Publications by authors named "Pawel J Schweiger"

10 Publications

  • Page 1 of 1

Intestinal Organoids: A Tool for Modelling Diet-Microbiome-Host Interactions.

Trends Endocrinol Metab 2020 11 9;31(11):848-858. Epub 2020 Mar 9.

CIBIO - Department of Cellular, Computational, and Integrative Biology, University of Trento, Via Sommarive 9, Trento, Italy.

Dietary patterns, microbiome dysbiosis, and gut microbial metabolites (GMMs) have a pivotal role in the homeostasis of intestinal epithelial cells and in disease progression, such as that of colorectal cancer (CRC). Although GMMs and microorganisms have crucial roles in many biological activities, models for deciphering diet-microbiome-host relationships are largely limited to animal models. Thus, intestinal organoids (IOs) have provided unprecedented opportunities for the generation of in vitro platforms with the sufficient level of complexity to model physiological and pathological diet-microbiome-host conditions. Overall, IO responses to GMM metabolites and microorganisms can provide new insights into the mechanisms by which those agents may prevent or trigger diseases, significantly extending our knowledge of diet-microbiome-host interactions.
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http://dx.doi.org/10.1016/j.tem.2020.02.004DOI Listing
November 2020

Lrig1 marks a population of gastric epithelial cells capable of long-term tissue maintenance and growth in vitro.

Sci Rep 2018 10 15;8(1):15255. Epub 2018 Oct 15.

BRIC - Biotech Research & Innovation Centre, University of Copenhagen, DK-2200, Copenhagen N, Denmark.

The processes involved in renewal of the epithelium that lines the mouse stomach remain unclear. Apart from the cells in the isthmus, several other populations located deeper in the gastric glands have been suggested to contribute to the maintenance of the gastric epithelium. Here, we reveal that Lrig1 is expressed in the basal layer of the forestomach and the lower part of glands in the corpus and pylorus. In the glandular epithelium of the stomach, Lrig1 marks a heterogeneous population comprising mainly non-proliferative cells. Yet, fate-mapping experiments using a knock-in mouse line expressing Cre specifically in Lrig1 cells demonstrate that these cells are able to contribute to the long-term maintenance of the gastric epithelium. Moreover, when cultured in vitro, cells expressing high level of Lrig1 have much higher organoid forming potential than the corresponding cellular populations expressing lower levels of Lrig1. Taken together, these observations show that Lrig1 is expressed primarily by differentiated cells, but that these cells can be recruited to contribute to the maintenance of the gastric epithelium. This confirms previous observations that cells located in the lower segments of gastric glands can participate in tissue replenishment.
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http://dx.doi.org/10.1038/s41598-018-33578-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6189208PMC
October 2018

YAP/TAZ-Dependent Reprogramming of Colonic Epithelium Links ECM Remodeling to Tissue Regeneration.

Cell Stem Cell 2018 01 14;22(1):35-49.e7. Epub 2017 Dec 14.

BRIC - Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloes Vej 5, 2200 Copenhagen N, Denmark; Novo Nordisk Foundation Center for Stem Cell Research, Faculty of Health Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark. Electronic address:

Tissue regeneration requires dynamic cellular adaptation to the wound environment. It is currently unclear how this is orchestrated at the cellular level and how cell fate is affected by severe tissue damage. Here we dissect cell fate transitions during colonic regeneration in a mouse dextran sulfate sodium (DSS) colitis model, and we demonstrate that the epithelium is transiently reprogrammed into a primitive state. This is characterized by de novo expression of fetal markers as well as suppression of markers for adult stem and differentiated cells. The fate change is orchestrated by remodeling the extracellular matrix (ECM), increased FAK/Src signaling, and ultimately YAP/TAZ activation. In a defined cell culture system recapitulating the extracellular matrix remodeling observed in vivo, we show that a collagen 3D matrix supplemented with Wnt ligands is sufficient to sustain endogenous YAP/TAZ and induce conversion of cell fate. This provides a simple model for tissue regeneration, implicating cellular reprogramming as an essential element.
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http://dx.doi.org/10.1016/j.stem.2017.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5766831PMC
January 2018

Dietary Control of Skin Lipid Composition and Microbiome.

J Invest Dermatol 2018 05 14;138(5):1225-1228. Epub 2017 Dec 14.

BRIC-Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen N, Denmark; Novo Nordisk Foundation Center for Stem Cell Research, University of Copenhagen, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N, Denmark. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2017.12.005DOI Listing
May 2018

A genetically inducible porcine model of intestinal cancer.

Mol Oncol 2017 11 10;11(11):1616-1629. Epub 2017 Oct 10.

Department of Molecular Medicine, Aarhus University Hospital, Denmark.

Transgenic porcine cancer models bring novel possibilities for research. Their physical similarities with humans enable the use of surgical procedures and treatment approaches used for patients, which facilitates clinical translation. Here, we aimed to develop an inducible oncopig model of intestinal cancer. Transgenic (TG) minipigs were generated using somatic cell nuclear transfer by handmade cloning. The pigs encode two TG cassettes: (a) an Flp recombinase-inducible oncogene cassette containing KRAS-G12D, cMYC, SV40LT - which inhibits p53 - and pRB and (b) a 4-hydroxytamoxifen (4-OHT)-inducible Flp recombinase activator cassette controlled by the intestinal epithelium-specific villin promoter. Thirteen viable transgenic minipigs were born. The ability of 4-OHT to activate the oncogene cassette was confirmed in vitro in TG colonic organoids and ex vivo in tissue biopsies obtained by colonoscopy. In order to provide proof of principle that the oncogene cassette could also successfully be activated in vivo, three pigs were perorally treated with 400 mg tamoxifen for 2 × 5 days. After two months, one pig developed a duodenal neuroendocrine carcinoma with a lymph node metastasis. Molecular analysis of the carcinoma and metastasis confirmed activation of the oncogene cassette. No tumor formation was observed in untreated TG pigs or in the remaining two treated pigs. The latter indicates that tamoxifen delivery can probably be improved. In summary, we have generated a novel inducible oncopig model of intestinal cancer, which has the ability to form metastatic disease already two months after induction. The model may be helpful in bridging the gap between basic research and clinical usage. It opens new venues for longitudinal studies of tumor development and evolution, for preclinical assessment of new anticancer regimens, for pharmacology and toxicology assessments, as well as for studies into biological mechanisms of tumor formation and metastasis.
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http://dx.doi.org/10.1002/1878-0261.12136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664002PMC
November 2017

Modeling human disease using organotypic cultures.

