cell renewal
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2022 ◽  
Vol 12 (1) ◽  
pp. 77
Author(s):  
Chih-Huang Tseng ◽  
Pei-Hsuan Lu ◽  
Yi-Ping Wang ◽  
Julia Yu Fong Chang

Ameloblastoma is the most common benign odontogenic neoplasm, but with an aggressive behavior and a high recurrence rate. Nowadays wide surgical resection is the current recommended treatment, which can cause further loss of function and esthetics. Recent studies point to the stem/progenitor cells as both initiators and propagators of the tumors. Elucidation of the cellular and molecular mechanisms underlying the tumor stem cells is of broad interest for understanding tumorigenesis and for developing effective targeted therapies. SRY related HMG box gene 2 (SOX2) is a transcription factor that plays important roles in development, stem cell renewal, and cancer formation. Few studies have revealed increased SOX2 expression in atypical ameloblastoma and ameloblastic carcinoma. For the development of personalized medicine for ameloblastoma, biomarkers that provide prognostic or predictive information regarding a tumor’s nature or its response to treatment are essential. Thus, in this study, we aimed to study if SOX2-positive cells exist in ameloblastomas and their correlation with the clinicopathologic parameters. Our data suggested BRAF(V600E) mutation might contribute to the expansion of SOX2-positive cells. The identification of BRAF(V600E) mutation and the amplification of SOX2-positive cells in ameloblastomas imply the possible benefit of applying BRAF and SOX2 inhibitors in recurrent and un-resectable ameloblastomas.


2022 ◽  
Vol 11 ◽  
Author(s):  
Kai Li ◽  
Shan Gao ◽  
Lei Ma ◽  
Ye Sun ◽  
Zi-Yang Peng ◽  
...  

The molecular mechanism of the tyrosine kinase inhibitor (TKI) resistant lung adenocarcinoma is currently unclear, and the role of methylated adenosine at the N6 position in the resistance of cancer stem cells (CSCs) therapy is unknown. This study identified a novel and effective strategy to enhance TKIs therapy response. We first confirmed the sensitization of Metformin enforcing on Osimertinib treatment and revealed the mature miRNAs signatures of the Osimertinib resistant H1975 and HCC827 cells. Let-7b expression was stimulated when adding Metformin and then increasing the therapy sensitivity by decreasing the stem cell groups expanding. Methyltransferase-like 3 (METTL3) increased the pri-Let-7b, decreased both the pre-Let-7b and mature Let-7b, attenuating the Let-7b controlling of stem cell renewal. The addition of Metformin increased the bindings of DNA methyltransferase-3a/b (DNMT3a/b) to the METTL3 promoter. With the help of the readers of NKAP and HNRNPA2B1, the cluster mediated m6A formation on pri-Let-7b processing increased the mature Let-7b, the key player in suppressing Notch signaling and re-captivating Osimertinib treatment. We revealed that the maturation processing signaling stimulated the methylation regulation of the miRNAs, and may determine the stemness control of the therapy resistance. Our findings may open up future drug development, targeting this pathway for lung cancer patients.


Author(s):  
Calum Gabbutt ◽  
Ryan O. Schenck ◽  
Daniel J. Weisenberger ◽  
Christopher Kimberley ◽  
Alison Berner ◽  
...  

AbstractMolecular clocks that record cell ancestry mutate too slowly to measure the short-timescale dynamics of cell renewal in adult tissues. Here, we show that fluctuating DNA methylation marks can be used as clocks in cells where ongoing methylation and demethylation cause repeated ‘flip–flops’ between methylated and unmethylated states. We identify endogenous fluctuating CpG (fCpG) sites using standard methylation arrays and develop a mathematical model to quantitatively measure human adult stem cell dynamics from these data. Small intestinal crypts were inferred to contain slightly more stem cells than the colon, with slower stem cell replacement in the small intestine. Germline APC mutation increased the number of replacements per crypt. In blood, we measured rapid expansion of acute leukemia and slower growth of chronic disease. Thus, the patterns of human somatic cell birth and death are measurable with fluctuating methylation clocks (FMCs).


