scholarly journals Gfi1-expressing Paneth cells revert to stem cells following intestinal injury

2018 ◽  
Author(s):  
Min-Shan Chen ◽  
Yuan-Hung Lo ◽  
Joann Butkus ◽  
Winnie Zou ◽  
Yu-Jung Tseng ◽  
...  
Keyword(s):  
Stem Cells ◽  
Intestinal Epithelium ◽  
Goblet Cells ◽  
Intestinal Injury ◽  
Model Systems ◽  
Treatment Modalities ◽  
Secretory Cells ◽  
Chemotherapy Drugs ◽  
Normal Tissues ◽  
Epithelial Regeneration

AbstractBackground＆AimChemotherapy drugs harm rapidly dividing normal healthy cells such as those lining the gastrointestinal tract, causing morbidity and mortality that complicates medical treatment modalities. Growth Factor-Independent 1 (GFI1) is a zinc finger transcriptional repressor implicated in the differentiation of secretory precursors into Paneth and goblet cells in the intestinal epithelium. We hypothesize that stimulating the reversion of Gfi1+ secretory cells into stem cells will improve intestinal epithelial regeneration and mitigate injury.MethodsGfi1 reporter mice (Gfi1cre/+; ROSA26 LSL-YFP) were treated with Doxorubicin, radiation, anti-CD3 antibody, and rotavirus to induce intestinal injury. Mice and intestinal organoids (enteroids) were used to investigate cellular repair mechanisms following injury.ResultsUnder homeostatic conditions, Gfi1-lineage cells are Paneth and goblet cells, which were non-proliferative and not part of the stem cell pool. After injury, Gfi1+ secretory cells can re-enter the cell cycle and give rise to all cell lineages of the intestinal epithelium including stem cells. Reversion of Gfi1-lineage cells was observed in other injury model systems, including irradiation and anti-CD3 treatment, but not in ISC-sparing rotavirus infection. Our results also demonstrated that PI3kinase/AKT activation improved cell survival, and elevated WNT signaling increased the efficiency of Gfi1+ cell reversion upon injury.ConclusionsThese findings indicate that Gfi1+ secretory cells display plasticity and reacquire stemness following severe damage. Moreover, PI3kinase/AKT and WNT are key regulators involved in injury-induced regeneration. Our studies identified potential therapeutic intervention strategies to mitigate the adverse effects of chemotherapy-induced damage to normal tissues and improve the overall effectiveness of cancer chemotherapy.

Resveratrol as an Enhancer of Apoptosis in Cancer: A Mechanistic Review

2020 ◽  
Vol 20 ◽  
Author(s):  
Milad Ashrafizadeh ◽  
Shahram Taeb ◽  
Hamed Haghi-Aminjan ◽  
Shima Afrashi ◽  
Kave Moloudi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cancer Cells ◽  
Fas Ligand ◽  
Inhibitory Effect ◽  
Mitochondrial Pathway ◽  
Multi Drug Resistance ◽  
Chemotherapy Drugs ◽  
Normal Tissues ◽  
Anti Cancer

: Resistance of cancer cells to therapy is a challenge for achieving an appropriate therapeutic outcome. Cancer (stem) cells possess several mechanisms for increasing their survival following exposure to toxic agents such as chemotherapy drugs, radiation as well as immunotherapy. Evidences show that apoptosis plays a key role in response of cancer (stem) cells and their multi drug resistance. Modulation of both intrinsic and extrinsic pathways of apoptosis can increase efficiency of tumor response and amplify the therapeutic effect of radiotherapy, chemotherapy, targeted therapy and also immunotherapy. To date, several agents as adjuvant have been proposed to overcome resistance of cancer cells to apoptosis. Natural products are interesting because of low toxicity on normal tissues. Resveratrol is a natural herbal agent that has shown interesting anti-cancer properties. It has been shown to kill cancer cells selectively, while protecting normal cells. Resveratrol can augment reduction/oxidation (redox) reactions, thus increases the production of ceramide and the expression of apoptosis receptors such as Fas ligand (FasL). Resveratrol also triggers some pathways which induce mitochondrial pathway of apoptosis. On the other hand, resveratrol has an inhibitory effect on anti-apoptotic mediators such as nuclear factor κ B (NFκB), cyclooxygenase-2 (COX-2), phosphatidylinositol 3–kinase (PI3K) and mTOR. In this review, we explain the modulatory effects of resveratrol on apoptosis, which can augment the therapeutic efficiency of anti-cancer drugs or radiotherapy.

scholarly journals Intestinal epithelial cell-specific IGF1 promotes the expansion of intestinal stem cells during epithelial regeneration and functions on the intestinal immune homeostasis

2018 ◽  
Vol 315 (4) ◽  
pp. E638-E649 ◽  
Author(s):  
Yu Zheng ◽  
Yongli Song ◽  
Qi Han ◽  
Wenjie Liu ◽  
Jiuzhi Xu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Epithelial Cell ◽  
Intestinal Epithelial Cell ◽  
High Throughput Sequencing ◽  
Secretory Cells ◽  
Intestinal Epithelial ◽  
Epithelial Stem Cells ◽  
Microbial Composition ◽  
Epithelial Regeneration

