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Mice lacking functional CD95-ligand display reduced proliferation of the intestinal epithelium without gross homeostatic alterations

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Abstract

Homeostasis of the continuously self-renewing intestinal tract involves cell proliferation, migration, differentiation along the crypt-villus-axis and shedding of cells into the gut lumen. CD95-ligand (FAS-ligand, CD95L) is a cytokine that is known for its capacity to induce apoptosis by binding its cognate receptor, CD95 (Fas). More recently, it was discovered that CD95L can also induce other cellular responses, such as proliferation, differentiation and cell migration. CD95L is highly expressed in Paneth cells of the small intestine which are in close contact with intestinal stem cells. This suggests a potential role for CD95L in controlling stem cell function and, possibly, intestinal homeostasis. We analyzed the intestines of mice deficient for functional CD95L (gld) for potential alterations in the diversity of stem-cell-lineages and parameters of intestinal homeostasis. Stem cell diversity was assessed by analyzing methylation patterns of the non-transcribed mMYOD gene. Proliferation was analyzed by BrdU labeling and differentiation was assessed by immunohistochemistry. Of all parameters analyzed, only epithelial cell proliferation was significantly reduced in the small intestines of gld-mice, but not in their colons which lack CD95L expression. We conclude that CD95L has a proliferation-stimulating role during normal turnover of the small intestine, but has a marginal effect on overall intestinal homeostasis.

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Abbreviations

CD95L:

CD95 ligand

BrdU:

Bromodeoxyuridine

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Acknowledgments

The authors thank all members of the Surgical Oncology research group for the input and constructive feedback during work discussions. The authors also thank the employees of the Pathology department and in particular P. van de Groep, D. Castigliego, P. Homoet and M. Huynh for their technical assistance and Marco Koudijs and Nicolle Besselink for the excellent technical assistance and knowledge of the Ion Torrent Platform. This study was supported by the PON foundation (KT; EJAS), “Vrienden UMC Utrecht” foundation (KT) and the Dutch Cancer Society (EJAS).

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Authors and Affiliations

  1. Department of Surgery, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands

    Kari Trumpi, Ernst J. A. Steller, Daniëlle A. Raats, Inne H. M. Borel Rinkes & Onno Kranenburg

  2. Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands

    Wendy W. de Leng & Folkert H. M. Morsink

  3. Hubrecht Institute, The Royal Dutch Academy of Arts and Sciences, University Medical Center Utrecht, Utrecht, The Netherlands

    Isaäc J. Nijman

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  1. Kari Trumpi
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  2. Ernst J. A. Steller
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  4. Daniëlle A. Raats
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  7. Inne H. M. Borel Rinkes
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  8. Onno Kranenburg
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Correspondence to Onno Kranenburg.

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Trumpi, K., Steller, E.J.A., de Leng, W.W. et al. Mice lacking functional CD95-ligand display reduced proliferation of the intestinal epithelium without gross homeostatic alterations. Med Mol Morphol 49, 110–118 (2016). https://doi.org/10.1007/s00795-015-0129-9

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  • DOI: https://doi.org/10.1007/s00795-015-0129-9

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