Organoid-based regenerative medicine for inflammatory bowel disease

Okamoto, Ryuichi; Shimizu, Hiromichi; Suzuki, Kohei; Kawamoto, Ami; Takahashi, Junichi; Kawai, Masahiro; Nagata, Sayaka; Hiraguri, Yui; Takeoka, Sayaka; Sugihara, Hady Yuki; Yui, Satoru; Watanabe, Mamoru

doi:10.1016/j.reth.2019.11.004

Cited by 47 publications

(36 citation statements)

References 51 publications

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“…Indeed, after acute inflammation, stem cells maintain their quiescent phenotype showing decreased proliferation and migration, as well as poor differentiation. In addition to immunity control, tissue regeneration is a major aim in IBD therapy [ 48 ].…”

Section: Consequences Of Prolonged Gsk3β Activation In Inflammatiomentioning

confidence: 99%

GSK3β, a Master Kinase in the Regulation of Adult Stem Cell Behavior

Racaud‐Sultan

Vergnolle

2021

Cells

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In adult stem cells, Glycogen Synthase Kinase 3β (GSK3β) is at the crossroad of signaling pathways controlling survival, proliferation, adhesion and differentiation. The microenvironment plays a key role in the regulation of these cell functions and we have demonstrated that the GSK3β activity is strongly dependent on the engagement of integrins and protease-activated receptors (PARs). Downstream of the integrin α5β1 or PAR2 activation, a molecular complex is organized around the scaffolding proteins RACK1 and β-arrestin-2 respectively, containing the phosphatase PP2A responsible for GSK3β activation. As a consequence, a quiescent stem cell phenotype is established with high capacities to face apoptotic and metabolic stresses. A protective role of GSK3β has been found for hematopoietic and intestinal stem cells. Latters survived to de-adhesion through PAR2 activation, whereas formers were protected from cytotoxicity through α5β1 engagement. However, a prolonged activation of GSK3β promoted a defect in epithelial regeneration and a resistance to chemotherapy of leukemic cells, paving the way to chronic inflammatory diseases and to cancer resurgence, respectively. In both cases, a sexual dimorphism was measured in GSK3β-dependent cellular functions. GSK3β activity is a key marker for inflammatory and cancer diseases allowing adjusted therapy to sex, age and metabolic status of patients.

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Section: Consequences Of Prolonged Gsk3β Activation In Inflammatiomentioning

confidence: 99%

GSK3β, a Master Kinase in the Regulation of Adult Stem Cell Behavior

Racaud‐Sultan

Vergnolle

2021

Cells

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“…After the rapid growth in technology to grow and maintain intestinal epithelial derived Lgr5 + stem cells as enteroids, studies of autologous organoid transplantation to re-populate the ISC niche have just started to take place. This type of methodology has been demonstrated using cancer models and has been extensively reviewed for use in the SI (Qi et al, 2020), and the possibility of it being used in IBD (Okamoto et al, 2020), although the FIGURE 3 | Potential for use of intestinal organoids as "grafts" for the damaged epithelium. Recent advances in epithelial regeneration via organoid transplantation have shown that it could be possible to recover a damaged intestine or colon with autologous organoid transplantation.…”

Section: Autologous Organoid Transplantation-can We Rescue the Damagementioning

confidence: 99%

Regenerative Intestinal Stem Cells Induced by Acute and Chronic Injury: The Saving Grace of the Epithelium?

Rees

Tandun

Yau

et al. 2020

Front. Cell Dev. Biol.

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The intestinal epithelium is replenished every 3–4 days through an orderly process that maintains important secretory and absorptive functions while preserving a continuous mucosal barrier. Intestinal epithelial cells (IECs) derive from a stable population of intestinal stem cells (ISCs) that reside in the basal crypts. When intestinal injury reaches the crypts and damages IECs, a mechanism to replace them is needed. Recent research has highlighted the existence of distinct populations of acute and chronic damage-associated ISCs and their roles in maintaining homeostasis in several intestinal perturbation models. What remains unknown is how the damage-associated regenerative ISC population functions in the setting of chronic inflammation, as opposed to acute injury. What long-term consequences result from persistent inflammation and other cellular insults to the ISC niche? What particular “regenerative” cell types provide the most efficacious restorative properties? Which differentiated IECs maintain the ability to de-differentiate and restore the ISC niche? This review will cover the latest research on damage-associated regenerative ISCs and epigenetic factors that determine ISC fate, as well as provide opinions on future studies that need to be undertaken to understand the repercussions of the emergence of these cells, their contribution to relapses in inflammatory bowel disease, and their potential use in therapeutics for chronic intestinal diseases.

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“…The European Crohn's and Colitis Organization lists mucosal healing as a therapeutic target in its 2017 consensus guidelines for both UC and CD ( 140 , 141 ). Local transplant of organoids to aid mucosal healing has been proposed as a potential therapy in IBD to aid epithelial regeneration and achieve mucosal healing ( 142 ). Studies using murine colitis models have demonstrated that human small bowel and colonic organoid cultures can engraft onto the ulcerated mucosa and reconstitute the normal crypt-villus architecture ( 58 , 143 , 144 ).…”

Section: Translational Application Of Organoid Models In Ibdmentioning

confidence: 99%

The Role of Organoids as a Novel Platform for Modeling of Inflammatory Bowel Disease

2021

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Inflammatory bowel disease (IBD) is a chronic relapsing-remitting immune-mediated disorder affecting the gut. It is common in Westernized regions and is increasing in incidence in developing countries. At a molecular level, intrinsic deficiencies in epithelial integrity, mucosal barrier function, and mechanisms of immune response and resolution contribute to the development of IBD. Traditionally two platforms have been utilized for disease modeling of IBD; in-vitro monolayer cell culture and in-vivo animal models. Both models have limitations, including cost, lack of representative cell types, lack of complexity of cellular interactions in a living organism, and xenogeneity. Organoids, three-dimensional cellular structures which recapitulate the basic architecture and functional processes of the organ of origin, hold potential as a third platform with which to investigate the pathogenesis and molecular defects which give rise to IBD. Organoids retain the genetic and transcriptomic profile of the tissue of origin over time and unlike monolayer cell culture can be induced to differentiate into most adult intestinal cell types. They may be used to model intestinal host-microbe interactions occurring at the mucosal barrier, are amenable to genetic manipulation and can be co-cultured with other cell lines of interest. Bioengineering approaches may be applied to render a more faithful representation of the intestinal epithelial niche. In this review, we outline the concept of intestinal organoids, discuss the advantages and disadvantages of the platform comparative to alternative models, and describe the translational applications of organoids in IBD.

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Organoid-based regenerative medicine for inflammatory bowel disease

Cited by 47 publications

References 51 publications

GSK3β, a Master Kinase in the Regulation of Adult Stem Cell Behavior

GSK3β, a Master Kinase in the Regulation of Adult Stem Cell Behavior

Regenerative Intestinal Stem Cells Induced by Acute and Chronic Injury: The Saving Grace of the Epithelium?

The Role of Organoids as a Novel Platform for Modeling of Inflammatory Bowel Disease

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