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Article ; Online: Updates and Challenges in ENS Cell Therapy for the Treatment of Neurointestinal Diseases.

Ohkura, Takahiro / Burns, Alan J / Hotta, Ryo

2024 Volume 14, Issue 2

Abstract: Neurointestinal diseases represent a significant challenge in clinical management with current palliative approaches failing to overcome disease and treatment-related morbidity. The recent progress with cell therapy to restore missing or defective ... ...

Abstract	Neurointestinal diseases represent a significant challenge in clinical management with current palliative approaches failing to overcome disease and treatment-related morbidity. The recent progress with cell therapy to restore missing or defective components of the gut neuromusculature offers new hope for potential cures. This review discusses the progress that has been made in the sourcing of putative stem cells and the studies into their biology and therapeutic potential. We also explore some of the practical challenges that must be overcome before cell-based therapies can be applied in the clinical setting. Although a number of obstacles remain, the rapid advances made in the enteric neural stem cell field suggest that such therapies are on the near horizon.
MeSH term(s)	Enteric Nervous System ; Neural Stem Cells ; Intestine, Small ; Cell- and Tissue-Based Therapy
Language	English
Publishing date	2024-02-16
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom14020229
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Article ; Online: Isolation, Expansion, and Endoscopic Delivery of Autologous Enteric Neuronal Stem Cells in Swine.

Hotta, Ryo / Pan, Weikang / Bhave, Sukhada / Nagy, Nandor / Stavely, Rhian / Ohkura, Takahiro / Krishnan, Kumar / de Couto, Geoffrey / Myers, Richard / Rodriguez-Borlado, Luis / Burns, Alan J / Goldstein, Allan M

Cell transplantation

2024 Volume 32, Page(s) 9636897231215233

Abstract: The enteric nervous system (ENS) is an extensive network of neurons and glia within the wall of the gastrointestinal (GI) tract that regulates many essential GI functions. Consequently, disorders of the ENS due to developmental defects, inflammation, ... ...

Abstract	The enteric nervous system (ENS) is an extensive network of neurons and glia within the wall of the gastrointestinal (GI) tract that regulates many essential GI functions. Consequently, disorders of the ENS due to developmental defects, inflammation, infection, or age-associated neurodegeneration lead to serious neurointestinal diseases. Despite the prevalence and severity of these diseases, effective treatments are lacking as they fail to directly address the underlying pathology. Neuronal stem cell therapy represents a promising approach to treating diseases of the ENS by replacing the absent or injured neurons, and an autologous source of stem cells would be optimal by obviating the need for immunosuppression. We utilized the swine model to address key questions concerning cell isolation, delivery, engraftment, and fate in a large animal relevant to human therapy. We successfully isolated neural stem cells from a segment of small intestine resected from 1-month-old swine. Enteric neuronal stem cells (ENSCs) were expanded as neurospheres that grew optimally in low-oxygen (5%) culture conditions. Enteric neuronal stem cells were labeled by lentiviral green fluorescent protein (GFP) transduction, then transplanted into the same swine from which they had been harvested. Endoscopic ultrasound was then utilized to deliver the ENSCs (10,000-30,000 neurospheres per animal) into the rectal wall. At 10 and 28 days following injection, autologously derived ENSCs were found to have engrafted within rectal wall, with neuroglial differentiation and no evidence of ectopic spreading. These findings strongly support the feasibility of autologous cell isolation and delivery using a clinically useful and minimally invasive technique, bringing us closer to first-in-human ENSC therapy for neurointestinal diseases.
MeSH term(s)	Humans ; Animals ; Swine ; Infant ; Neurons/metabolism ; Neural Stem Cells ; Enteric Nervous System ; Intestine, Small ; Neuroglia
Language	English
Publishing date	2024-01-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1135816-6
ISSN	1555-3892 ; 0963-6897
ISSN (online)	1555-3892
ISSN	0963-6897
DOI	10.1177/09636897231215233
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Zs.A 3556: Show issues

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Article ; Online: Autologous cell transplantation for treatment of colorectal aganglionosis in mice.

