Smooth muscle-specific MMP17 (MT4-MMP) regulates the intestinal stem cell niche and regeneration after damage

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

10.1101/2020.06.18.147769 ◽

2020 ◽

Author(s):

Mara Martín-Alonso ◽

Håvard T. Lindholm ◽

Sharif Iqbal ◽

Pia Vornewald ◽

Sigrid Hoel ◽

...

Keyword(s):

Smooth Muscle ◽

Stem Cell ◽

Intestinal Stem Cell ◽

Matricellular Protein ◽

Intestinal Epithelial ◽

Stem Cell Maintenance ◽

Epithelial Regeneration ◽

The Matrix ◽

Signaling Axis ◽

Cell Niche

SUMMARYSmooth 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 may have. Here, we show that smooth muscle is the dominant supplier of BMP antagonists, which are niche factors that are essential for intestinal stem cell maintenance. Furthermore, muscle-derived factors can render epithelium reparative and fetal-like, which includes heightened YAP activity. Mechanistically, we find that the matrix metalloproteinase MMP17, which is exclusively expressed by smooth muscle, is required for intestinal epithelial repair after inflammation- or irradiation-induced injury. Furthermore, we provide evidence that MMP17 affects intestinal epithelial reprogramming indirectly by cleaving the matricellular protein PERIOSTIN, which itself is able to activate YAP. Together, we identify an important signaling axis that firmly establishes a role for smooth muscle as a modulator of intestinal epithelial regeneration and the intestinal stem cell niche.

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Mitochondrial Metabolism in the Intestinal Stem Cell Niche—Sensing and Signaling in Health and Disease

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.602814 ◽

2021 ◽

Vol 8 ◽

Author(s):

Elisabeth Urbauer ◽

Eva Rath ◽

Dirk Haller

Keyword(s):

Stem Cell ◽

Epithelial Cell ◽

Mitochondrial Function ◽

Stem Cell Niche ◽

Intestinal Epithelial Cell ◽

Mitochondrial Metabolism ◽

Intestinal Stem Cell ◽

Intestinal Epithelial ◽

Health And Disease ◽

Cell Niche

Mitochondrial metabolism, dynamics, and stress responses in the intestinal stem cell niche play a pivotal role in regulating intestinal epithelial cell homeostasis, including self-renewal and differentiation. In addition, mitochondria are increasingly recognized for their involvement in sensing the metabolic environment and their capability of integrating host and microbial-derived signals. Gastrointestinal diseases such as inflammatory bowel diseases and colorectal cancer are characterized by alterations of intestinal stemness, the microbial milieu, and mitochondrial metabolism. Thus, mitochondrial function emerges at the interface of determining health and disease, and failure to adapt mitochondrial function to environmental cues potentially results in aberrant tissue responses. A mechanistic understanding of the underlying role of mitochondrial fitness in intestinal pathologies is still in its infancy, and therapies targeting mitochondrial (dys)function are currently lacking. This review discusses mitochondrial signaling and metabolism in intestinal stem cells and Paneth cells as critical junction translating host- and microbe-derived signals into epithelial responses. Consequently, we propose mitochondrial fitness as a hallmark for intestinal epithelial cell plasticity, determining the regenerative capacity of the epithelium.

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ANGPTL 2 expression in the intestinal stem cell niche controls epithelial regeneration and homeostasis

The EMBO Journal ◽

10.15252/embj.201695690 ◽

2017 ◽

Vol 36 (4) ◽

pp. 409-424 ◽

Cited By ~ 23

Author(s):

Haruki Horiguchi ◽

Motoyoshi Endo ◽

Kohki Kawane ◽

Tsuyoshi Kadomatsu ◽

Kazutoyo Terada ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Niche ◽

Intestinal Stem Cell ◽

Epithelial Regeneration ◽

Cell Niche

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Faculty Opinions recommendation of Parabronchial smooth muscle constitutes an airway epithelial stem cell niche in the mouse lung after injury.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13372972.14743080 ◽

2011 ◽

Author(s):

Herman Meurs ◽

Reinoud Gosens

Keyword(s):

Smooth Muscle ◽

Stem Cell ◽

Stem Cell Niche ◽

Mouse Lung ◽

Airway Epithelial ◽

Epithelial Stem Cell ◽

Cell Niche

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Faculty Opinions recommendation of Visualization of a short-range Wnt gradient in the intestinal stem-cell niche.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726134575.793554531 ◽

2018 ◽

Author(s):

Mirna Perez-Moreno

Keyword(s):

Stem Cell ◽

Stem Cell Niche ◽

Short Range ◽

Intestinal Stem Cell ◽

Cell Niche

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Human-Induced Pluripotent Stem-Cell-Derived Smooth Muscle Cells Increase Angiogenesis to Treat Hindlimb Ischemia

Cells ◽

10.3390/cells10040792 ◽

2021 ◽

Vol 10 (4) ◽

pp. 792

Author(s):

Xixiang Gao ◽

Mingjie Gao ◽

Jolanta Gorecka ◽

John Langford ◽

Jia Liu ◽

...

Keyword(s):

Stem Cells ◽

Smooth Muscle ◽

Stem Cell ◽

Smooth Muscle Cells ◽

Functional Outcomes ◽

Ethical Issues ◽

Muscle Cells ◽

Doppler Imaging ◽

Hindlimb Ischemia ◽

Induced Pluripotent

Induced pluripotent stem cells (iPSC) represent an innovative, somatic cell-derived, easily obtained and renewable stem cell source without considerable ethical issues. iPSC and their derived cells may have enhanced therapeutic and translational potential compared with other stem cells. We previously showed that human iPSC-derived smooth muscle cells (hiPSC-SMC) promote angiogenesis and wound healing. Accordingly, we hypothesized that hiPSC-SMC may be a novel treatment for human patients with chronic limb-threatening ischemia who have no standard options for therapy. We determined the angiogenic potential of hiPSC-SMC in a murine hindlimb ischemia model. hiPSC-SMC were injected intramuscularly into nude mice after creation of hindlimb ischemia. Functional outcomes and perfusion were measured using standardized scores, laser Doppler imaging, microCT, histology and immunofluorescence. Functional outcomes and blood flow were improved in hiPSC-SMC-treated mice compared with controls (Tarlov score, p < 0.05; Faber score, p < 0.05; flow, p = 0.054). hiPSC-SMC-treated mice showed fewer gastrocnemius fibers (p < 0.0001), increased fiber area (p < 0.0001), and enhanced capillary density (p < 0.01); microCT showed more arterioles (<96 μm). hiPSC-SMC treatment was associated with fewer numbers of macrophages, decreased numbers of M1-type (p < 0.05) and increased numbers of M2-type macrophages (p < 0.0001). Vascular endothelial growth factor (VEGF) expression in ischemic limbs was significantly elevated with hiPSC-SMC treatment (p < 0.05), and inhibition of VEGFR-2 with SU5416 was associated with fewer capillaries in hiPSC-SMC-treated limbs (p < 0.0001). hiPSC-SMC promote VEGF-mediated angiogenesis, leading to improved hindlimb ischemia. Stem cell therapy using iPSC-derived cells may represent a novel and potentially translatable therapy for limb-threatening ischemia.

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