Intestinal Stem Cell Research
Dr. Anika BöttcherThe gut as the body’s largest endocrine system is a central regulator of energy and glucose homeostasis. Gut functions are exerted by specialized epithelial cells: absorptive enterocytes, antimicrobial-peptide secreting Paneth cells, hormone-secreting enteroendocrine cells (EEC), mucus-secreting goblet and chemosensory tuft cells that are continuously generated from intestinal stem cells (ISCs). ISC maintenance, self-renewal, and cell fate decisions are regulated by the ISC niche which consist of Paneth cells, stromal cells, smooth muscle cells, and neural cells as well as the extracellular matrix (ECM).
Constant overnutrition leads to intestinal maladaptation and dysfunction and contributes to the development of obesity and prediabetes. This is evident as two hallmarks of obesity - excessive food intake and a reduced stimulation of postprandial insulin secretion by gut hormones - are linked to impaired gut function. Pharmacotherapy of the gut at an early stage of disease might be a promising treatment option for obesity. This is proven by the potent effects of bariatric surgery, which achieves long-term weight-loss and leads to diabetes remission partly due to intestinal adaptation and altered circulating gut hormone levels.
Our recent study has identified the Wnt/Planar cell polarity (PCP) pathway as a new niche signal and polarity cue regulating ISC fate. Wnt/PCP signaling is involved in the regulation of actin and microtubule dynamics and has also been shown to promote local ECM secretion. Our data indicate that active Wnt/PCP signaling represents one of the earliest events in ISC lineage priming towards the Paneth and enteroendocrine cell fate, preceding lateral inhibition and expression of secretory lineage-specifying gene.
The major goal of our group is to elucidate the molecular mechanisms regulating ISC lineage decisions in the gut. In particular, we would like to understand the signals that drive the formation of the different enteroendocrine cell types.
For this we use state-of-the-art single cell genomics and CRISPR/Cas9 technology in combination with cell biology and confocal microscopy. We use reporter and KO mouse models and large animal pig models. Using these techniques, we want to unravel which and how biomechanical niche signals and cell-cell interactions regulate gene expression and ISC fate in order to provide new tools to manipulate lineage decisions in disease conditions.
The gut as the body’s largest endocrine system is a central regulator of energy and glucose homeostasis. Gut functions are exerted by specialized epithelial cells: absorptive enterocytes, antimicrobial-peptide secreting Paneth cells, hormone-secreting enteroendocrine cells (EEC), mucus-secreting goblet and chemosensory tuft cells that are continuously generated from intestinal stem cells (ISCs). ISC maintenance, self-renewal, and cell fate decisions are regulated by the ISC niche which consist of Paneth cells, stromal cells, smooth muscle cells, and neural cells as well as the extracellular matrix (ECM).
Constant overnutrition leads to intestinal maladaptation and dysfunction and contributes to the development of obesity and prediabetes. This is evident as two hallmarks of obesity - excessive food intake and a reduced stimulation of postprandial insulin secretion by gut hormones - are linked to impaired gut function. Pharmacotherapy of the gut at an early stage of disease might be a promising treatment option for obesity. This is proven by the potent effects of bariatric surgery, which achieves long-term weight-loss and leads to diabetes remission partly due to intestinal adaptation and altered circulating gut hormone levels.
Our recent study has identified the Wnt/Planar cell polarity (PCP) pathway as a new niche signal and polarity cue regulating ISC fate. Wnt/PCP signaling is involved in the regulation of actin and microtubule dynamics and has also been shown to promote local ECM secretion. Our data indicate that active Wnt/PCP signaling represents one of the earliest events in ISC lineage priming towards the Paneth and enteroendocrine cell fate, preceding lateral inhibition and expression of secretory lineage-specifying gene.
The major goal of our group is to elucidate the molecular mechanisms regulating ISC lineage decisions in the gut. In particular, we would like to understand the signals that drive the formation of the different enteroendocrine cell types.