Pan, Weikang / Rahman, Ahmed A / Ohkura, Takahiro / Stavely, Rhian / Ohishi, Kensuke / Han, Christopher Y / Leavitt, Abigail / Kashiwagi, Aki / Burns, Alan J / Goldstein, Allan M / Hotta, Ryo

Nature communications

2024 Volume 15, Issue 1, Page(s) 2479

Abstract: Neurointestinal diseases cause significant morbidity and effective treatments are lacking. This study aimes to test the feasibility of transplanting autologous enteric neural stem cells (ENSCs) to rescue the enteric nervous system (ENS) in a model of ... ...

Abstract	Neurointestinal diseases cause significant morbidity and effective treatments are lacking. This study aimes to test the feasibility of transplanting autologous enteric neural stem cells (ENSCs) to rescue the enteric nervous system (ENS) in a model of colonic aganglionosis. ENSCs are isolated from a segment of small intestine from Wnt1::Cre;R26iDTR mice in which focal colonic aganglionosis is simultaneously created by diphtheria toxin injection. Autologous ENSCs are isolated, expanded, labeled with lentiviral-GFP, and transplanted into the aganglionic segment in vivo. ENSCs differentiate into neurons and glia, cluster to form neo-ganglia, and restore colonic contractile activity as shown by electrical field stimulation and optogenetics. Using a non-lethal model of colonic aganglionosis, our results demonstrate the potential of autologous ENSC therapy to improve functional outcomes in neurointestinal disease, laying the groundwork for clinical application of this regenerative cell-based approach.
MeSH term(s)	Mice ; Animals ; Hirschsprung Disease/therapy ; Stem Cell Transplantation/methods ; Neural Stem Cells/transplantation ; Neurons ; Enteric Nervous System ; Colorectal Neoplasms
Language	English
Publishing date	2024-03-20
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-46793-9
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Article ; Online: Transplanted ENSCs form functional connections with intestinal smooth muscle and restore colonic motility in nNOS-deficient mice.

Hotta, Ryo / Rahman, Ahmed / Bhave, Sukhada / Stavely, Rhian / Pan, Weikang / Srinivasan, Shriya / de Couto, Geoffrey / Rodriguez-Borlado, Luis / Myers, Richard / Burns, Alan J / Goldstein, Allan M

Stem cell research & therapy

2023 Volume 14, Issue 1, Page(s) 232

Abstract: Background: Enteric neuropathies, which result from abnormalities of the enteric nervous system, are associated with significant morbidity and high health-care costs, but current treatments are unsatisfactory. Cell-based therapy offers an innovative ... ...

Abstract	Background: Enteric neuropathies, which result from abnormalities of the enteric nervous system, are associated with significant morbidity and high health-care costs, but current treatments are unsatisfactory. Cell-based therapy offers an innovative approach to replace the absent or abnormal enteric neurons and thereby restore gut function. Methods: Enteric neuronal stem cells (ENSCs) were isolated from the gastrointestinal tract of Wnt1-Cre;R26tdTomato mice and generated neurospheres (NS). NS transplants were performed via injection into the mid-colon mesenchyme of nNOS Results: Transplanted ENSCs formed nitrergic neurons in the nNOS Conclusions: These results demonstrate that transplanted ENSCs can form effective neuromuscular connections and improve colonic motor function in a model of colonic dysmotility, and additionally reveal that multiple sites of cell delivery led to an improved response, paving the way for optimized clinical trial design.
MeSH term(s)	Animals ; Mice ; Neurons ; Muscle, Smooth ; Cell- and Tissue-Based Therapy ; Colon ; Electric Stimulation
Language	English
Publishing date	2023-09-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2548671-8
ISSN	1757-6512 ; 1757-6512
ISSN (online)	1757-6512
ISSN	1757-6512
DOI	10.1186/s13287-023-03469-3
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Article ; Online: Development of the aganglionic colon following surgical rescue in a cell therapy model of Hirschsprung disease in rat.

Furness, John B / Lei, Enie / Hunne, Billie / Adams, Cameron D / Burns, Alan J / Wykosky, Jill / Fazio Coles, Therese E / Fothergill, Linda J / Molero, Juan C / Pustovit, Ruslan V / Stamp, Lincon A

Disease models & mechanisms

2023 Volume 16, Issue 6

Abstract: Patients with Hirschsprung disease lack enteric ganglia in the distal colon and propulsion of colorectal content is substantially impaired. Proposed stem cell therapies to replace neurons require surgical bypass of the aganglionic bowel during re- ... ...

