstein, A. M., Newgreen, D. F., Stamp, L., Schaefer, K. -. H., Metzger, M., . . . Vanden Berghe, P. (2016). White paper on guidelines concerning enteric nervous system stem cell therapy for enteric neuropathiesDEVELOPMENTAL BIOLOGY, 417 (2), 229-251. doi:10.1016/j.ydbio.2016.04.001

Binder, E., Natarajan, D., Cooper, J., Kronfli, R., Cananzi, M., Delalande, J. M., . . . Thapar, N. (2015). Enteric neurospheres are not specific to neural crest cultures: implications for neural stem cell therapiesPLoS One, 10 (3), e0119467-?. doi:10.1371/journal.pone.0119467

McCann, C. J., Hwang, S. J., Hennig, G. W., Ward, S. M., & Sanders, K. M. (2014). Bone marrow derived kit-positive cells colonize the gut but fail to restore pacemaker function in intestines lacking interstitial cells of CajalJournal of Neurogastroenterology and Motility, 20 (3), 326-337. doi:10.5056/jnm14026

Natarajan, D., Cooper, J., Choudhury, S., Delalande, J. M., Howe, S. J., Thapar, N., & Burns, A. J. (2014). Lentiviral labeling of mouse and human enteric nervous system stem cells for regenerative medicine studiesNeurogastroenterology and Motility, 26 (10), 1513-1518. doi:10.1111/nmo.12420

McCann, C. J., Hwang, S. J., Bayguinov, Y., Colletti, E. J., Sanders, K. M., & Ward, S. M. (2013). Establishment of pacemaker activity in tissues allotransplanted with interstitial cells of CajalNeurogastroenterology & Motility, 25 (6), e418-e428. doi:10.1111/nmo.12140

Carnaghan, H., Roberts, T., Savery, D., Norris, F., McCann, C. J., Copp, A. J., . . . Eaton, S. (2013). Novel exomphalos genetic mouse model: the importance of accurate phenotypic characterisationJournal of Pediatric Surgery, 48 (10), 2036-2042. doi:10.1016/j.jpedsurg.2013.04.010

Heredia, D. J., Grainger, N., McCann, C. J., & Smith, T. K. (2012). Insights from a novel model of slow-transit constipation generated by partial outlet obstruction in the murine large intestineAmerican Journal of Physiology-Gastrointestinal and Liver Physiology, 303 (9), G1004-G1016. doi:10.1152/ajpgi.00238.2012

Dickson, E. J., Heredia, D. J., McCann, C. J., Hennig, G. W., & Smith, T. K. (2010). The mechanisms underlying the generation of the colonic migrating motor complex in both wild-type and nNOS knockout miceAMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY, 298 (2), G222-G232. doi:10.1152/ajpgi.00399.2009

Kwon, J. G., Hwang, S. J., Hennig, G. W., Bayguinov, Y., McCann, C., Chen, H., . . . Ward, S. M. (2009). Changes in the Structure and Function of ICC Networks in ICC Hyperplasia and Gastrointestinal Stromal TumorsGASTROENTEROLOGY, 136 (2), 630-639. doi:10.1053/j.gastro.2008.10.031

Navoly, G., & McCann, C. J. (n.d.). Dynamic integration of enteric neural stem cells in ex vivo organotypic colon cultures. Cold Spring Harbor Laboratory. doi:10.1101/2020.06.12.147652

Funders, Collaborators and Partners
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