Cellular shape reinforces niche to stem cell signaling in the small intestine

Pentinmikko, Nalle; Lozano, Rodrigo; Scharaw, Sandra; Andersson, Simon; Englund, Johanna; Castillo-Azofeifa, David; Gallagher, Aaron; Broberg, Martin; Song, Ki-Young; Sola-Carvajal, Agustín; Speidel, Alessondra T.; Sundström, M.; Allbritton, Nancy L.; Stevens, Molly M.; Klein, Ophir D.; Teixeira, Ana I.; Katajisto, Pekka

doi:10.1126/sciadv.abm1847

Cited by 30 publications

(24 citation statements)

References 81 publications

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“…ISC growth-induced changes in the relative contact surface to the basement membrane could potentially alter the niche derived signaling strength, and hence, the outcome of the daughter cell fate. In line with this idea, it was recently shown that ISC shape, which is linked to its surface to volume ratio, changed the strength of the niche derived intracellular signaling activities of the ISC in mouse small intestine 44 .…”

Section: Discussionmentioning

confidence: 79%

Stem cell growth directs region-specific cell fate decisions during intestinal nutrient adaptation

Mattila

Viitanen

Fabris

et al. 2023

Preprint

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The adult intestine is a regionalized organ, whose size and cellular composition is adjusted in response to nutrient status. This involves dynamic regulation of intestinal stem cell (ISC) proliferation and differentiation. How nutrient signaling controls cell fate decisions to drive regional changes in cell type composition remains unclear. Here we show that nutrient adaptation involves region-specific control of intestinal cell size, number and differentiation. We uncovered that activation of mTOR complex 1 increases ISC size in a region-specific manner. This promotes Delta expression to direct cell fate towards the absorptive enteroblast lineage, while inhibiting secretory enteroendocrine cell differentiation. The observed coupling between nutrient sensing and cell fate enabled mitigation of aging-induced ISC misdifferentiation through intermittent fasting. In conclusion, ISC size acts as an early fate determinant allowing regional control of intestinal cell differentiation in response to nutrition with relevance to maintenance of tissue integrity during aging.

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Section: Discussionmentioning

confidence: 79%

Stem cell growth directs region-specific cell fate decisions during intestinal nutrient adaptation

Mattila

Viitanen

Fabris

et al. 2023

Preprint

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“…2a-c). Importantly, the extended lateral Golgi morphology coincided with the region harbouring ISCs and Paneth cells, which display a particular large lateral plasma membrane interface aiding their interactions 8 . Moreover, similar lateral Golgi morphology was also observed in the columnar ISCs of the colon (Extended Data Fig.…”

Section: Lateral Golgi Stacks Mediate Efficient Receptor Transportmentioning

confidence: 94%

“…1h). Moreover, amongst the ISCs located centrally within the niche, intensity of the Lgr5-linked eGFP expression, which correlates with stemness potential 8 , was higher in ISCs with two lateral Golgi as compared to ISCs with one lateral Golgi (Fig. 1i).…”

Section: Lateral Golgi Stacks Mediate Efficient Receptor Transportmentioning

confidence: 96%

“…To choose the receptor for assessing ISC receptor transport, we analysed the RNA expression levels of known receptors crucial for ISC function between Lgr5-eGFP high ISCs, transit-amplifying (TA) progenitor eGFP low cells and Paneth cells 4,7,8 . Amongst these, epidermal growth factor receptor (Egfr) showed a clear gradual increase in expression from Paneth cells to TAs and ISCs (Extended Data Fig.…”

Section: Development Of a Receptor Transport Assay In Intestinal Stem...mentioning

confidence: 99%

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Golgi organization is a determinant of stem cell function in the small intestine

Scharaw

Sola-Carvajal

Belevich

et al. 2023

Preprint

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Cell-to-cell signalling between niche and stem cells regulates tissue regeneration. While the identity of many mediating factors is known, it is largely unknown whether stem cells optimize their receptiveness to niche signals according to the niche organization. Here, we show that Lgr5+ small intestinal stem cells (ISCs) regulate the morphology and orientation of their secretory apparatus to match the niche architecture, and to increase transport efficiency of niche signal receptors. Unlike the progenitor cells lacking lateral niche contacts, ISCs orient Golgi apparatus laterally towards Paneth cells of the epithelial niche, and divide Golgi into multiple stacks reflecting the number of Paneth cell contacts. Stem cells with a higher number of lateral Golgi transported Epidermal growth factor receptor (Egfr) with a higher efficiency than cells with one Golgi. The lateral Golgi orientation and enhanced Egfr transport required A-kinase anchor protein 9 (Akap9), and was necessary for normal regenerative capacity in vitro. Moreover, reduced Akap9 in aged ISCs renders ISCs insensitive to niche-dependent modulation of Golgi stack number and transport efficiency. Our results reveal stem cell-specific Golgi complex configuration that facilitates efficient niche signal reception and tissue regeneration, which is compromised in the aged epithelium.

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“…These models are specifically a breakthrough for intestinal studies given the complex native crypt-villus geometry, which is required for efficient intestinal stem cells self-renewal and for the generation of biochemical gradients that mediate cell communication, differentiation and proliferation. 168 , 169 A variety of biomaterials have been used to create the scaffolds, ranging from biocompatible hydrogels based on natural or synthetic biopolymers with tunable physiochemical properties 170 , 171 to decellularized extracellular matrix. 172 Besides the biochemical scaffold composition, also its stiffness impacts the morphology and differentiation of intestinal epithelial cells.…”

Section: Advanced Intestinal Culture Systemsmentioning

confidence: 99%

In vitro and ex vivo modeling of enteric bacterial infections

2022

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Enteric bacterial infections contribute substantially to global disease burden and mortality, particularly in the developing world. In vitro 2D monolayer cultures have provided critical insights into the fundamental virulence mechanisms of a multitude of pathogens, including Salmonella enterica serovars Typhimurium and Typhi, Vibrio cholerae, Shigella spp., Escherichia coli and Campylobacter jejuni , which have led to the identification of novel targets for antimicrobial therapy and vaccines. In recent years, the arsenal of experimental systems to study intestinal infections has been expanded by a multitude of more complex models, which have allowed to evaluate the effects of additional physiological and biological parameters on infectivity. Organoids recapitulate the cellular complexity of the human intestinal epithelium while 3D bioengineered scaffolds and microphysiological devices allow to emulate oxygen gradients, flow and peristalsis, as well as the formation and maintenance of stable and physiologically relevant microbial diversity. Additionally, advancements in ex vivo cultures and intravital imaging have opened new possibilities to study the effects of enteric pathogens on fluid secretion, barrier integrity and immune cell surveillance in the intact intestine. This review aims to present a balanced and updated overview of current intestinal in vitro and ex vivo methods for modeling of enteric bacterial infections. We conclude that the different paradigms are complements rather than replacements and their combined use promises to further our understanding of host-microbe interactions and their impacts on intestinal health.

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Cellular shape reinforces niche to stem cell signaling in the small intestine

Cited by 30 publications

References 81 publications

Stem cell growth directs region-specific cell fate decisions during intestinal nutrient adaptation

Stem cell growth directs region-specific cell fate decisions during intestinal nutrient adaptation

Golgi organization is a determinant of stem cell function in the small intestine

In vitro and ex vivo modeling of enteric bacterial infections

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