Abstract	Patients with Hirschsprung disease lack enteric ganglia in the distal colon and propulsion of colorectal content is substantially impaired. Proposed stem cell therapies to replace neurons require surgical bypass of the aganglionic bowel during re-colonization, but there is inadequate knowledge of the consequences of bypass. We performed bypass surgery in Ednrb-/- Hirschsprung rat pups. Surgically rescued rats failed to thrive, an outcome reversed by supplying electrolyte- and glucose-enriched drinking water. Histologically, the bypassed colon had normal structure, but grew substantially less in diameter than the functional region proximal to the bypass. Extrinsic sympathetic and spinal afferent neurons projected to their normal targets, including arteries and the circular muscle, in aganglionic regions. However, although axons of intrinsic excitatory and inhibitory neurons grew into the aganglionic region, their normally dense innervation of circular muscle was not restored. Large nerve trunks that contained tyrosine hydroxylase (TH)-, calcitonin gene-related peptide (CGRP, encoded by Calca or Calcb)-, neuronal nitric oxide synthase (nNOS or NOS1)-, vasoactive intestinal peptide (VIP)- and tachykinin (encoded by Tac1)-immunoreactive axons occurred in the distal aganglionic region. We conclude that the rescued Ednrb-/- rat provides a good model for the development of cell therapies for the treatment of Hirschsprung disease.
MeSH term(s)	Rats ; Animals ; Hirschsprung Disease/therapy ; Hirschsprung Disease/pathology ; Colon/pathology ; Neurons/pathology ; Intestines/pathology ; Cell- and Tissue-Based Therapy
Language	English
Publishing date	2023-04-27
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2451104-3
ISSN	1754-8411 ; 1754-8403
ISSN (online)	1754-8411
ISSN	1754-8403
DOI	10.1242/dmm.050055
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Article ; Online: Disorders of interstitial cells of Cajal.

Burns, Alan J

Journal of pediatric gastroenterology and nutrition

2007 Volume 45 Suppl 2, Page(s) S103–6

Abstract: Interstitial cells of Cajal (ICCs) have, in the past 2 decades, been recognised as important elements in the regulation of gastrointestinal motility. Specifically, they have been shown to be critical for the generation and propagation of electrical slow ... ...

Abstract	Interstitial cells of Cajal (ICCs) have, in the past 2 decades, been recognised as important elements in the regulation of gastrointestinal motility. Specifically, they have been shown to be critical for the generation and propagation of electrical slow waves that regulate the phasic contractile activity of gastrointestinal smooth muscle, and for mediating neurotransmission from enteric motor neurons to smooth muscle cells. These different functional roles are carried out by different phenotypic classes of ICC that have discrete distributions within the tunica muscularis. Identifying the functional roles of ICC within the gut has been facilitated by studying mutant mice deficient in ICC, either as a consequence of loss of the tyrosine kinase receptor, Kit, or its ligand, stem cell factor, both of which are necessary for normal ICC development. In humans, under certain pathophysiological conditions, loss or defects in ICC networks appear to play a role in the generation of certain motility disorders. Alterations in ICC distribution have been reported in conditions such as achalasia, chronic intestinal pseudoobstruction, Hirschsprung disease, inflammatory bowel diseases, and slow transit constipation. Molecular and genetic techniques are helping researchers to determine whether defects in ICC networks are the cause of motility disorders, or whether the disrupted ICC networks are a consequence of gut dysfunction.
MeSH term(s)	Enteric Nervous System/cytology ; Enteric Nervous System/physiology ; Gastrointestinal Motility/genetics ; Gastrointestinal Motility/physiology ; Humans ; Intestinal Diseases/genetics ; Intestinal Diseases/physiopathology ; Intestines/innervation ; Intestines/physiopathology ; Muscle Contraction/physiology
Language	English
Publishing date	2007-12
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	603201-1
ISSN	1536-4801 ; 0277-2116
ISSN (online)	1536-4801
ISSN	0277-2116
DOI	10.1097/MPG.0b013e31812e65e0
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Zs.A 1728: Show issues

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Article ; Online: Transplanted enteric neural stem cells integrate within the developing chick spinal cord: implications for spinal cord repair.

