Intestinal stem cell dynamics: a story of mice and humans

Stem cell dynamics define the probability of accumulating mutations within the intestinal epithelium. In this issue of Cell Stem Cell, Nicholson et al. (2018) report that human intestinal stem cell dynamics differ significantly from those of mice and establish that oncogenic mutations are more likely to expand; therefore, "normal" epithelium may carry multiple mutations

The evaluation of medical devices with healthy people?

Much of the research of thermal and physical comfort is completed with healthy participants in regular life scenarios. The translation of these findings into clinical settings for people with disease, deficiency or restrictions adds a level of complexity. As an example this study evaluated the effectiveness of a patient warming mattress device on body temperature and ratings of thermal comfort/sensation. Hypothermia has been linked to higher mortality rates in trauma patients admitted to hospital. Patient warming devices have been developed to assist the temperature of the patient and studies on these report varied effects. Laboratory trials with shivering inhibition (Goheen et al, 1997, Greif et al, 2000) found improvements from forced air and resistive blankets but without shivering inhibition (Williams et al, 2005) showed no benefit in warming from 35°C. A physical evaluation of the warming mattress device with a thermal manikin reported an energy contribution to the user (~70W). To support the physical evaluation a user trial was conducted. Nine healthy volunteer participants (27.78+4.99 Years) were exposed to three conditions using a repeated measures counterbalanced design. The participants were cooled in an environment with an air temperature of 0°C (60 minutes) then exposed to 30 minutes of a warming intervention. 1.Hot mattress HM. Mattress preheated to 18°C, under standard blankets 2.Warmed mattress WM. Mattress turned on at start of warming period, under standard blankets 3.Cold mattress CM. Control condition, no power to mattress, under standard blankets. During the cooling phase, aural and mean skin temperature (Tsk) significantly decreased for all conditions (p<0.01). Tsk increased following each warming intervention but aural temperature continued to decline. Significant increase in overall mean thermal comfort was seen during the first ten minutes of the warming phase for HM in comparison to CM and WM (p<0.05) but not at 20 and 30 minutes. This was mirrored by the overall mean thermal sensation rating across the same timeframe. HM increased thermal sensation from very cold to cool with CM and WM showing and increase from very cold to cold. This study revealed the effect of the device (HM) gave short term comfort and sensation gains at the start of the warming phase but the passive insulation provided (CM) also allowed re-warming to occur. This was the expected thermoregulatory response for a group of healthy participants. This group does not necessarily represent the hospital population with pathology that inhibits their normal responses to cold, e.g. circulatory shut-down, shock or trauma. For accurate application, the trial data needs to be closely matched with the limitations of the health condition in the target population. The challenge is now to explore the relationship between data from healthy cohorts and how that can be used for groups of patients with known physical and physiological conditions and limitations. The validity of a patient’s subjective assessment of their condition lying in a hospital bed is currently unclear. Evidence needs to show whether a patient in a hospital bed can accurately report joint position, thermal comfort, skin wettedness, pressure points etc to assist in the management of their condition

The archival geographies of twentieth-century internationalism: Nation, empire and race

© 2020 The Authors This paper argues that more explicitly geographical methodologies are required to study twentieth-century internationalism, which invite different conversations between international historians and historical geographers. We show how the form and location of international archival records is itself evidence of multiple, interlocking modes of internationalism which unevenly intersected with national, imperial, and pan-national pasts. This is explored through three case studies: the archive of the International Institute of Intellectual Cooperation (IIIC), located in the UNESCO headquarters in Paris; the Maharaja Ganga Singh Archive in the Indian city of Bikaner; and the papers of Lydia Brown in New Bedford, Massachusetts, a translator and interpreter at the Second Pan-African Congress. We argue that bringing the archives of large international organisations into dialogue with a wider overlooked field of international archival evidence offers new perspectives on what internationalism was, where it happened, and to whom it mattered

Subversion of niche-signalling pathways in colorectal cancer: what makes and breaks the intestinal stem cell

