Enteric neural stem cell therapies for enteric neuropathies

McCann, Conor J.; Thapar, Nikhil

doi:10.1111/nmo.13369

Cited by 12 publications

(10 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Regenerative medicine and trophic factor modulation hold promise for treating life-threatening enteric neuropathies. 2 , 3 To facilitate reprogramming and improve bowel function, better understanding of the molecular identity and characteristics of ENS subtypes is needed. 2 We used single-cell transcriptomics to identify hundreds of neurotransmitters, receptors, ion channels, signaling molecules, and messenger RNA regulatory genes differentially expressed in 7 mouse myenteric neuron subclasses in adult distal colon and 8 neuron groups at E17.5.…”

Section: Discussionmentioning

confidence: 99%

“…Unfortunately, we have limited ability to identify missing or defective ENS cell populations in people with bowel dysmotility, and therapies are inadequate. Promising new approaches like regenerative medicine 2 or glial cell line–derived neurotrophic factor (GDNF)–induced regeneration of the ENS 3 would benefit from a more thorough characterization of the transcription factors, receptors, and signaling pathways that define enteric neuron subclasses.…”

mentioning

confidence: 99%

See 1 more Smart Citation

scRNA-Seq Reveals New Enteric Nervous System Roles for GDNF, NRTN, and TBX3

Wright

Schneider

Smith‐Edwards

et al. 2021

Cellular and Molecular Gastroenterology and Hepatology

113

View full text Add to dashboard Cite

Background and Aims Bowel function requires coordinated activity of diverse enteric neuron subtypes. Our aim was to define gene expression in these neuron subtypes to facilitate development of novel therapeutic approaches to treat devastating enteric neuropathies, and to learn more about enteric nervous system function. Methods To identify subtype–specific genes, we performed single-nucleus RNA-seq on adult mouse and human colon myenteric plexus, and single-cell RNA-seq on E17.5 mouse ENS cells from whole bowel. We used immunohistochemistry, select mutant mice, and calcium imaging to validate and extend results. Results RNA-seq on 635 adult mouse colon myenteric neurons and 707 E17.5 neurons from whole bowel defined seven adult neuron subtypes, eight E17.5 neuron subtypes and hundreds of differentially expressed genes. Manually dissected human colon myenteric plexus yielded RNA-seq data from 48 neurons, 3798 glia, 5568 smooth muscle, 377 interstitial cells of Cajal, and 2153 macrophages. Immunohistochemistry demonstrated differential expression for BNC2, PBX3, SATB1, RBFOX1, TBX2, and TBX3 in enteric neuron subtypes. Conditional Tbx3 loss reduced NOS1-expressing myenteric neurons. Differential Gfra1 and Gfra2 expression coupled with calcium imaging revealed that GDNF and neurturin acutely and differentially regulate activity of ∼50% of myenteric neurons with distinct effects on smooth muscle contractions. Conclusion Single cell analyses defined genes differentially expressed in myenteric neuron subtypes and new roles for TBX3, GDNF and NRTN. These data facilitate molecular diagnostic studies and novel therapeutics for bowel motility disorders.

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

scRNA-Seq Reveals New Enteric Nervous System Roles for GDNF, NRTN, and TBX3

Wright

Schneider

Smith‐Edwards

et al. 2021

Cellular and Molecular Gastroenterology and Hepatology

113

View full text Add to dashboard Cite

show abstract

“…This DT-induced model of focal enteric aganglionosis can be leveraged to explore neuronal stem cell therapy for the treatment of intestinal aganglionosis and also to study interactions between the ENS and other cell types within the gut wall. To date, neuronal stem cell transplantation studies in HSCR models have been restricted to 1–2 weeks duration due to the poor survival of these animals, which has been a significant limitation in the field 45–47 . While our model has distinct advantages over existing mouse models of HSCR, it is important to note that our DT model does not represent a true etiological model of the disease since, unlike HSCR, the aganglionosis in our model is not congenital.…”

