Loss of Indian Hedgehog Activates Multiple Aspects of a Wound Healing Response in the Mouse Intestine

Dop, Willemijn A. van; Heijmans, Jarom; Büller, Nikè V. J. A.; Snoek, Susanne A.; Rosekrans, Sanne; Wassenberg, Elisabeth A.; Weerman, Marius A. van den Bergh; Lanske, Beate; Clarke, Alan R.; Winton, Douglas J.; Wijgerde, Mark; Offerhaus, G. Johan A.; Hommes, Daan W.; Hardwick, James C.H.; Jonge, Wouter J. de; Biemond, I.; Brink, Gijs R. van den

doi:10.1053/j.gastro.2010.07.045

Cited by 80 publications

(86 citation statements)

References 27 publications

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“…Furthermore, HH signaling has been found to be downregulated during repair following gastric ulcer induction, whereas inhibition of SMO via cyclopamine treatment of injured mice further inhibits gastric progenitor cell differentiation (Kang et al, 2009). In mouse models of HH pathway inhibition, atrophy of the small intestinal villi is observed resulting from the loss of villus smooth muscle cells, which is also accompanied by inflammation and an increase in proliferation in the epithelial compartment (van Dop et al, 2010;Zacharias et al, 2010). Conversely, upregulation of IHH expression in adult intestine promotes villus smooth muscle differentiation (Zacharias et al, 2011), indicating that HH signaling in the adult murine intestine regulates tissue homeostasis in a concentration-dependent manner.…”

Section: Respiratory and Gastrointestinal Systemsmentioning

confidence: 99%

“…Shh and Ihh expression continues to be detected throughout the adult gastrointestinal tract of both humans and rodents where it signals to the Gli-expressing mesenchyme (Kolterud et al, 2009;van den Brink et al, 2002van den Brink et al, , 2001van Dop et al, 2010). In the adult murine stomach, HH signaling is thought to be responsible for inhibiting proliferation and stimulating the differentiation of the gastric epithelium (van den Brink et al, 2002(van den Brink et al, , 2001.…”

Section: Respiratory and Gastrointestinal Systemsmentioning

confidence: 99%

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Roles for Hedgehog signaling in adult organ homeostasis and repair

2014

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The hedgehog (HH) pathway is well known for its mitogenic and morphogenic functions during development, and HH signaling continues in discrete populations of cells within many adult mammalian tissues. Growing evidence indicates that HH regulates diverse quiescent stem cell populations, but the exact roles that HH signaling plays in adult organ homeostasis and regeneration remain poorly understood. Here, we review recently identified functions of HH in modulating the behavior of tissue-specific adult stem and progenitor cells during homeostasis, regeneration and disease. We conclude that HH signaling is a key factor in the regulation of adult tissue homeostasis and repair, acting via multiple different routes to regulate distinct cellular outcomes, including maintenance of plasticity, in a context-dependent manner.

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Section: Respiratory and Gastrointestinal Systemsmentioning

confidence: 99%

Section: Respiratory and Gastrointestinal Systemsmentioning

confidence: 99%

Roles for Hedgehog signaling in adult organ homeostasis and repair

2014

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“…The increases in FGF-9 and FGF-18 mRNA preceded Paneth cell expansion. Varnat et al (37) reported that Paneth cell specification was regulated by Ihh signaling, a finding substantiated in mice with intestinal epithelial-specific knockout of Ihh (19,33). Therefore, we evaluated Ihh mRNA expression after Dox treatment and found significant decreases in Ihh from 24 to 168 h, concomitant with Paneth cell expansion (Fig.…”

Section: Dox Treatment Alters Mrnas Linked To Paneth Cell Specificatimentioning

confidence: 99%

Paneth cells expand from newly created and preexisting cells during repair after doxorubicin-induced damage

