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A stem cell therapy for Hirschsprung Disease

Hirschsprung disease is a common disorder affecting newborn children. To save lives, the infants are operated on in the first few weeks. However, they suffer long term complications, which we hope to prevent through stem cell replacement of missing neurons.

Hirschsprung disease (HSCR) is a congenital enteric neuropathy characterised by the lack of enteric neurons in the distal bowel, which results in a loss of propulsive motility and life-threatening constipation. Without surgical removal of the defective bowel, the infant dies. Current surgical intervention, while life-saving, frequently results in chronic, long-term complications, including constipation, faecal soiling, and associated psychosocial problems Consequently, alternative treatments are needed.

Our studies have shown that following transplantation into the bowel, endogenous enteric neural progenitors give rise to new neurons that are electrically active, integrate into the enteric nervous system circuitry and functionally innervate the gut muscle. We have embarked on a program to rescue rats from certain death by bypassing the defective bowel, restoring function by stem cell therapy and then re-joining the bowel as illustrated below.

In this project you will participate in the rescue of Hirschsprung rats and you will evaluate recolonization using structural and functional methods. 

References:

Simkin, J. E.; Zhang, D.; Stamp, L. A.; Newgreen, D. F. Fine scale differences within the vagal neural crest for enteric nervous system formation Developmental Biology (2019) 446 1 22-33

Stamp LA, Gwynne RM, Foong JP, Lomax AE, Hao MM, Kaplan DI, Reid CA, Petrou S, Allen AM, Bornstein JC, and Young HM (2017). Optogenetic demonstration of functional innervation of mouse colon by neurons derived from transplanted neural cells. Gastroenterology 152(6):1407-1418.

McKeown SJ, Mohsenipour M, Bergner AJ, Young HM, and Stamp LA. Exposure to GDNF Enhances the Ability of Enteric Neural Progenitors to Generate an Enteric Nervous System. Stem Cell Reports 8(2):476-488, 2017.

Stamp LA. Cell therapy for GI motility disorders: comparison of cell sources and proposed steps for treating Hirschsprung disease (2017). American journal of physiology Gastrointestinal and liver physiology 1;312(4):G348-G354.

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