Smooth muscle-specific MMP17 (MT4-MMP) defines the intestinal ECM niche

Abstract

21 22 SUMMARY (~150 words) 23Smooth muscle is an essential component of the intestine, both to maintain its structure and 24 produce peristaltic and segmentation movements. However, very little is known about other 25 putative roles that smooth muscle may have. Here, we show that smooth muscle is the 26 dominant supplier of BMP antagonists, which are niche factors that are essential for 27intestinal stem cell maintenance. Furthermore, muscle-derived factors can render epithelium 28 reparative and fetal-like, which includes heightened YAP activity. Mechanistically, we find 29 that the matrix metalloproteinase MMP17, which is exclusively expressed by smooth muscle, 30 is required for intestinal epithelial repair after inflammation-or irradiation-induced injury. 31Furthermore, we provide evidence that MMP17 affects intestinal epithelial reprogramming 32 indirectly by cleaving the matricellular protein PERIOSTIN, which itself is able to activate 33 YAP. Together, we identify an important signaling axis that firmly establishes a role for 34 smooth muscle as a modulator of intestinal epithelial regeneration and the intestinal stem 35 cell niche. 36 37

Molecular Mechanisms Driven by MT4-MMP in Cancer Progression

“…MT4-MMP knockout mice have dysfunctional VSMCs and dilated aortas [9] and displayed adventitial fibrosis and hypotension, like mouse models of thoracic aortic aneurisms and dissections (TAAD) (Figure 1A) [62]. Recently, periostin has been identified as a novel substrate for SMCs in the stem cell niche of the intestine [10] with actions in intestinal homeostasis and repair. Whether MT4-MMP-periostin axis plays a role in tumor cell development and progression deserves further investigation.…”

“…This feature may explain the specificity and exclusivity of the substrates to be cleaved by MT4-MMP [1,8]. In fact, only a limited number of substrates have been identified for this endopeptidase, including matrix and matricellular proteins such as fibrin/fibrinogen, gelatin [8], osteopontin [9], periostin [10], proteases like ADAMTS-4 [11,12], and membrane proteins as αM-integrin [13], Pro-TNFα [8] and LRP [14].…”