The intestinal epithelium fulfils pleiotropic functions in nutrient uptake, waste elimination, and immune surveillance while also forming a barrier against luminal toxins and gut-resident microbiota. Incessantly barraged by extraneous stresses, the intestine must continuously replenish its epithelial lining and regenerate the full gamut of specialized cell types that underpin its functions. Homeostatic remodelling is orchestrated by the intestinal stem cell (ISC) niche: a convergence of epithelial- and stromal-derived cues, which maintains ISCs in a multipotent state. Following demise of homeostatic ISCs post injury, plasticity is pervasive among multiple populations of reserve stem-like cells, lineage-committed progenitors, and/or fully differentiated cell types, all of which can contribute to regeneration and repair. Failure to restore the epithelial barrier risks seepage of toxic luminal contents, resulting in inflammation and likely predisposing to tumour formation. Here, we explore how homeostatic niche-signalling pathways are subverted in tumorigenesis, enabling ISCs to gain autonomy from niche restraints (“ISC emancipation”) and transform into cancer stem cells capable of driving tumour initiation, progression, and therapy resistance. We further consider the implications of the pervasive plasticity of the intestinal epithelium for the trajectory of colorectal cancer, the emergence of distinct molecular subtypes, the propensity to metastasize, and the development of effective therapeutic strategies

Harnessing the power of advertising to prevent childhood obesity

Background: Social marketing integrates communication campaigns with behavioural and environmental change strategies. Childhood obesity programs could benefit significantly from social marketing but communication campaigns on this issue tend to be stand-alone. Methods: A large-scale multi-setting child obesity prevention program was implemented in the Hunter New England (HNE) region of New South Wales (NSW), Australia from 2005-2010. The program included a series of communication campaigns promoting the program and its key messages: drinking water; getting physically active and; eating more vegetables and fruit. Pre-post telephone surveys (n = 9) were undertaken to evaluate awareness of the campaigns among parents of children aged 2-15 years using repeat cross-sections of randomly selected cohorts. A total of 1,367 parents (HNE = 748, NSW = 619) participated. Results: At each survey post baseline, HNE parents were significantly more likely to have seen, read or heard about the program and its messages in the media than parents in the remainder of the state (p < 0.001). Further, there was a significant increase in awareness of the program and each of its messages over time in HNE compared to no change over time in NSW (p < 0.001). Awareness was significantly higher (p < 0.05) in HNE compared to NSW after each specific campaign (except the vegetable one) and significantly higher awareness levels were sustained for each campaign until the end of the program. At the end of the program participants without a tertiary education were significantly more likely (p = 0.04) to be aware of the brand campaign (31%) than those with (20%) but there were no other statistically significant socio-demographic differences in awareness. Conclusions: The Good for Kids communication campaigns increased and maintained awareness of childhood obesity prevention messages. Moreover, messages were delivered equitably to diverse socio-demographic groups within the region

High Redshift LAEs and their Cosmic Evolution: Morphologies, SFR and AGN Activity from z~2 to 6

We studied a large sample of ∼ 4000 high redshift Lyman-alpha Emitters (LAEs) in order to determine their properties and infer how they might have evolved into the local Universe. This was done through the exploration of the SC4K survey (Sobral et al. 2018a) and making use of the Hubble Space Telescope (HST), Chandra X-ray Observatory (Chandra) and the Very Large Array (VLA). We find that SC4K LAEs are mostly (69 ± 4%) compact disky galaxies (average S ́ersic index, n = 1.9 ± 2.2) The average star formation rate SFRLyα of LAEs is ≈ 17 M⊙ yr−1 . We find that SFR increases with increasing stellar mass. We also observed a characteristic ‘peak’ in SFR at M ∼ 10^9.3 M⊙, at redshift z ∼ 2.5, and progressing to higher stellar masses at higher redshifts. We find a total of 303 X-ray or radio detected active galactic nuclei (AGN) within the SC4K catalogue. These AGN have a range of black hole accretion rates (BHARs) from ∼ 0.03 M⊙ yr−1 to ∼ 3.3 M⊙ yr−1. The AGN fraction increases with increasing Lyα luminosity and decreases with increasing redshift, peaking at z ∼ 3. LAEs found at z ∼ 2−6 with a stellar mass M ∼ 10^10 M⊙ and a SFR ∼ 5.4M⊙yr−1 are consistent with being progenitors of Milky Way-like galaxies progenitor. Additionally, we found that the majority of the SC4K LAEs consists of cluster-like progenitors that will go on to form the brightest cluster galaxies (BCGs) in the local Universe

RAL GTPases drive intestinal stem cell function and regeneration through internalization of WNT signalosomes