2022 ◽  
Vol 1 (1) ◽  
pp. 67-84
Author(s):  
Gloria E. Hernandez ◽  
Feiyang Ma ◽  
Guadalupe Martinez ◽  
Nadia B. Firozabadi ◽  
Jocelynda Salvador ◽  
...  

AbstractLeukocytes and endothelial cells frequently cooperate to resolve inflammatory events. In most cases, these interactions are transient in nature and triggered by immunological insults. Here, we report that, in areas of disturbed blood flow, aortic endothelial cells permanently and intimately associate with a population of specialized macrophages. These macrophages are recruited at birth from the closing ductus arteriosus and share the luminal surface with the endothelium, becoming interwoven in the tunica intima. Anatomical changes that affect hemodynamics, such as in patent ductus arteriosus, alter macrophage seeding to coincide with regions of disturbed flow. Aortic resident macrophages expand in situ via direct cell renewal. Induced depletion of intimal macrophages leads to thrombin-mediated endothelial cell contraction, progressive fibrin accumulation and formation of microthrombi that, once dislodged, cause blockade of vessels in several organs. Together the findings reveal that intravascular resident macrophages are essential to regulate thrombin activity and clear fibrin deposits in regions of disturbed blood flow.


2021 ◽  
Vol 12 ◽  
Author(s):  
Oana-Maria Thoma ◽  
Markus F. Neurath ◽  
Maximilan J. Waldner

Cyclin-dependent kinases (CDKs) are key players in cell cycle regulation. So far, more than ten CDKs have been described. Their direct interaction with cyclins allow progression through G1 phase, transitions to S and G2 phase and finally through mitosis (M). While CDK activation is important in cell renewal, its aberrant expression can lead to the development of malignant tumor cells. Dysregulations in CDK pathways are often encountered in various types of cancer, including all gastrointestinal (GI) tract tumors. This prompted the development of CDK inhibitors as novel therapies for cancer. Currently, CDK inhibitors such as CDK4/6 inhibitors are used in pre-clinical studies for cancer treatment. In this review, we will focus on the therapeutic role of various CDK inhibitors in colorectal cancer, with a special focus on the CDK4/6 inhibitors.


2021 ◽  
Vol 11 (6-S) ◽  
pp. 156-160
Author(s):  
S Seshadhri ◽  
Sundaram Rajagopal Shanmuga ◽  
Ramanathan Sambathkumar

Background: Human tissues are sustained by stem cells, the balance between stem cell self-renewal and differentiation, and cell death is the crucial element of haemostasis, which plays a vital role in tissue remodelling. Stem cell therapy is recognized as regenerative medicine. We can stimulate stem cell growth/regeneration through various events. Objectives: In this review, we illustrate whether fasting can stimulate stem cell regeneration. Methodology: A literature survey was undertaken to gather recent research and address the effects of fasting on stem cell renewal, which was the review's purpose. Results:  Enterocytes in drosophila were restored after exposure to the dietary restriction. As the result, fasting before etoposide exposure safeguarded mice against harm caused by etoposide when compared with the fed group. A study conducted on the effects of periodic fasting in yeast, mice, and humans shows the increase in lifespan and stress resistance of yeast fasting reduces the risks due to age factors and diseases like diabetes, cardiovascular diseases and promotes a healthy life span of mice and human. Conclusion: Dietary limitations will be used in conjunction with the existing therapeutic approach as adjuvant therapy. It will be a more effective treatment. Fasting has the potential to protect against the negative effects of chemotherapy while also boosting stem cell regeneration, according to preclinical findings. Even though regenerative medicine and stem cell therapy are still in their embryonic stage, greater interventions are needed to show the target pathway of fasting in stem cell renewal. Keywords: Fasting, stem cell regeneration, emerging therapy.


BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Jianshuang Li ◽  
Likang Lyu ◽  
Haishen Wen ◽  
Yun Li ◽  
Xiaojie Wang ◽  
...  

