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Gut Development and Repair Group
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.
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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 - Research Assistant
Ben Jevans - Post Doctoral Fellow
- 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
- 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 scaffolds. Eur 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 Resolution. mBio, 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 Crest. Stem 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 System. Gastroenterology. 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 Neuropathies. Hirschsprung'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 gut. Biochimica 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 Neuropathies. Neurogastroenterology and Motility. doi:10.1111/nmo.13369
Perin, S., McCann, C. J., De Coppi, P., & Thapar, N. (2018). Isolation and characterisation of mouse intestinal mesoangioblasts. Pediatric 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 progenitors. Nature Communications. doi:10.1038/s41467-018-06385-w
McCann, C. J., Borrelli, O., & Thapar, N. (2018). Stem cell therapy in severe pediatric motility disorders. Current 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 repair. Journal 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 cells. Neurogastroenterology 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 colon. NATURE 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 Therapies. FRONTIERS 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 2015. Regenerative 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 Safety. PLOS 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 neuropathies. DEVELOPMENTAL 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 therapies. PLoS 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 Cajal. Journal 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 studies. Neurogastroenterology 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 Cajal. Neurogastroenterology & 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 characterisation. Journal 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 intestine. American 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 mice. AMERICAN 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 Tumors. GASTROENTEROLOGY, 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