Jevans, Benjamin / McCann, Conor J / Thapar, Nikhil / Burns, Alan J

Journal of anatomy

2018 Volume 233, Issue 5, Page(s) 592–606

Abstract: Spinal cord injury (SCI) causes paralysis, multisystem impairment and reduced life expectancy, as yet with no cure. Stem cell therapy can potentially replace lost neurons, promote axonal regeneration and limit scar formation, but an optimal stem cell ... ...

Abstract	Spinal cord injury (SCI) causes paralysis, multisystem impairment and reduced life expectancy, as yet with no cure. Stem cell therapy can potentially replace lost neurons, promote axonal regeneration and limit scar formation, but an optimal stem cell source has yet to be found. Enteric neural stem cells (ENSC) isolated from the enteric nervous system (ENS) of the gastrointestinal (GI) tract are an attractive source. Here, we used the chick embryo to assess the potential of ENSC to integrate within the developing spinal cord. In vitro, isolated ENSC formed extensive cell connections when co-cultured with spinal cord (SC)-derived cells. Further, qRT-PCR analysis revealed the presence of TuJ1
MeSH term(s)	Animals ; Chick Embryo ; Enteric Nervous System/cytology ; Neural Stem Cells/transplantation ; Spinal Cord ; Spinal Cord Regeneration/physiology ; Stem Cell Transplantation/methods
Language	English
Publishing date	2018-09-07
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2955-5
ISSN	1469-7580 ; 0021-8782
ISSN (online)	1469-7580
ISSN	0021-8782
DOI	10.1111/joa.12880
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Article ; Online: Combined treatment with enteric neural stem cells and chondroitinase ABC reduces spinal cord lesion pathology.

Jevans, Benjamin / James, Nicholas D / Burnside, Emily / McCann, Conor J / Thapar, Nikhil / Bradbury, Elizabeth J / Burns, Alan J

Stem cell research & therapy

2021 Volume 12, Issue 1, Page(s) 10

Abstract: Background: Spinal cord injury (SCI) presents a significant challenge for the field of neurotherapeutics. Stem cells have shown promise in replenishing the cells lost to the injury process, but the release of axon growth-inhibitory molecules such as ... ...

Abstract	Background: Spinal cord injury (SCI) presents a significant challenge for the field of neurotherapeutics. Stem cells have shown promise in replenishing the cells lost to the injury process, but the release of axon growth-inhibitory molecules such as chondroitin sulfate proteoglycans (CSPGs) by activated cells within the injury site hinders the integration of transplanted cells. We hypothesised that simultaneous application of enteric neural stem cells (ENSCs) isolated from the gastrointestinal tract, with a lentivirus (LV) containing the enzyme chondroitinase ABC (ChABC), would enhance the regenerative potential of ENSCs after transplantation into the injured spinal cord. Methods: ENSCs were harvested from the GI tract of p7 rats, expanded in vitro and characterised. Adult rats bearing a contusion injury were randomly assigned to one of four groups: no treatment, LV-ChABC injection only, ENSC transplantation only or ENSC transplantation+LV-ChABC injection. After 16 weeks, rats were sacrificed and the harvested spinal cords examined for evidence of repair. Results: ENSC cultures contained a variety of neuronal subtypes suitable for replenishing cells lost through SCI. Following injury, transplanted ENSC-derived cells survived and ChABC successfully degraded CSPGs. We observed significant reductions in the injured tissue and cavity area, with the greatest improvements seen in the combined treatment group. ENSC-derived cells extended projections across the injury site into both the rostral and caudal host spinal cord, and ENSC transplantation significantly increased the number of cells extending axons across the injury site. Furthermore, the combined treatment resulted in a modest, but significant functional improvement by week 16, and we found no evidence of the spread of transplanted cells to ectopic locations or formation of tumours. Conclusions: Regenerative effects of a combined treatment with ENSCs and ChABC surpassed either treatment alone, highlighting the importance of further research into combinatorial therapies for SCI. Our work provides evidence that stem cells taken from the adult gastrointestinal tract, an easily accessible source for autologous transplantation, could be strongly considered for the repair of central nervous system disorders.
MeSH term(s)	Animals ; Axons ; Chondroitin ABC Lyase/pharmacology ; Chondroitin Sulfate Proteoglycans ; Nerve Regeneration ; Neural Stem Cells/transplantation ; Rats ; Spinal Cord ; Spinal Cord Injuries/therapy
Chemical Substances	Chondroitin Sulfate Proteoglycans ; Chondroitin ABC Lyase (EC 4.2.2.20)
Language	English
Publishing date	2021-01-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2548671-8
ISSN	1757-6512 ; 1757-6512
ISSN (online)	1757-6512
ISSN	1757-6512
DOI	10.1186/s13287-020-02031-9
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Article ; Online: Neural stem cell therapies for enteric nervous system disorders.

