Elsevier

Early Human Development

Volume 84, Issue 12, December 2008, Pages 801-804
Early Human Development

Hirschsprung's disease: Current management and prospects for transplantation of enteric nervous system progenitor cells

https://doi.org/10.1016/j.earlhumdev.2008.09.007Get rights and content

Abstract

Hirschsprung's disease affects 1 in 5000 newborns and is caused by an absence of ganglion cells in a variable length of the distal gut. It commonly presents in the newborn period with life-threatening bowel obstruction requiring surgery. Despite apparently successful surgery the long-term outcomes are often unsatisfactory with some children facing a lifetime of continence issues or debilitating constipation. This article exams the reasons for this and describes advances that have occurred in the surgical management of the disease. In the last two decades rapid progress has been made in understanding the genetics and molecular pathology of Hirschsprung's disease. The potential for harnessing this knowledge to develop a stem cell based therapy for Hirschsprung's disease is discussed.

Introduction

Hirschsprung's disease (HSCR) results from a congenital absence of ganglion cells (aganglionosis) in a variable part of the distal gut and affected children usually present shortly after birth with symptoms and signs of distal bowel obstruction. It affects 1 in 5000 newborns in Europe, Asia and North America although the incidence can be significantly higher in communities with a homogeneous genetic background such as the Mennonites [1]. Typical operative findings are of an apparently normal distal rectum and a massively dilated proximal colon. Such findings led early investigators to assume that the dilated bowel was diseased. It was over 60 years following Hirschsprung's first description of the disease in 1887 before the absence of ganglion cells in the apparently normal distal rectum was recognized as the cause of the disease.

These ganglion cells are cell bodies of neurons belonging to a major subset of the autonomic nervous system, the enteric nervous system (ENS), and are found in the myenteric and submucosal plexus of the large bowel. The ENS is vast, containing a similar number of neurons to that in the central nervous system (CNS) and neurons release a diverse range of neurotransmitters. The complex process of mixing and propulsion of gut contents through the digestive tract is a result of interactions between several components of the bowel wall—the enteric nervous system, gut ‘pacemaker’ cells (known as interstitial cells of Cajal), and circular and longitudinal smooth muscle [2]. The ENS is also involved in fluid and electrolyte balance and gut immunity. An analogy to this system is that the ENS can be likened to the conductor; the other components are the orchestra. The ENS itself is subject to afferent inputs from the CNS that can modulate gut motility. Aganglionosis results in an uncoordinated tonic state in the affected gut segment resulting in the clinical presentation of bowel obstruction as luminal contents fail to progress. A variable length of bowel can be affected—in over 80% of cases the aganglionosis is restricted to the internal sphincter, rectum and a few centimeters of sigmoid colon and is termed short segment disease. Less commonly a more extensive length of distal bowel is affected causing long segment or total colonic disease. Total intestinal aganglionosis is a rare and serious form of the disease for which small bowel transplantation may be the only effective form of treatment. A serious complication of HSCR is enterocolitis, the causes of which are multifactorial but which can be life-threatening.

Section snippets

Surgery for Hirschsprung's disease

The first effective surgery for Hirschsprung's disease was performed by Olvar Swenson in 1948 and the principles of this operation still apply: resection of the distal aganglionic bowel and a low anastomosis of ganglionic bowel to the rectum. Various modifications of this surgery have been described, largely technical modifications to avoid anastomotic complications or the requirement for extensive pelvic dissection (Table 1). Long-term outcome data suggests no clear advantage of any particular

Outcomes of surgery

There are increasing data on long-term outcomes from Hirschsprung's surgery although it should be borne in mind that the oldest recipients of the earliest ‘pull-through’ procedures are only in their 6th decade. Clinicians are now assessing the outcomes of procedures that are now no longer performed in the same way. The long-term outcomes of current management approaches are obviously a matter of conjecture. There has been a huge variation in methodologies employed when assessing outcomes for

Stem cells, genes and the origins of Hirschsprung's disease

The ENS is principally derived from the embryonic vagal neural crest [6] although a small sacral component has also been identified. During the first trimester, cells migrate through the oesophagus and down the developing gut in a rostro-caudal direction. Through a process of migration, cell division and differentiation the entire gut is colonized with neurons and glia with the distal colon, rectum and internal sphincter being the last to be colonized. Cells migrate through the embryonic bowel

Developing a stem cell based therapy for HSCR

We have seen that current surgical strategies are failing a significant proportion of children with HSCR. Advances in developmental biology have led to the discovery that ENSC are present in the postnatal human gut [10], [15] has led to the hope that these cells could be used autologously to colonize the aganglionic bowel in children with HSCR as a primary or adjunctive treatment. Furthermore, multipotent stem cells could potentially be isolated from the CNS [16] or bone marrow derived

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    However, all the known mutations account for less than 50% of HSCR cases, suggesting that some mutations may involve noncoding regulatory regions of known genes.43 Although the current curative treatment for HSCR is surgery, there is a rapidly expanding field endeavoring to develop a stem cell therapy for this disorder, the aim being to replace the missing ENS cells in the distal gut with stem cells derived from gut or other sources.15,44-47 Such stem cells, when transplanted to the gut, would subsequently differentiate into neurons and thus functionally innervate the affected gut segment and restore gut function.

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    Given the genetic and phenotypic heterogeneity in HSCR, multiinstitutional studies with standardized molecular genetic and pathologic protocols may be required to derive meaningful conclusions in a reasonable time period. Stem cell therapy for HSCR has engendered some enthusiasm as a potential treatment for HSCR.85 The hypothesis has been advanced that function of the aganglionic bowel might be restored by neurons that differentiate from autologous or heterologous neural stem cells.

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