scholarly journals Growth factors protect intestinal stem cells from radiation-induced apoptosis by suppressing PUMA through the PI3K/AKT/p53 axis

Oncogene ◽  
2009 ◽  
Vol 29 (11) ◽  
pp. 1622-1632 ◽  
Author(s):  
W Qiu ◽  
B Leibowitz ◽  
L Zhang ◽  
J Yu
Keyword(s):  
Stem Cells ◽  
Growth Factors ◽  
Intestinal Stem Cells ◽  
Radiation Induced ◽  
Induced Apoptosis

scholarly journals Interplay among p21Waf1/Cip1, MUSASHI-1 and Krüppel-like factor 4 in activation of Bmi1-CreER reserve intestinal stem cells after gamma radiation-induced injury

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Emilia J. Orzechowska ◽  
Takahito Katano ◽  
Agnieszka B. Bialkowska ◽  
Vincent W. Yang
Keyword(s):  
Stem Cells ◽  
Gamma Radiation ◽  
Therapeutic Potential ◽  
Mrna Translation ◽  
Negative Regulator ◽  
Intestinal Stem Cells ◽  
Quiescent State ◽  
Γ Radiation ◽  
Regenerative Response ◽  
Radiation Induced

Abstract Gamma radiation is a commonly used adjuvant treatment for abdominally localized cancer. Since its therapeutic potential is limited due to gastrointestinal (GI) syndrome, elucidation of the regenerative response following radiation-induced gut injury is needed to develop a preventive treatment. Previously, we showed that Krüppel-like factor 4 (KLF4) activates certain quiescent intestinal stem cells (ISCs) marked by Bmi1-CreER to give rise to regenerating crypts following γ irradiation. In the current study, we showed that γ radiation-induced expression of p21Waf1/Cip1 in Bmi1-CreER cells is likely mitigated by MUSASHI-1 (MSI1) acting as a negative regulator of p21Waf1/Cip1 mRNA translation, which promotes exit of the Bmi1-CreER cells from a quiescent state. Additionally, Bmi1-specific Klf4 deletion resulted in decreased numbers of MSI1+ cells in regenerating crypts compared to those of control mice. We showed that KLF4 binds to the Msi1 promoter and activates its expression in vitro. Since MSI1 has been shown to be crucial for crypt regeneration, this finding elucidates a pro-proliferative role of KLF4 during the postirradiation regenerative response. Taken together, our data suggest that the interplay among p21Waf1/Cip1, MSI1 and KLF4 regulates Bmi1-CreER cell survival, exit from quiescence and regenerative potential upon γ radiation-induced injury.

scholarly journals Nonmicrobial Activation of TLRs Controls Intestinal Growth, Wound Repair, and Radioprotection

2021 ◽  
Vol 11 ◽  
Author(s):  
William F. Stenson ◽  
Matthew A. Ciorba
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Hyaluronic Acid ◽  
Wound Repair ◽  
Epithelial Proliferation ◽  
Epithelial Stem Cells ◽  
Radiation Induced ◽  
Induced Apoptosis ◽  
A Site ◽  
Hyaluronic Acid Binding

TLRs, key components of the innate immune system, recognize microbial molecules. However, TLRs also recognize some nonmicrobial molecules. In particular, TLR2 and TLR4 recognize hyaluronic acid, a glycosaminoglycan in the extracellular matrix. In neonatal mice endogenous hyaluronic acid binding to TLR4 drives normal intestinal growth. Hyaluronic acid binding to TLR4 in pericryptal macrophages results in cyclooxygenase2- dependent PGE2 production, which transactivates EGFR in LGR5+ crypt epithelial stem cells leading to increased proliferation. The expanded population of LGR5+ stem cells leads to crypt fission and lengthening of the intestine and colon. Blocking this pathway at any point (TLR4 activation, PGE2 production, EGFR transactivation) results in diminished intestinal and colonic growth. A similar pathway leads to epithelial proliferation in wound repair. The repair phase of dextran sodium sulfate colitis is marked by increased epithelial proliferation. In this model, TLR2 and TLR4 in pericryptal macrophages are activated by microbial products or by host hyaluronic acid, resulting in production of CXCL12, a chemokine. CXCL12 induces the migration of cyclooxygenase2-expressing mesenchymal stem cells from the lamina propria of the upper colonic crypts to a site adjacent to LGR5+ epithelial stem cells. PGE2 released by these mesenchymal stem cells transactivates EGFR in LGR5+ epithelial stem cells leading to increased proliferation. Several TLR2 and TLR4 agonists, including hyaluronic acid, are radioprotective in the intestine through the inhibition of radiation-induced apoptosis in LGR5+ epithelial stem cells. Administration of exogenous TLR2 or TLR4 agonists activates TLR2/TLR4 on pericryptal macrophages inducing CXCL12 production with migration of cyclooxygenase2-expressing mesenchymal stem cells from the lamina propria of the villi to a site adjacent to LGR5+ epithelial stem cells. PGE2 produced by these mesenchymal stem cells, blocks radiation-induced apoptosis in LGR5+ epithelial stem cells by an EGFR mediated pathway.