Ral GTPases are RAS effector molecules and by implication a potential therapeutic target for RAS mutant cancer. However, very little is known about their roles in stem cells and tissue homeostasis. Using Drosophila, we identified expression of RalA in intestinal stem cells (ISCs) and progenitor cells of the fly midgut. RalA was required within ISCs for efficient regeneration downstream of Wnt signaling. Within the murine intestine, genetic deletion of either mammalian ortholog, Rala or Ralb, reduced ISC function and Lgr5 positivity, drove hypersensitivity to Wnt inhibition, and impaired tissue regeneration following damage. Ablation of both genes resulted in rapid crypt death. Mechanistically, RALA and RALB were required for efficient internalization of the Wnt receptor Frizzled-7. Together, we identify a conserved role for RAL GTPases in the promotion of optimal Wnt signaling, which defines ISC number and regenerative potential

Expression of R-Spondin 1 in Apc(Min/+) Mice Suppresses Growth of Intestinal Adenomas by Altering Wnt and Transforming Growth Factor Beta Signaling

BACKGROUND & AIMS: Mutations in the APC gene and other genes in the Wnt signaling pathway contribute to development of colorectal carcinomas. R-spondins (RSPOs) are secreted proteins that amplify Wnt signaling in intestinal stem cells. Alterations in RSPO genes have been identified in human colorectal tumors. We studied the effects of RSPO1 overexpression in ApcMin/thorn mutant mice. METHODS: An adeno associated viral vector encoding RSPO1-Fc fusion protein, or control vector, was injected into ApcMin/thornmice. Their intestinal crypts were isolated and cultured as organoids. which were incubated with or without RSPO1-Fc and an inhibitor of transforming growth factor beta receptor (TGFBR). Livers were collected from mice and analyzed by immunohistochemistry. Organoids and adenomas were analyzed by quantitative reverse-transcription PCR, single cell RNA sequencing, and immunohistochemistry. RESULTS: Intestines from Apcthorn/thorn mice injected with the vector encoding RSPO1-Fc had significantly deeper crypts, longer villi, with increased EdU labeling, indicating increased proliferation of epithelial cells, in comparison to mice given control vector. AAV-RSPO1-Fctransduced ApcMin/thorn mice also developed fewer and smaller intestinal tumors and had significantly longer survival times. Adenomas of ApcMin/thorn mice injected with the RSPO1-Fc vector showed a rapid increase in apoptosis and in the expression of Wnt target genes, followed by reduced expression of messenger RNAs and proteins regulated by the Wnt pathway, reduced cell proliferation, and less crypt branching than adenomas of mice given the control vector. Addition of RSPO1 reduced the number of adenoma organoids derived from ApcMin/thorn mice and suppressed expression of Wnt target genes but increased phosphorylation of SMAD2 and transcription of genes regulated by SMAD. Inhibition of TGFBR signaling in organoids stimulated with RSPO1-Fc restored organoid formation and expression of genes regulated by Wnt. The TGFBR inhibitor restored apoptosis in adenomas from ApcMin/thorn mice expressing RSPO1Fc back to the same level as in the adenomas from mice given the control vector. CONCLUSIONS: Expression of RSPO1 in ApcMin/thorn mice increases apoptosis and reduces proliferation and Wnt signaling in adenoma cells, resulting in development of fewer and smaller intestinal tumors and longer mouse survival. Addition of RSPO1 to organoids derived from adenomas inhibits their growth and promotes proliferation of intestinal stem cells that retain the APC protein; these effects are reversed by TGFB inhibitor. Strategies to increase the expression of RSPO1 might be developed for the treatment of intestinal adenomas.Peer reviewe

Loss of BCL9/9l suppresses Wnt driven tumourigenesis in models that recapitulate human cancer.

Different thresholds of Wnt signalling are thought to drive stem cell maintenance, regeneration, differentiation and cancer. However, the principle that oncogenic Wnt signalling could be specifically targeted remains controversial. Here we examine the requirement of BCL9/9l, constituents of the Wnt-enhanceosome, for intestinal transformation following loss of the tumour suppressor APC. Although required for Lgr5+ intestinal stem cells and regeneration, Bcl9/9l deletion has no impact upon normal intestinal homeostasis. Loss of BCL9/9l suppressed many features of acute APC loss and subsequent Wnt pathway deregulation in vivo. This resulted in a level of Wnt pathway activation that favoured tumour initiation in the proximal small intestine (SI) and blocked tumour growth in the colon. Furthermore, Bcl9/9l deletion completely abrogated β-catenin driven intestinal and hepatocellular transformation. We speculate these results support the just-right hypothesis of Wnt-driven tumour formation. Importantly, loss of BCL9/9l is particularly effective at blocking colonic tumourigenesis and mutations that most resemble those that occur in human cancer