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The underlying pathophysiology includes a defect in neural crest cells migration, proliferation and differentiation, which are partially explained by identified genetic and epigenetic alterations. Despite the high success rate of the curative surgeries, they are associated with significant adverse outcomes such as enterocolitis, fecal soiling, and chronic constipation. In addition, some patients suffer from extensive lethal variants of the disease, all of which justify the need for an alternative cure. During the last 5 years, there has been considerable progress in HSCR stem cell-based therapy research. However, many major issues remain unsolved. This review will provide concise background information on HSCR, outline the future approaches of stem cell-based HSCR therapy, review recent key publications, discuss technical and ethical challenges the field faces prior to clinical translation, and tackle such challenges by proposing solutions and evaluating existing approaches to progress further.<\/jats:p>","DOI":"10.1038\/s41434-021-00268-4","type":"journal-article","created":{"date-parts":[[2021,6,13]],"date-time":"2021-06-13T23:14:00Z","timestamp":1623626040000},"page":"578-587","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Stem cell-based therapy for hirschsprung disease, do we have the guts to treat?"],"prefix":"10.1038","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6165-3617","authenticated-orcid":false,"given":"Ali Fouad","family":"Alhawaj","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,6,14]]},"reference":[{"key":"268_CR1","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1136\/archdischild-2016-311872","volume":"102","author":"TJ Bradnock","year":"2017","unstructured":"Bradnock TJ, Knight M, Kenny S, Nair M, Walker GM. 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