scholarly journals RBM5-AS1 promotes radioresistance in medulloblastoma through stabilization of SIRT6 protein

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Chuanying Zhu ◽  
Keke Li ◽  
Mawei Jiang ◽  
Siyu Chen
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Xenograft Model ◽  
Clonogenic Survival ◽  
In Vivo Studies ◽  
Radiation Induced ◽  
Non Coding Rnas ◽  
Potential Strategy ◽  
Induced Apoptosis

AbstractCancer stem cells (CSCs) contribute to radioresistance in medulloblastoma. Thus, identification of key regulators of medulloblastoma stemness is critical for improving radiotherapy for medulloblastoma. In the present study, we profiled CSC-related long non-coding RNAs (lncRNAs) between radioresistant and parental medulloblastoma cells. The roles of the lncRNA RBM5-AS1 in the stemness and radiosensitivity of medulloblastoma cells were investigated. We found that RBM5-AS1, a novel inducer of medulloblastoma stemness, was significantly upregulated in radioresistant medulloblastoma cells compared to parental cells. Knockdown of RBM5-AS1 diminished the viability and clonogenic survival of both radioresistant and parental medulloblastoma cells after radiation. Silencing of RBM5-AS1 significantly enhanced radiation-induced apoptosis and DNA damage. In vivo studies confirmed that depletion of RBM5-AS1 inhibited tumor growth and increased radiosensitivity in a medulloblastoma xenograft model. In contrast, overexpression of RBM5-AS1 reduced radiation-induced apoptosis and DNA damage in medulloblastoma cells. Mechanistically, RBM5-AS1 interacted with and stabilized sirtuin 6 (SIRT6) protein. Silencing of SIRT6 reduced the stemness and reinforced radiation-induced DNA damage in medulloblastoma cells. Overexpression of SIRT6 rescued medulloblastoma cells from RBM5-AS1 depletion-induced radiosensitization and DNA damage. Overall, we identify RBM5-AS1 as an inducer of stemness and radioresistance in medulloblastoma. Targeting RBM5-AS1 may represent a potential strategy to overcome the resistance to radiotherapy in this malignancy.

scholarly journals Hyaluronic acid is radioprotective in the intestine through a TLR4 and COX-2-mediated mechanism

2012 ◽  
Vol 302 (3) ◽  
pp. G309-G316 ◽  
Author(s):  
Terrence E. Riehl ◽  
Lynne Foster ◽  
William F. Stenson
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Radiation Therapy ◽  
Hyaluronic Acid ◽  
Intestinal Epithelium ◽  
Fold Increase ◽  
Radiation Induced ◽  
Cox 2 ◽  
Total Body ◽  
Induced Apoptosis

The intestinal epithelium is sensitive to radiation injury. Damage to the intestinal epithelium is dose limiting in radiation therapy of abdominal cancers. There is a need for agents that can be given before radiation therapy to protect the intestinal epithelium. C57BL6 mice were subjected to 12 Gy of total body radiation. Some mice received intraperitoneal hyaluronic acid (HA) before radiation. Mice were killed 6 h after radiation to assess radiation-induced apoptosis in the intestine; other mice were killed at 84 h to assess crypt survival. Total body radiation (12 Gy) resulted in increased expression of HA synthases and HA in the intestine and increased plasma HA (5-fold). Intraperitoneal injection of HA (30 mg/kg) before radiation resulted in a 1.8-fold increase in intestinal crypt survival and a decrease in radiation-induced apoptosis. The radioprotective effects of HA were not seen in Toll-like receptor 4 (TLR4)- or cyclooxygenase-2 (COX-2)-deficient mice. Intraperitoneal injection of HA induced a 1.5-fold increase in intestinal COX-2 expression, a 1.5-fold increase in intestinal PGE2, and the migration of COX-2-expressing mesenchymal stem cells from the lamina propria in the villi to the lamina propria near the crypt. We conclude that 1) radiation induces increased HA expression through inducing HA synthases, 2) intraperitoneal HA given before radiation reduces radiation-induced apoptosis and increases crypt survival, and 3) these radioprotective effects are mediated through TLR4, COX-2, and the migration of COX-2-expressing mesenchymal stem cells.

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