Every year, hundreds of children are born with Hirschsprung’s disease, missing the nerve cells in their rectum that make the bowel work properly. Even after surgery to remove the affected section, many suffer long-term complications like severe constipation or life-threatening bowel infections. This project compares two potential sources of replacement nerve cells—clusters called neurosphere-like bodies (NLBs)—to determine which is safer and more effective for transplant. One source comes from the child’s own bowel tissue (hNLBs), avoiding the need for immune-suppressing drugs but varying between individuals. The other is grown from embryonic stem cells (hESC-NLBs), which can be tightly controlled but would require immunosuppression. Using single-cell RNA sequencing, the researchers will map the types and arrangement of neurons in each NLB type and compare them to the normal bowel’s neuronal diversity. If successful, this work will establish quality-control measures for regenerative therapies, moving toward a reliable treatment that could restore normal bowel function in children with Hirschsprung’s disease and reduce their dependence on lifelong surgical management.
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Hirschsprung’s Disease (HSCR) is a congenital condition characterised by the absence of neurons in the rectum. This results in intestinal obstruction and potentially life-threatening enterocolitis. Despite current surgical management, many children have long-term complications. Regenerative medicine therapies (RMTs) show promise as a treatment for HSCR in the form of neurosphere-like bodies (NLBs), organoids consisting of neurons and glia. NLBs can be grown from human primary neural progenitor cells cultured from explants of bowel (hNLBs) and human Embryonic Stem Cells (hESC-NLBs). Safe RMT development requires robust characterisation of the cells being transplanted. hNLBs are an attractive therapeutic choice as immunosuppression would not be required, but may have wide variability between individuals. Conversely hESC-NLB production can be very tightly controlled but would require immunosuppression. For NLBs to be a safe treatment, the cell types and distribution present should be predictable and amenable to measures of quality control. Advances in single cell RNA sequencing have enabled detailed characterisation of neurons present in normal human bowel. It is to be expected that NLBs which are effective in treating HSCR have a diversity of neuronal sub-types which mirrors that seen in normal bowel. To address these important factors of efficacy and safety the aims of this project are: i. To compare the neuronal diversity of hNLBs and hESC-NLBs ii. To define and compare the variability of cell type and number within hNLBs to hESC-NLBs iii. To robustly characterise the cells present within hNLBs and hESC-NLBs and their respective spatial relationships
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