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  • Bidaud-Meynard, Aurelien (1)
  • Farin, Henner (1)
  • Maschalidi, Sophia (1)
  • Menche, Constantin (1)
  • Michaux, Grégoire (1)
  • Michels, Birgitta Elisabeth (1)
  • Mosa, Mohammed Hossameldin (1)
  • Nicolle, Ophélie (1)
  • Saint Basile, Geneviève de (1)
  • Sepulveda, Fernando E. (1)
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  • 2018 (1)

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Keywords

  • Apical Vesicular Transport (1)
  • Brush Border Formation (1)
  • Disease Modeling (1)
  • Microvillus Atrophy (1)

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  • Biowissenschaften (1)
  • Georg-Speyer-Haus (1)

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Dynamic formation of microvillus inclusions during enterocyte differentiation in Munc18-2–deficient intestinal organoids (2018)
Mosa, Mohammed Hossameldin ; Nicolle, Ophélie ; Maschalidi, Sophia ; Sepulveda, Fernando E. ; Bidaud-Meynard, Aurelien ; Menche, Constantin ; Michels, Birgitta Elisabeth ; Michaux, Grégoire ; Saint Basile, Geneviève de ; Farin, Henner
Background & Aims: Microvillus inclusion disease (MVID) is a congenital intestinal malabsorption disorder caused by defective apical vesicular transport. Existing cellular models do not fully recapitulate this heterogeneous pathology. The aim of this study was to characterize 3-dimensional intestinal organoids that continuously generate polarized absorptive cells as an accessible and relevant model to investigate MVID. Methods: Intestinal organoids from Munc18-2/Stxbp2-null mice that are deficient for apical vesicular transport were subjected to enterocyte-specific differentiation protocols. Lentiviral rescue experiments were performed using human MUNC18-2 variants. Apical trafficking and microvillus formation were characterized by confocal and transmission electron microscopy. Spinning disc time-lapse microscopy was used to document the lifecycle of microvillus inclusions. Results: Loss of Munc18-2/Stxbp2 recapitulated the pathologic features observed in patients with MUNC18-2 deficiency. The defects were fully restored by transgenic wild-type human MUNC18-2 protein, but not the patient variant (P477L). Importantly, we discovered that the MVID phenotype was correlated with the degree of enterocyte differentiation: secretory vesicles accumulated already in crypt progenitors, while differentiated enterocytes showed an apical tubulovesicular network and enlarged lysosomes. Upon prolonged enterocyte differentiation, cytoplasmic F-actin–positive foci were observed that further progressed into classic microvillus inclusions. Time-lapse microscopy showed their dynamic formation by intracellular maturation or invagination of the apical or basolateral plasma membrane. Conclusions: We show that prolonged enterocyte-specific differentiation is required to recapitulate the entire spectrum of MVID. Primary organoids can provide a powerful model for this heterogeneous pathology. Formation of microvillus inclusions from multiple membrane sources showed an unexpected dynamic of the enterocyte brush border.
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