Smooth muscle-specific MMP17 (MT4-MMP) regulates the intestinal stem cell niche and regeneration after damage
Martín-Alonso, Mara; Iqbal, Sharif; Vornewald, Pia M.; Lindholm, Håvard T.; Damen, Mirjam J.; Martínez, Fernando; Hoel, Sigrid; Díez-Sánchez, Alberto; Altelaar, Maarten; Katajisto, Pekka; Arroyo, Alicia G.; Oudhoff, Menno J.
(2021) Nature Communications, volume 12, issue 1, pp. 1 - 17
(Article)
Abstract
Smooth muscle is an essential component of the intestine, both to maintain its structure and produce peristaltic and segmentation movements. However, very little is known about other putative roles that smooth muscle cells may have. Here, we show that smooth muscle cells may be the dominant suppliers of BMP antagonists,
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which are niche factors essential for intestinal stem cell maintenance. Furthermore, muscle-derived factors render epithelium reparative and fetal-like, which includes heightened YAP activity. Mechanistically, we find that the membrane-bound matrix metalloproteinase MMP17, which is exclusively expressed by smooth muscle cells, is required for intestinal epithelial repair after inflammation- or irradiation-induced injury. Furthermore, we propose that MMP17 affects intestinal epithelial reprogramming after damage indirectly by cleaving diffusible factor(s) such as the matricellular protein PERIOSTIN. Together, we identify an important signaling axis that establishes a role for smooth muscle cells as modulators of intestinal epithelial regeneration and the intestinal stem cell niche.
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Keywords: Animals, Humans, Intestinal Mucosa/metabolism, Intestines/cytology, Matrix Metalloproteinase 17/metabolism, Muscle, Smooth/metabolism, Regeneration/physiology, Signal Transduction/physiology, Stem Cell Niche/physiology, Stem Cells/metabolism
ISSN: 2041-1723
Publisher: Nature Publishing Group
Note: Funding Information: We would like to thank Dr. Motoharu Seiki for kindly sharing the Mmp17KO/KI mouse line and Dr. Kaisa Lehti for first inspiring this study. We would like to thank to Anne Beate L. Marthinsen for performing the irradiation, and the Department of Radiology and Nuclear Medicine (St. Olav’s Hospital) for allowing the use of their instruments. We also thank Arne Wibe and Elin Rønne for their evaluation of colon crypt reactive atypia. We thank Shreya Gopalakrishnan for sharing reagents and input on organoids growth, Yashwanth Subbannayya and Time Veth for input on MS analysis, and Rosalie Zwig-gelaar for assisting in mouse experiments. We thank the imaging (CMIC) and animal care (CoMed) core facilities (NTNU), as well as the histology and animal facilities at CNIC for assisting in this work. The WT KO crypt-muscle RNA-seq was done by the Genomics Core Facility at NTNU, which receives funding from the Faculty of Medicine and Health Sciences and Central Norway Regional Health Authority. This research was part of the Netherlands X-omics Initiative and partially funded by NWO (project 184.034.019). This work was further financially supported by the Norwegian Research Council (Centre of Excellence grant 223255/F50, and ‘Young Research Talent’ 274760 to M.J.O.) and the Norwegian Cancer Society (182767 to M.J.O.). MMA is the recipient of a Marie Skłodowska-Curie IF (DLV-794391). Publisher Copyright: © 2021, The Author(s).
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