Burns, Alan J / Thapar, Nikhil

Nature reviews. Gastroenterology & hepatology

2013 Volume 11, Issue 5, Page(s) 317–328

Abstract: The enteric nervous system is vulnerable to a range of congenital and acquired disorders that disrupt the function of its neurons or lead to their loss. The resulting enteric neuropathies are some of the most challenging clinical conditions to manage. ... ...

Abstract	The enteric nervous system is vulnerable to a range of congenital and acquired disorders that disrupt the function of its neurons or lead to their loss. The resulting enteric neuropathies are some of the most challenging clinical conditions to manage. Neural stem cells offer the prospect of a cure given their potential ability to replenish missing or dysfunctional neurons. This article discusses diseases that might be targets for stem cell therapies and the barriers that could limit treatment application. We explore various sources of stem cells and the proof of concept for their use. The critical steps that remain to be addressed before these therapies can be used in patients are also discussed. Key milestones include the harvesting of neural stem cells from the human gut and the latest in vivo transplantation studies in animals. The tremendous progress in the field has brought experimental studies exploring the potential of stem cell therapies for the management of enteric neuropathies to the cusp of clinical application.
MeSH term(s)	Animals ; Disease Models, Animal ; Enteric Nervous System/cytology ; Humans ; Intestinal Pseudo-Obstruction/therapy ; Neural Stem Cells/cytology ; Neural Stem Cells/transplantation ; Stem Cell Transplantation/methods ; Stem Cell Transplantation/trends ; Stem Cells/cytology ; Treatment Outcome
Language	English
Publishing date	2013-12-10
Publishing country	England
Document type	Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2493722-8
ISSN	1759-5053 ; 1759-5045
ISSN (online)	1759-5053
ISSN	1759-5045
DOI	10.1038/nrgastro.2013.226
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Zs.A 6020: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MG 97: Show issues

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Article ; Online: Enteric nervous system development in avian and zebrafish models.

Heanue, Tiffany A / Shepherd, Iain T / Burns, Alan J

Developmental biology

2016 Volume 417, Issue 2, Page(s) 129–138

Abstract: Our current understanding of the developmental biology of the enteric nervous system (ENS) and the genesis of ENS diseases is founded almost entirely on studies using model systems. Although genetic studies in the mouse have been at the forefront of this ...

Abstract	Our current understanding of the developmental biology of the enteric nervous system (ENS) and the genesis of ENS diseases is founded almost entirely on studies using model systems. Although genetic studies in the mouse have been at the forefront of this field over the last 20 years or so, historically it was the easy accessibility of the chick embryo for experimental manipulations that allowed the first descriptions of the neural crest origins of the ENS in the 1950s. More recently, studies in the chick and other non-mammalian model systems, notably zebrafish, have continued to advance our understanding of the basic biology of ENS development, with each animal model providing unique experimental advantages. Here we review the basic biology of ENS development in chick and zebrafish, highlighting conserved and unique features, and emphasising novel contributions to our general understanding of ENS development due to technical or biological features.
MeSH term(s)	Animals ; Animals, Genetically Modified ; Chick Embryo ; Enteric Nervous System/embryology ; Enteric Nervous System/physiology ; Gastrointestinal Tract/embryology ; Gastrointestinal Tract/innervation ; Gene Expression Regulation, Developmental ; Models, Animal ; Neural Crest/embryology ; Neural Crest/physiology ; Organogenesis/physiology ; Zebrafish/embryology
Language	English
Publishing date	2016--15
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	1114-9
ISSN	1095-564X ; 0012-1606
ISSN (online)	1095-564X
ISSN	0012-1606
DOI	10.1016/j.ydbio.2016.05.017
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