King

Mohiuddin

Dekaney

2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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King SL, Mohiuddin JJ, Dekaney CM. Paneth cells expand from newly created and preexisting cells during repair after doxorubicin-induced damage. Am J Physiol Gastrointest Liver Physiol 305: G151-G162, 2013. First published May 9, 2013 doi:10.1152/ajpgi.00441.2012.-Paneth cell numbers increase following intestinal damage, but mechanisms driving this process are not understood. We hypothesized that the increase in Paneth cell numbers is due to recruitment of cells from a preexisting pool of secretory progenitors. Mice were given a single injection of doxorubicin (Dox), and intestinal tissue was collected 0 -168 h after treatment. Paneth, goblet, and intermediate cells were counted and evaluated for cell morphology. Quantitative RT-PCR was used to measure expression of various genes associated with Paneth cell allocation and maturation. Paneth cells were birth dated using incorporation of thymidine analogs given before or after Dox. Staining revealed "intermediate" cells, which were rarely observed in control crypts but increased significantly in number 96 and 120 h after Dox treatment. Birth dating of intermediate cells 5 days after Dox treatment revealed that 24% of these cells took up thymidine analog given prior to Dox treatment and 36% took up thymidine analog given after Dox treatment. Quantitative RT-PCR demonstrated a significant increase in Spdef, Atoh1, Sox9, EphB3, Mist, Wnt5a, FGF-9, and FGF-18 mRNAs and a significant decrease in Indian hedgehog mRNA. Expansion of the Paneth cell compartment after Dox treatment is due to generation of new cells and recruitment of cells from an existing pool. These cells express Paneth and goblet biomarkers and are found only during repair. Expansion of these cells correlates temporally with reduced Indian hedgehog and increased FGF and Wnt mRNA. These findings are significant, as they provide a first step in understanding mechanisms of Paneth cell expansion during mucosal repair. Paneth cell; doxorubicin; intermediate cell PANETH CELLS ARE ONE OF FOUR differentiated cell lineages that arise from intestinal stem cells (ISC), and unlike the other three cell lineages found in small intestinal epithelium, they migrate toward and reside in the base of intestinal crypts (5, 6). Paneth cells are part of the innate mucosal immune system in the intestine and protect against microbial infection and overgrowth. Antimicrobial peptides, including cryptdins (␣-defensins), lysozyme, secretory phospholipase A 2 , and matrilysin [matrix metalloproteinase 7 (MMP-7)], are secreted from granules localized to the apical membrane of Paneth cells upon bacterial stimulation (2,25). At the crypt base, Paneth cells are adjacent to and intercalated among ISC and are, therefore, in an advantageous position to influence the stem cell microenvironment (5, 6). In addition to secreting numerous antimicrobial factors, Paneth cells synthesize and secrete factors that are capable of influencing proliferation and migration of intestinal epithelial cells, including EGF, granulocyte-macrophage colony-stimul...

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“…Hh signaling mediates the reciprocal interaction between intestinal epithelium and mesenchyme (2,6,7,31) mice, partial inhibition of Hh signaling leads to Wnt pathway activation and intestinal epithelial overproliferation in newborn animals (2, 31). Therefore, we further analyzed the intestinal epithelial development in Nkx3.2 Cre ;Smo C/C mutant embryos.…”

Section: Genetic Removal Of Smo From the Developing Intestinalmentioning

confidence: 99%

Specific Requirement of Gli Transcription Factors in Hedgehog-mediated Intestinal Development

Huang

Cotton²,

Wang³

et al. 2013

Journal of Biological Chemistry

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Hedgehog (Hh) signaling is involved in multiple aspects of embryonic gut development, including mesenchymal growth and smooth muscle differentiation. The Gli family transcription factors is thought to collectively mediate Hh signaling in mammals. However, the function of different Gli proteins in gut development remains uncharacterized. Here, we genetically dissect the contribution of Gli transcriptional activation and de-repression in intestinal growth and patterning. We find that removal of the Gli3 repressor is dispensable for intestinal development and does not play a major role in Hh-controlled gut development. However, Gli2 activation is able to fully rescue the Smoothened (Smo)-null intestinal phenotype, suggesting that the Gli2 transcription factor is the main effector for Hh signaling in the intestine. To understand further the molecular mechanism underlying Hh/Gli function in the developing gut, we identify a subset of small leucine-rich glycoproteins (SLRPs) that may function downstream of Hh signaling in the mesenchyme. We show that osteoglycin, a SLRP, inhibits Hh-induced differentiation toward the smooth muscle lineage in C3H10T1/2 pluripotent mesenchymal cells. Taken together, our study reveals, for the first time, the distinct roles of Gli proteins in intestine development and suggests SLRPs as novel regulators of smooth muscle cell differentiation

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Loss of Indian Hedgehog Activates Multiple Aspects of a Wound Healing Response in the Mouse Intestine

Cited by 80 publications

References 27 publications

Roles for Hedgehog signaling in adult organ homeostasis and repair

Roles for Hedgehog signaling in adult organ homeostasis and repair

Paneth cells expand from newly created and preexisting cells during repair after doxorubicin-induced damage

Specific Requirement of Gli Transcription Factors in Hedgehog-mediated Intestinal Development

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