Sonic Hedgehog acts as a macrophage chemoattractant during regeneration of the gastric epithelium

AbstractSonic Hedgehog (Shh), secreted from gastric parietal cells, contributes to the regeneration of the epithelium. The recruitment of macrophages plays a central role in the regenerative process. The mechanism that regulates macrophage recruitment in response to gastric injury is largely unknown. Here we tested the hypothesis that Shh stimulates macrophage chemotaxis to the injured epithelium and contributes to gastric regeneration. A mouse model expressing a myeloid cell-specific deletion of Smoothened (LysMcre/+;Smof/f) was generated using transgenic mice bearing loxP sites flanking the Smo gene (Smo loxP) and mice expressing a Cre recombinase transgene from the Lysozyme M locus (LysMCre). Acetic acid injury was induced in the stomachs of both control and LysMcre/+;Smof/f (SmoKO) mice and gastric epithelial regeneration and macrophage recruitment analyzed over a period of 7 days post-injury. Bone marrow-derived macrophages (BM-Mø) were collected from control and SmoKO mice. Human-derived gastric organoid/macrophage co-cultures were established, and macrophage chemotaxis measured. Compared to control mice, SmoKO animals exhibited inhibition of ulcer repair and normal epithelial regeneration, which correlated with decreased macrophage infiltration at the site of injury. Bone marrow chimera experiments using SmoKO donor cells showed that control chimera mice transplanted with SmoKO bone marrow donor cells exhibited a loss of ulcer repair, and transplantation of control bone marrow donor cells to SmoKO mice rescued epithelial cell regeneration. Histamine-stimulated Shh secretion in human organoid/macrophage co-cultures resulted in macrophage migration toward the gastric epithelium, a response that was blocked with Smo inhibitor Vismodegib. Shh-induced macrophage migration was mediated by AKT signaling. In conclusion, Shh signaling acts as a macrophage chemoattractant via a Smo-dependent mechanism during gastric epithelial regeneration in response to injury.

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Role of metaplasia during gastric regeneration

AJP Cell Physiology ◽

10.1152/ajpcell.00415.2019 ◽

2020 ◽

Vol 319 (6) ◽

pp. C947-C954

Author(s):

Emma Teal ◽

Martha Dua-Awereh ◽

Sabrina T. Hirshorn ◽

Yana Zavros

Keyword(s):

Cell Proliferation ◽

Glutamate Transporter ◽

Cell Loss ◽

Redox Balance ◽

Gastric Epithelium ◽

Gastric Injury ◽

M2 Macrophage ◽

Cd44 Variant ◽

Epithelial Regeneration

Spasmolytic polypeptide/trefoil factor 2 (TFF2)-expressing metaplasia (SPEM) is a mucous-secreting reparative lineage that emerges at the ulcer margin in response to gastric injury. Under conditions of chronic inflammation with parietal cell loss, SPEM has been found to emerge and evolve into neoplasia. Cluster-of-differentiation gene 44 (CD44) is known to coordinate normal and metaplastic epithelial cell proliferation. In particular, CD44 variant isoform 9 (CD44v9) associates with the cystine-glutamate transporter xCT, stabilizes the protein, and provides defense against reactive oxygen species (ROS). xCT stabilization by CD44v9 leads to defense against ROS by cystine uptake, glutathione (GSH) synthesis, and maintenance of the redox balance within the intracellular environment. Furthermore, p38 signaling is a known downstream ROS target, leading to diminished cell proliferation and migration, two vital processes of gastric epithelial repair. CD44v9 emerges during repair of the gastric epithelium after injury, where it is coexpressed with other markers of SPEM. The regulatory mechanisms for the emergence of CD44v9 and the role of CD44v9 during the process of gastric epithelial regeneration are largely unknown. Inflammation and M2 macrophage infiltration have recently been demonstrated to play key roles in the induction of SPEM after injury. The following review proposes new insights into the functional role of metaplasia in the process of gastric regeneration in response to ulceration. Our insights are extrapolated from documented studies reporting oxyntic atrophy and SPEM development and our current unpublished findings using the acetic acid-induced gastric injury model.

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The Acid-Secreting Parietal Cell as an Endocrine Source of Sonic Hedgehog During Gastric Repair

Endocrinology ◽

10.1210/en.2013-1483 ◽

2013 ◽

Vol 154 (12) ◽

pp. 4627-4639 ◽

Cited By ~ 18

Author(s):

Amy C. Engevik ◽

Rui Feng ◽

Li Yang ◽

Yana Zavros

Keyword(s):