For this we use state-of-the-art single cell genomics and CRISPR/Cas9 technology in combination with cell biology and confocal microscopy. We use reporter and KO mouse models and large animal pig models. Using these techniques, we want to unravel which and how biomechanical niche signals and cell-cell interactions regulate gene expression and ISC fate in order to provide new tools to manipulate lineage decisions in disease conditions.
Research Topics
Dr. Anika Böttcher
Dr. Michael Sterr
- Uncovering how hormone-producing enteroendocrine cells are recruited from intestinal stem cells and which pathways regulate enteroendocrine subset specification
- Dissecting the role of the pioneer transcription factor Foxa2 in endocrine lineage formation
- Elucidating the cellular and molecular mechanisms underlying intestinal/ enteroendocrine dysfunction in obesity and diabetes
Falk Farkas, PhD student
- Characterization of the human and porcine ISC niche to identify new ISC niche components
- Determine if niche composition is altered in obesity and diabetes and contributes to diet-induced intestinal dysfunction
Tobias Greisle, PhD student
Falk Farkas, PhD student
- Identifying the molecular mechanisms by which actin dynamics and nuclear actin regulate gene expression and ISC fate
- Dissecting the role of Wnt/planar cell polarity signaling in endocrine lineage formation in the pancreas and gut
Dr. Anika Böttcher
Dr. Michael Sterr
- Uncovering how hormone-producing enteroendocrine cells are recruited from intestinal stem cells and which pathways regulate enteroendocrine subset specification
- Dissecting the role of the pioneer transcription factor Foxa2 in endocrine lineage formation
- Elucidating the cellular and molecular mechanisms underlying intestinal/ enteroendocrine dysfunction in obesity and diabetes
Falk Farkas, PhD student
- Characterization of the human and porcine ISC niche to identify new ISC niche components
- Determine if niche composition is altered in obesity and diabetes and contributes to diet-induced intestinal dysfunction
Tobias Greisle, PhD student
Falk Farkas, PhD student
- Identifying the molecular mechanisms by which actin dynamics and nuclear actin regulate gene expression and ISC fate
- Dissecting the role of Wnt/planar cell polarity signaling in endocrine lineage formation in the pancreas and gut
Who we are
Most important publications
Read more2022 Scientific Article in Molecular Metabolism
A transcriptional cross species map of pancreatic islet cells.
2022 Scientific Article in Nature Communications
Primary cilia and SHH signaling impairments in human and mouse models of Parkinson's disease.
2022 Scientific Article in Xenotransplantation
Transgenic pigs expressing near infrared fluorescent protein-A novel tool for noninvasive imaging of islet xenotransplants.
2021 Scientific Article in Nature Communications
scPower accelerates and optimizes the design of multi-sample single cell transcriptomic studies.
2021 Scientific Article in Molecular Metabolism
Vertical sleeve gastrectomy triggers fast β-cell recovery upon overt diabetes.
2021 Scientific Article in Nature metabolism
Diet-induced alteration of intestinal stem cell function underlies obesity and prediabetes in mice.
2021 Nature Cell Biology
Publisher Correction: Epithelial cell plasticity drives endoderm formation during gastrulation.
2021 Scientific Article in Nature Cell Biology
Epithelial cell plasticity drives endoderm formation during gastrulation.
2021 Nature Cell Biology
Author Correction: Non-canonical Wnt/PCP signalling regulates intestinal stem cell lineage priming towards enteroendocrine and Paneth cell fates.
2021 Scientific Article in Journal of Biological Chemistry, The
Disruption of the integrin-linked kinase (ILK) pseudokinase domain affects kidney development in mice.
2021 Scientific Article in Nature Communications
Asc-1 regulates white versus beige adipocyte fate in a subcutaneous stromal cell population.
2021 Scientific Article in Molecular Metabolism
CD81 marks immature and dedifferentiated pancreatic β-cells.
