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Helmholtz Munich - Mara Catani

Intestinal Stem Cell Research

Dr. Anika Böttcher

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.

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

  1. Uncovering how hormone-producing enteroendocrine cells are recruited from intestinal stem cells and which pathways regulate enteroendocrine subset specification
  2. Dissecting the role of the pioneer transcription factor Foxa2 in endocrine lineage formation
  3. Elucidating the cellular and molecular mechanisms underlying intestinal/ enteroendocrine dysfunction in obesity and diabetes

Falk Farkas, PhD student

  1. Characterization of the human and porcine ISC niche to identify new ISC niche components
  2. 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

  1. Identifying the molecular mechanisms by which actin dynamics and nuclear actin regulate gene expression and ISC fate
  2. Dissecting the role of Wnt/planar cell polarity signaling in endocrine lineage formation in the pancreas and gut

Dr. Anika Böttcher

Dr. Michael Sterr

  1. Uncovering how hormone-producing enteroendocrine cells are recruited from intestinal stem cells and which pathways regulate enteroendocrine subset specification
  2. Dissecting the role of the pioneer transcription factor Foxa2 in endocrine lineage formation
  3. Elucidating the cellular and molecular mechanisms underlying intestinal/ enteroendocrine dysfunction in obesity and diabetes

Falk Farkas, PhD student

  1. Characterization of the human and porcine ISC niche to identify new ISC niche components
  2. 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

  1. Identifying the molecular mechanisms by which actin dynamics and nuclear actin regulate gene expression and ISC fate
  2. Dissecting the role of Wnt/planar cell polarity signaling in endocrine lineage formation in the pancreas and gut

Who we are

Tobias Greisle

PhD student - Intestinal Stem Cell Research

Ines Kunze

Technical Assistant - Intestinal stem cells

Falk Farkas

PhD Student - Intestinal Stem Cell Research

Most important publications

Read more

2022 Scientific Article in Nature Communications

Schmidt, S. ; Luecken, M. ; Trümbach, D. ; Hembach, S. ; Niedermeier, K.M. ; Wenck, N. ; Pflügler, K. ; Stautner, C. ; Böttcher, A. ; Lickert, H. ; Ramirez Suastegui, C. ; Ahmad, R. ; Ziller, M.J. ; Fitzgerald, J.C. ; Ruf, V. ; van de Berg, W.D.J. ; Jonker, A.J. ; Gasser, T. ; Winner, B. ; Winkler, J. ; Weisenhorn, D.M. ; Giesert, F. ; Theis, F.J. ; Wurst, W.

Primary cilia and SHH signaling impairments in human and mouse models of Parkinson's disease.

2021 Scientific Article in Life Science Alliance

Karlina, R. ; Lutter, D. ; Miok, V. ; Fischer, D.S. ; Altun, I. ; Schöttl, T. ; Schorpp, K.K. ; Israel, A. ; Cero, C. ; Johnson, J.W. ; Kapser-Fischer, I. ; Böttcher, A. ; Keipert, S. ; Feuchtinger, A. ; Graf, E. ; Strom, T.M. ; Walch, A.K. ; Lickert, H. ; Walzthoeni, T. ; Heinig, M. ; Theis, F.J. ; García-Cáceres, C. ; Cypess, A.M. ; Ussar, S.

Identification and characterization of distinct brown adipocyte subtypes in C57BL/6J mice.

Contact

Dr. Anika Böttcher

Group Leader Intestinal stem cells

Campus Neuherberg, building 3620, room 034c