Section: Discussionmentioning

confidence: 99%

Enteric neuronal cell therapy reverses architectural changes in a novel diphtheria toxin-mediated model of colonic aganglionosis

Bhave

Arciero

Baker

et al. 2019

Sci Rep

View full text Add to dashboard Cite

Hirschsprung disease (HSCR) is characterized by absence of the enteric nervous system (ENS) in the distal bowel. Despite removal of the aganglionic segment, gastrointestinal (GI) problems persist. Cell therapy offers potential treatment but use of genetic models is limited by their poor survival. We have developed a novel model of aganglionosis in which enteric neural crest-derived cells (ENCDCs) express diphtheria toxin (DT) receptor. Local DT injection into the colon wall results in focal, specific, and sustained ENS ablation without altering GI transit or colonic contractility, allowing improved survival over other aganglionosis models. Focal ENS ablation leads to increased smooth muscle and mucosal thickness, and localized inflammation. Transplantation of ENCDCs into this region leads to engraftment, migration, and differentiation of enteric neurons and glial cells, with restoration of normal architecture of the colonic epithelium and muscle, reduction in inflammation, and improved survival.

show abstract

“…regarding feasibility of generating a functional multi-layered intestinal graft 42,73 , albeit the full diversity of enteric neuron cell types has yet to be determined 157 . However, such approach lacks scaffolding with limited upscaling potential to generate robust constructs which might subsequently be amenable to surgical transplantation.…”

Section: Subsequent Addition Of Nccs and Formation Of Primitive Neuro...mentioning

confidence: 99%

Building gut from scratch — progress and update of intestinal tissue engineering

Tullie

Jones

Coppi

et al. 2022

Nat Rev Gastroenterol Hepatol

View full text Add to dashboard Cite

Short bowel syndrome (SBS), a condition defined by insufficient absorptive intestinal epithelium, is a rare disease, with an estimated prevalence up to 0.4 in 10,000 people. However, it has substantial morbidity and mortality for affected patients. The mainstay of treatment in SBS is supportive, in the form of intravenous parenteral nutrition, with the aim of achieving intestinal autonomy. The lack of a definitive curative therapy has led to attempts to harness innate developmental and regenerative mechanisms to engineer neo-intestine as an alternative approach to address this unmet clinical need. Exciting advances have been made in the field of intestinal tissue engineering (ITE) over the past decade, making a review in this field timely. In this Review, we discuss the latest advances in the components required to engineer intestinal grafts and summarise the progress of ITE. We also explore some key factors to consider and challenges to overcome when transitioning tissue engineered intestine towards clinical translation and provide the future outlook of ITE in therapeutic applications and beyond. BlurbIntestinal tissue engineering offers a potential therapeutic option for short bowel syndrome. This Review examines the progress in intestinal tissue engineering, discusses the components required for engineered intestinal grafts, preclinical progress and efforts towards clinical translation, including challenges to overcome. Key points• Intestinal tissue engineering has the potential to offer curative therapy for patients with short bowel syndrome • Multiple components, including an absorptive mucosa, smooth muscle, enteric nerves and vasculature are required to generate a functional full thickness intestinal graft• Advances in intestinal tissue engineering include endothelial cell reprogramming and vascular engineering, generation of mucosal grafts using patient-derived materials and colon mucosal repurposing using small intestinal organoids.• Vascularisation and lymphatic engineering, generation of multi-layered personalised intestinal grafts and scaling-up of graft size present some of the future challenges in

show abstract

Enteric neural stem cell therapies for enteric neuropathies

Cited by 12 publications

References 64 publications

scRNA-Seq Reveals New Enteric Nervous System Roles for GDNF, NRTN, and TBX3

scRNA-Seq Reveals New Enteric Nervous System Roles for GDNF, NRTN, and TBX3

Enteric neuronal cell therapy reverses architectural changes in a novel diphtheria toxin-mediated model of colonic aganglionosis

Building gut from scratch — progress and update of intestinal tissue engineering

Contact Info

Product

Resources

About