Abstract Background The black rockfish (Sebastes schlegelii) has an ovoviviparous reproductive pattern and long-term sperm storage, resulting in asynchronous gonadal development between the sexes. However, the comprehensive understanding of gonadal development in black rockfish has not yet been achieved. Here, we studied gonadal development and germ cell renewal using histology and RNA-seq. Results In this study, RNA-seq was performed on testes and ovaries to characterize key pathways and genes that are active during development and gamete maturation in black rockfish. Differentially expressed genes (DEGs) were identified and annotated in 4 comparisons (F_III vs. F_IV, F_IV vs. F_V, M_III vs. M_IV and M_IV vs. M_V). Based on analysis of DEGs enriched in the testis, 11 and 14 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were mapped to the M_III vs. M_IV group and the M_IV vs. M_V group, respectively. DEGs in ovarian development were also classified into 10 groups according to their biological functions. The expression patterns of the selected genes determined by qPCR were significantly correlated with the RNA-Seq results, supporting the reliability and accuracy of the RNA-Seq analysis. E2 levels showed down regulation from previtellogenesis to mature stage in female and T level showed down regulation from spermatogenesis to regressed stage in the male. Conclusions The categories “intercellular interaction and cytoskeleton”, “molecule amplification” and “repair in the cell cycle” were revealed to be crucial in testis development and spermatogenesis, as was the biosynthesis of a series of metabolites. Our results provide comprehensive insight into black rockfish gonadal development and provide a basis for further study of reproductive physiology and molecular biology in ovoviviparity teleosts.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4472-4472
Author(s):  
Sumedha Saluja ◽  
Jay Singh ◽  
Ayushi Jain ◽  
Shilpi Chaudhary ◽  
Karthikeyan Pethusamy ◽  
...  

Abstract Introduction: N-6-methyladenosine (m6A) is the most common, dynamic and reversible RNA modification with implications in various cancers including leukemia. Deregulation of m6A writer METTL3 has been shown to promote disease progression in various cancers, including Acute Myeloid Leukemia(AML). Overexpression of METTL3 led to increase in cell growth and inhibition of apoptosis, thereby promoting leukemia progression. Interestingly, m6A demethylases (erasers) ALKBH5 and FTO have also seen to play a critical role in progression of AML by mediating cancer stem cell renewal. The IGF2BP family of RNA binding, oncofetal proteins have recently been identified as m6A readers and have also been shown to be deregulated in B-ALL. In this work, we have studied the expression of m6A machinery (writers, erasers and readers) in primary (naïve and relapsed) B-ALL patient samples. The percentage of methylated RNA (m6A%) was also evaluated in B-ALL patient samples. Materials and Methods: 91 newly diagnosed (naïve) and 47 relapsed B-ALL pediatric patient bone marrow samples were collected from BRAIRCH, AIIMS, New Delhi. Gene expression of m6A writer (METTL3), readers (IGF2BP1/3) and erasers (ALKBH5, FTO) was studied by RT-qPCR. Peripheral blood (PB) of 20 healthy individuals and 18 uninvolved bone marrow (BM) samples of patients with other malignancies were used as controls. m6A% was also measured in B-ALL patients (naïve n=47, relapsed n=43,) and controls (PB n=20, BM n=16, CD34+ cells from normal donors n=5) by an anti-m6A based colorimetric assay. Results: The ratio of m6A writer METTL3 to m6A eraser ALKBH5 was significantly higher in the naïve and relapsed B-ALL patients as compared to all controls. Interestingly, the ratio of the m6A writer METTL3 to m6A eraser FTO was also significantly high in naïve BM patient sample than controls. The expression of m6A readers IGF2BP1/3 that stabilize the methylated target mRNA, was also studied. IGF2BP1/3 m6A reader was significantly higher in naïve and relapsed patient samples. Increased expression of the writers and readers implied an increase in the m6A levels in B-ALL patients. The m6A% assay showed that the percentage of m6A was significantly higher in naïve and relapsed BM patient samples than both controls corroborating the RT-qPCR data. Discussion: METTL3 m6A methyl transferase has been identified a key factor in mediating the pathogenesis of AML. In our data, we have shown overexpression of METTL3 in B-ALL patient BM samples compared to controls. We have also seen an overexpression of m6A demethylase FTO in B-ALL patient samples. In order to identify the major factor among m6A writers and erasers that might play a role in pathogenesis of B-ALL, we calculated the ratio of m6A writer to m6A eraser. We have observed that ratio of METTL3 to ALKBH5 and METTL3 to FTO was significantly higher in B-ALL patient samples than both the controls. This signifies that overexpression of METTL3 subsequently leading to dysregulated methylation of its targets might influence the development and onset of relapse in B-ALL. It is well known that m6A bound target mRNAs are read by m6A readers like IGF2BPs that stabilize these m6A bound mRNAs leading to overexpression and thereby cancer progression. We have also studied expression of IGF2BP1/3 in B-ALL and seen significant overexpression of both IGF2BP1 and IGF2BP3 in B-ALL samples. These findings indicate a combined dysregulation of m6A writers, erasers and readers in B-ALL. This corroborates with the findings seen in AML, which also shows overexpression of METTL3, ALKBH5 and FTO. Our gene expression studies together point towards an increased percentage of m6A methylated RNA in B-ALL. We have evaluated the percentage of m6A in B-ALL patient samples to confirm our gene expression findings. We observed presence of significantly higher percentage of m6A in B-ALL patient samples (naïve and relapse) than both the controls. m6A% was significantly higher in naïve B-ALL patient samples compared to CD34+ HSCs also. Our findings reveal overall high m6A% in B-ALL, attributed to overexpression of m6A writer METTL3 and m6A readers IGF2BP1/3. This RNA methylation and stabilization might be dysregulated and concentrated in oncogenic genes leading to leukemogenesis. Our results provide a rationale for targeting of these m6A machinery genes dysregulation of which can be instrumental in pathogenesis of B-ALL. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.