Sonic Hedgehog ◽

Parietal Cell ◽

Plasma Concentrations ◽

Gastric Epithelium ◽

Gastric Ulcers ◽

Gastric Injury ◽

Gastric Tissue ◽

Β Subunit ◽

Exon 2 ◽

Acid Secreting

Sonic Hedgehog (Shh) has been shown to regulate wound healing in various tissues. Despite its known function in tissue regeneration, the role of Shh secreted from the gastric epithelium during tissue repair in the stomach remains unknown. Here we tested the hypothesis that Shh secreted from the acid-secreting parietal cell is a fundamental circulating factor that drives gastric repair. A mouse model expressing a parietal cell-specific deletion of Shh (PC-ShhKO) was generated using animals bearing loxP sites flanking exon 2 of the Shh gene (Shhflx/flx) and mice expressing a Cre transgene under the control of the H+,K+-ATPase β-subunit promoter. Shhflx/flx, the H+,K+-ATPase β-subunit promoter, and C57BL/6 mice served as controls. Ulcers were induced via acetic acid injury. At 1, 2, 3, 4, 5, and 7 days after the ulcer induction, gastric tissue and blood samples were collected. Parabiosis experiments were used to establish the effect of circulating Shh on ulcer repair. Control mice exhibited an increased expression of Shh in the gastric tissue and plasma that correlated with the repair of injury within 7 days after surgery. PC-ShhKO mice showed a loss of ulcer repair and reduced Shh tissue and plasma concentrations. In a parabiosis experiment whereby a control mouse was paired with a PC-ShhKO littermate and both animals subjected to gastric injury, a significant increase in the circulating Shh was measured in both parabionts. Elevated circulating Shh concentrations correlated with the repair of gastric ulcers in the PC-ShhKO parabionts. Therefore, the acid-secreting parietal cell within the stomach acts as an endocrine source of Shh during repair.

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The macrophage migration inhibitory factor (MIF)/CXCR4 axis regulates migration of bone marrow derived mesenchymal stem cells towards pancreatic ß-cells under lipotoxic conditions

Diabetologie und Stoffwechsel ◽

10.1055/s-0035-1549512 ◽

2015 ◽

Vol 10 (S 01) ◽

Author(s):

B Mihic-Necic ◽

S Taromi ◽

C Liu ◽

J Straetener ◽

M Ihle ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Migration Inhibitory Factor ◽

Macrophage Migration Inhibitory Factor ◽

Inhibitory Factor ◽

Macrophage Migration ◽

Cxcr4 Axis

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Macrophage Migration Inhibitory Factor Induces Macrophage Recruitment via CC Chemokine Ligand 2

The Journal of Immunology ◽

10.4049/jimmunol.177.11.8072 ◽

2006 ◽

Vol 177 (11) ◽

pp. 8072-8079 ◽

Cited By ~ 110

Author(s):

Julia L. Gregory ◽

Eric F. Morand ◽

Sonja J. McKeown ◽

Jennifer A. Ralph ◽

Pamela Hall ◽

...

Keyword(s):

Migration Inhibitory Factor ◽

Macrophage Migration Inhibitory Factor ◽

Inhibitory Factor ◽

Macrophage Migration ◽

Cc Chemokine ◽

Macrophage Recruitment ◽

Chemokine Ligand ◽

Cc Chemokine Ligand 2 ◽

Chemokine Ligand 2

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Antioxidant Fusion Protein SOD1-Tat Increases the Engraftment Efficiency of Total Bone Marrow Cells in Irradiated Mice

Molecules ◽

10.3390/molecules26113395 ◽

2021 ◽

Vol 26 (11) ◽

pp. 3395

Author(s):

Ting Bei ◽

Xusong Cao ◽

Yun Liu ◽

Jinmei Li ◽

Haihua Luo ◽

...

Keyword(s):

Bone Marrow ◽

Fusion Protein ◽

Bone Marrow Cells ◽

Standard Procedure ◽

Severe Infection ◽

Copper Zinc Superoxide Dismutase ◽

Donor Cells ◽

Total Bone Marrow ◽

Marrow Cells

Total body irradiation is a standard procedure of bone marrow transplantation (BMT) which causes a rapid increase in reactive oxygen species (ROS) in the bone marrow microenvironment during BMT. The increase in ROS reduces the engraftment ability of donor cells, thereby affecting the bone marrow recovery of recipients after BMT. In the early weeks following transplantation, recipients are at high risk of severe infection due to weakened hematopoiesis. Thus, it is imperative to improve engraftment capacity and accelerate bone marrow recovery in BMT recipients. In this study, we constructed recombinant copper/zinc superoxide dismutase 1 (SOD1) fused with the cell-penetrating peptide (CPP), the trans-activator of transcription (Tat), and showed that this fusion protein has penetrating ability and antioxidant activity in both RAW264.7 cells and bone marrow cells in vitro. Furthermore, irradiated mice transplanted with SOD1-Tat-treated total bone marrow donor cells showed an increase in total bone marrow engraftment capacity two weeks after transplantation. This study explored an innovative method for enhancing engraftment efficiency and highlights the potential of CPP-SOD1 in ROS manipulation during BMT.

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Induction of classical transplantation tolerance in the adult.

Journal of Experimental Medicine ◽

10.1084/jem.169.3.779 ◽

1989 ◽

Vol 169 (3) ◽

pp. 779-794 ◽

Cited By ~ 230

Author(s):

S X Qin ◽

S Cobbold ◽

R Benjamin ◽

H Waldmann

Keyword(s):

Bone Marrow ◽

Transplantation Tolerance ◽

Donor Strain ◽

Skin Grafts ◽

Donor Cells ◽

Transplantation Antigens ◽

Adult Bone ◽

Tolerant State ◽

Clonal Anergy

Transplantation tolerance across histoincompatibilities in multiple non-H-2 minors (B10.BR into CBA/Ca) and "minor" plus H-2D (B10.A into CBA/Ca) antigens has been achieved successfully by combined adult bone marrow transplantation and treatment with CD4 and CD8 mAbs. The tolerant state was confirmed by permanent acceptance of donor strain skin grafts, and in vitro unresponsiveness to donor cells. Tolerance was associated with partial donor chimerism to various degrees. Tolerance to minor transplantation antigens induced in this manner was restricted to recipient-type MHC. The possibility was raised that tolerance resulted, at least in part, from clonal anergy rather than deletion.

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