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1.
Int J Mol Sci ; 18(10)2017 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-28954442

RESUMO

Effective digestion requires propagation of food along the entire length of the gastrointestinal tract. This process involves coordinated waves of peristalsis produced by enteric neural cell types, including different categories of interstitial cells of Cajal (ICC). Impaired food transport along the gastrointestinal tract, either too fast or too slow, causes a range of gut motility disorders that affect millions of people worldwide. Notably, loss of ICC has been shown to affect gut motility. Patients that suffer from gut motility disorders regularly experience diarrhoea and/or constipation, insomnia, anxiety, attention lapses, irritability, dizziness, and headaches that greatly affect both physical and mental health. Limited treatment options are available for these patients, due to the scarcity of human gut tissue for research and transplantation. Recent advances in stem cell technology suggest that large amounts of rudimentary, yet functional, human gut tissue can be generated in vitro for research applications. Intriguingly, these stem cell-derived gut organoids appear to contain functional ICC, although their frequency and functional properties are yet to be fully characterised. By reviewing methods of gut organoid generation, together with what is known of the molecular and functional characteristics of ICC, this article highlights short- and long-term goals that need to be overcome in order to develop ICC-based therapies for gut motility disorders.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos , Células Intersticiais de Cajal/metabolismo , Células Intersticiais de Cajal/transplante , Organoides/citologia , Animais , Biomarcadores , Diferenciação Celular , Separação Celular/métodos , Transplante de Células , Citometria de Fluxo , Motilidade Gastrointestinal/fisiologia , Humanos , Células Intersticiais de Cajal/citologia , Fenótipo , Regeneração , Transdução de Sinais , Técnicas de Cultura de Tecidos
2.
Gastroenterology ; 148(5): 978-90, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25637652

RESUMO

BACKGROUND & AIMS: After allogeneic transplantation, murine stem cells (SCs) for interstitial cells of Cajal (ICCs), electrical pacemaker, and neuromodulator cells of the gut, were incorporated into gastric ICC networks, indicating in vivo immunosuppression. Immunosuppression is characteristic of bone marrow- and other non-gut-derived mesenchymal stem cells (MSCs), which are emerging as potential therapeutic agents against autoimmune diseases, including inflammatory bowel disease. Therefore, we investigated whether gut-derived ICC-SCs could also mitigate experimental colitis and studied the mechanisms of ICC-SC-mediated immunosuppression in relation to MSC-induced pathways. METHODS: Isolated ICC-SCs were studied by transcriptome profiling, cytokine assays, flow cytometry, mixed lymphocyte reaction, and T-cell proliferation assay. Mice with acute and chronic colitis induced by dextran sulfate sodium and T-cell transfer, respectively, were administered ICC-SCs intraperitoneally and evaluated for disease activity by clinical and pathological assessment and for ICC-SC homing by live imaging. RESULTS: Unlike strain-matched dermal fibroblasts, intraperitoneally administered ICC-SCs preferentially homed to the colon and reduced the severity of both acute and chronic colitis assessed by clinical and blind pathological scoring. ICC-SCs profoundly suppressed T-cell proliferation in vitro. Similar to MSCs, ICC-SCs strongly expressed cyclooxygenase 1/2 and basally secreted prostaglandin E2. Indomethacin, a cyclooxygenase inhibitor, countered the ICC-SC-mediated suppression of T-cell proliferation. In contrast, we found no role for regulatory T-cell-, programmed death receptor-, and transforming growth factor-ß-mediated mechanisms reported in MSCs; and transcriptome profiling did not support a relationship between ICC-SCs and MSCs. CONCLUSIONS: Murine ICC-SCs belong to a class different from MSCs and potently mitigate experimental colitis via prostaglandin E2-mediated immunosuppression.


Assuntos
Colite/prevenção & controle , Colo , Dinoprostona/metabolismo , Imunidade Celular , Células Intersticiais de Cajal/transplante , Transplante de Células-Tronco , Transferência Adotiva , Animais , Proliferação de Células , Células Cultivadas , Colite/induzido quimicamente , Colite/imunologia , Colite/metabolismo , Colite/patologia , Colo/imunologia , Colo/metabolismo , Colo/patologia , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Sulfato de Dextrana , Perfilação da Expressão Gênica , Marcadores Genéticos , Proteínas de Homeodomínio/genética , Hospedeiro Imunocomprometido , Células Intersticiais de Cajal/imunologia , Células Intersticiais de Cajal/metabolismo , Ativação Linfocitária , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/transplante , Fatores de Tempo
3.
J Cell Mol Med ; 18(5): 780-9, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24655344

RESUMO

The midterm effects of cardiac telocytes (CTs) transplantation on myocardial infarction (MI) and the cellular mechanisms involved in the beneficial effects of CTs transplantation are not understood. In the present study, we have revealed that transplantation of CTs was able to significantly decrease the infarct size and improved cardiac function 14 weeks after MI. It has established that CT transplantation exerted a protective effect on the myocardium and this was maintained for at least 14 weeks. The cellular mechanism behind this beneficial effect on MI was partially attributed to increased cardiac angiogenesis, improved reconstruction of the CT network and decreased myocardial fibrosis. These combined effects decreased the infarct size, improved the reconstruction of the LV and enhanced myocardial function in MI. Our findings suggest that CTs could be considered as a potential cell source for therapeutic use to improve cardiac repair and function following MI, used either alone or in tandem with stem cells.


Assuntos
Células Intersticiais de Cajal/transplante , Infarto do Miocárdio/fisiopatologia , Infarto do Miocárdio/terapia , Miocárdio/patologia , Animais , Antígenos CD34/metabolismo , Colágeno/metabolismo , Feminino , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Infarto do Miocárdio/patologia , Neovascularização Fisiológica , Proteínas Proto-Oncogênicas c-kit/metabolismo , Ratos Sprague-Dawley , Transplante de Células-Tronco
4.
Neurogastroenterol Motil ; 25(6): e418-28, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23638836

RESUMO

BACKGROUND: Loss or disruption of Kit(+) -interstitial cells of Cajal (ICC) capable of generating pacemaker activity has been implicated in the development of numerous gastrointestinal motility disorders. We sought to develop a model where ICC could be allotransplanted into intestines naturally devoid of these cells. METHODS: Enzymatically dispersed cells from the intestinal tunica muscularis of Kit(+/copGFP) and Kit(V558Δ) /+ gain-of-function mice were allotransplanted into myenteric plexus regions of W/W(V) mutant intestines that lack ICC at the level of the myenteric plexus (ICC-MY) and pacemaker activity. Immunohistochemical analysis fate mapped the development of ICC-MY networks and intracellular microelectrode recordings provided evidence for the development of functional pacemaker activity. KEY RESULTS: Kit(+) -ICC developed into distinct networks at the level of the myenteric plexus in organotypic cultures over 28 days and displayed robust rhythmic pacemaker activity. CONCLUSIONS & INFERENCES: This study demonstrates the feasibility of allotransplantation of ICC into the myenteric region of the small intestine and the establishment of functional pacemaker activity into tissues normally devoid of ICC-MY and slow waves, thus providing a possible basis for the therapeutic treatment of patients where ICC networks have been disrupted due to a variety of pathophysiological conditions.


Assuntos
Relógios Biológicos/fisiologia , Células Intersticiais de Cajal/transplante , Músculo Liso/citologia , Plexo Mientérico/citologia , Aloenxertos , Animais , Células Intersticiais de Cajal/citologia , Camundongos , Músculo Liso/fisiologia , Plexo Mientérico/fisiologia
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