2021 ◽  
Author(s):  
Alia Hadefi ◽  
Morgane Leprovots ◽  
Max Thulliez ◽  
Orianne Bastin ◽  
Anne Lefort ◽  
...  

Cold atmospheric plasma (CAP) treatment has been proposed as a potentially innovative therapeutic tool in the biomedical field, notably for cancer due to its proposed toxic selectivity on cancer cells versus healthy cells. In the present study, we addressed the relevance of three-dimensional organoid technology to investigate the biological effects of CAP on normal epithelial stem cells and tumor cells isolated from mouse small intestine. CAP treatment exerted dose-dependent cytotoxicity on normal organoids and induced major transcriptomic changes associated with global response to oxidative stress, fetal-like regeneration reprogramming and apoptosis-mediated cell death. Moreover, we explored the potential selectivity of CAP on tumor-like Apc-deficient versus normal organoids in the same genetic background. Unexpectedly, tumor organoids exhibited higher resistance to CAP treatment, correlating with higher antioxidant activity at baseline as compared to normal organoids. This pilot study suggests that the ex vivo culture system could be a relevant alternative model to further investigate translational medical applications of CAP technology.


Nephron ◽  
2021 ◽  
pp. 1-4
Author(s):  
Joseph V. Bonventre

DNA damage is an important consequence of injury to the proximal tubule. The proximal tubule cell responds to this damage by mounting a DNA damage response (DDR). Two protein kinases, ataxia-telangiectasia mutated (ATM) or ataxia telangiectasia and Rad3-related (ATR), play an important role in this DDR. If efficient, the DDR can lead to repair of the DNA, cell renewal, and return to a healthy state. In many cases, however, especially in the setting of baseline kidney injury, there is incomplete repair. In human chronic kidney disease (CKD) and in human kidney organoids exposed to acute injury, there is increased evidence of DNA damage and activation of ATR. This review focuses on 3 aspects of the DNA damage and response to it: (1) DNA damage and the DDR precipitated by acute injury; (2) protection afforded by the DDR kinase, ATR, in multiple mouse models of acute kidney injury; and (3) downstream effects of genetic inhibition of ATR in the proximal tubule, leading to maladaptive repair, fibrosis, and CKD.


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