Curr Opin Cell Biol 2016 12 27;43:22-29. Epub 2016 Jul 27.

BRIC-Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen N, Denmark. Electronic address:

Reliable disease models are needed in order to improve quality of healthcare. This includes gaining better understanding of disease mechanisms, developing new therapeutic interventions and personalizing treatment. Up-to-date, the majority of our knowledge about disease states comes from in vivo animal models and in vitro cell culture systems. However, it has been exceedingly difficult to model disease at the tissue level. Since recently, the gap between cell line studies and in vivo modeling has been narrowing thanks to progress in biomaterials and stem cell research. Development of reliable 3D culture systems has enabled a rapid expansion of sophisticated in vitro models. Here we focus on some of the latest advances and future perspectives in 3D organoids for human disease modeling.
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http://dx.doi.org/10.1016/j.ceb.2016.07.003DOI Listing
December 2016

The Androgen Receptor Antagonizes Wnt/β-Catenin Signaling in Epidermal Stem Cells.

J Invest Dermatol 2015 Nov 29;135(11):2753-2763. Epub 2015 Jun 29.

Centre for Stem Cells and Regenerative Medicine, King's College London, Guy's Hospital Campus, London, UK. Electronic address:

Activation of Wnt/β-catenin signaling in adult mouse epidermis leads to expansion of the stem cell compartment and redirects keratinocytes in the interfollicular epidermis and sebaceous glands (SGs) to differentiate along the hair follicle (HF) lineages. Here we demonstrate that during epidermal development and homeostasis there is reciprocal activation of the androgen receptor (AR) and β-catenin in cells of the HF bulb. AR activation reduced β-catenin-dependent transcription, blocked β-catenin-induced induction of HF growth, and prevented β-catenin-mediated conversion of SGs into HFs. Conversely, AR inhibition enhanced the effects of β-catenin activation, promoting HF proliferation and differentiation, culminating in the formation of benign HF tumors and a complete loss of SG identity. We conclude that AR signaling has a key role in epidermal stem cell fate selection by modulating responses to β-catenin in adult mouse skin.
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http://dx.doi.org/10.1038/jid.2015.242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4641324PMC
November 2015

Transplantation of expanded fetal intestinal progenitors contributes to colon regeneration after injury.

Cell Stem Cell 2013 Dec 17;13(6):734-44. Epub 2013 Oct 17.

Wellcome Trust & Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, CB2 1QR, UK; Anne McLaren Laboratory for Regenerative Medicine, Department of Surgery, University of Cambridge, Cambridge, CB2 0SZ, UK.

Regeneration and homeostasis in the adult intestinal epithelium is driven by proliferative resident stem cells, whose functional properties during organismal development are largely unknown. Here, we show that human and mouse fetal intestine contains proliferative, immature progenitors, which can be expanded in vitro as Fetal Enterospheres (FEnS). A highly similar progenitor population can be established during intestinal differentiation of human induced pluripotent stem cells. Established cultures of mouse fetal intestinal progenitors express lower levels of Lgr5 than mature progenitors and propagate in the presence of the Wnt antagonist Dkk1, and new cultures can be induced to form mature intestinal organoids by exposure to Wnt3a. Following transplantation in a colonic injury model, FEnS contribute to regeneration of colonic epithelium by forming epithelial crypt-like structures expressing region-specific differentiation markers. This work provides insight into mechanisms underlying development of the mammalian intestine and points to future opportunities for patient-specific regeneration of the digestive tract.
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http://dx.doi.org/10.1016/j.stem.2013.09.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3858813PMC
December 2013

Biological techniques: An embryonic view of tumour development.

Nature 2013 Sep 14;501(7466):171-2. Epub 2013 Aug 14.

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http://dx.doi.org/10.1038/nature12547DOI Listing
September 2013

c-MYC-induced sebaceous gland differentiation is controlled by an androgen receptor/p53 axis.

Cell Rep 2013 Feb 9;3(2):427-41. Epub 2013 Feb 9.

Wellcome Trust-Medical Research Council Stem Cell Institute SCI, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.

Although the sebaceous gland (SG) plays an important role in skin function, the mechanisms regulating SG differentiation and carcinoma formation are poorly understood. We previously reported that c-MYC overexpression stimulates SG differentiation. We now demonstrate roles for the androgen receptor (AR) and p53. MYC-induced SG differentiation was reduced in mice lacking a functional AR. High levels of MYC triggered a p53-dependent DNA damage response, leading to accumulation of proliferative SG progenitors and inhibition of AR signaling. Conversely, testosterone treatment or p53 deletion activated AR signaling and restored MYC-induced differentiation. Poorly differentiated human sebaceous carcinomas exhibited high p53 and low AR expression. Thus, the consequences of overactivating MYC in the SG depend on whether AR or p53 is activated, as they form a regulatory axis controlling proliferation and differentiation.
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http://dx.doi.org/10.1016/j.celrep.2013.01.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3778892PMC
February 2013