It is well known that insulin-like growth factor 1 (IGF1) acts as a trophic factor in small intestine under both physiological and pathophysiological conditions. However, it still lacks direct in vivo evidence of the functions of intestinal epithelial cell (IEC)-specific IGF1 under both normal and pathological conditions. Using IEC-specific IGF1-knockout (cKO) mice and Lgr5-eGFP-CreERT mice, we demonstrate that IEC-specific IGF1 can enhance nutrient uptake, reduce protein catabolism and energy consumption, and promote the proliferation and expansion of intestinal epithelial cells, including intestinal epithelial stem cells and intestinal secretory cells. Next, we showed that IEC-specific IGF1 renders IECs resistant to irradiation and promotes epithelial regeneration. Strikingly, transcriptome profiling assay revealed that many differentially expressed genes involved in the differentiation and maturation of lymphoid lineages were significantly suppressed in the cKO mice as compared with the control mice. We demonstrated that deletion of IGF1 in IECs enhances bacterial translocation to the mesenteric lymph nodes and liver. Furthermore, high-throughput sequencing of 16S ribosomal RNA genes of gut microbiota revealed that IEC-specific IGF1 loss profoundly affected the gut microbial composition at various levels of classification. Therefore, our findings shed light on the in vivo roles of IEC-specific IGF1 in intestinal homeostasis, epithelial regeneration, and immunity, broadening our current insights on IGF1 functions.

scholarly journals Plasticity of Intestinal Epithelium: Stem Cell Niches and Regulatory Signals

2020 ◽  
Vol 22 (1) ◽  
pp. 357
Author(s):  
Ken Kurokawa ◽  
Yoku Hayakawa ◽  
Kazuhiko Koike
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Inflammatory Cytokines ◽  
Intestinal Epithelium ◽  
Intestinal Stem Cells ◽  
Signal Pathways ◽  
Epithelial Regeneration ◽  
Cell Functions ◽  
Differentiated Cells ◽  
Stem Cell Niches

The discovery of Lgr5+ intestinal stem cells (ISCs) triggered a breakthrough in the field of ISC research. Lgr5+ ISCs maintain the homeostasis of the intestinal epithelium in the steady state, while these cells are susceptible to epithelial damage induced by chemicals, pathogens, or irradiation. During the regeneration process of the intestinal epithelium, more quiescent +4 stem cells and short-lived transit-amplifying (TA) progenitor cells residing above Lgr5+ ISCs undergo dedifferentiation and act as stem-like cells. In addition, several recent reports have shown that a subset of terminally differentiated cells, including Paneth cells, tuft cells, or enteroendocrine cells, may also have some degree of plasticity in specific situations. The function of ISCs is maintained by the neighboring stem cell niches, which strictly regulate the key signal pathways in ISCs. In addition, various inflammatory cytokines play critical roles in intestinal regeneration and stem cell functions following epithelial injury. Here, we summarize the current understanding of ISCs and their niches, review recent findings regarding cellular plasticity and its regulatory mechanism, and discuss how inflammatory cytokines contribute to epithelial regeneration.

scholarly journals Stable Long-Term Culture of Human Distal Airway Stem Cells for Transplantation

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Yueqing Zhou ◽  
Yujia Wang ◽  
Dandan Li ◽  
Ting Zhang ◽  
Yu Ma ◽  
...  
Keyword(s):  
Stem Cells ◽  
Lung Model ◽  
Mouse Lung ◽  
Secretory Cells ◽  
Type I ◽  
Alveolar Cells ◽  
Epithelial Regeneration ◽  
Distal Airway ◽  
Promising Therapeutic Approach

There is a population of p63+/Krt5+ distal airway stem cells (DASCs) quiescently located in the airway basal epithelium of mammals, responding to injury and airway epithelial regeneration. They hold the ability to differentiate into multiple pulmonary cell types and can repopulate the epithelium after damage. The current study aims at gaining further insights into the behavior and characteristics of the DASCs isolated from the patient lung and exploring their clinical translational potential. Human DASCs were brushed off through the bronchoscopic procedure and expanded under the pharmaceutical-grade condition. Their phenotype stability in long-term cell culture was analyzed, followed by safety evaluation and tumorigenic analysis using multiple animal models including rodents and nonhuman primate. The chimerism of the human-mouse lung model indicated that DASC pedigrees could give rise to multiple epithelial types, including type I alveolar cells as well as bronchiolar secretory cells, to regenerate the distal lung. Taken together, the results suggested that DASC transplantation could be a promising therapeutic approach for unmet needs in respiratory medicine including the COVID-19-related diseases.

scholarly journals Goblet cell LRRC26 regulates BK channel activation and protects against colitis in mice

2020 ◽  
Author(s):  
Vivian Gonzalez-Perez ◽  
Pedro L. Martinez-Espinosa ◽  
Monica Sala-Rabanal ◽  
Nikhil Bharadwaj ◽  
Xiao-Ming Xia ◽  
...  
Keyword(s):  
Intestinal Epithelium ◽  
Goblet Cells ◽  
Bk Channels ◽  
Bk Channel ◽  
Intestinal Lumen ◽  
Regulatory Subunit ◽  
Secretory Cells ◽  
Mucus Layer ◽  
Α Subunit ◽  
Genetic Ablation

AbstractGoblet cells (GCs) are specialized cells of the intestinal epithelium contributing critically to mucosal homeostasis. One of the functions of GCs is to produce and secrete MUC2, the mucin that forms the scaffold of the intestinal mucus layer coating the epithelium and separates the luminal pathogens and commensal microbiota from the host tissues. Although a variety of ion channels and transporters are thought to impact on MUC2 secretion, the specific cellular mechanisms that regulate GC function remain incompletely understood. Previously, we demonstrated that leucine-rich-repeat-containing protein 26 (LRRC26), a known regulatory subunit of the Ca2+-and voltage-activated K+ channel (BK channel), localizes specifically to secretory cells within the intestinal tract. Here, utilizing a mouse model in which MUC2 is fluorescently tagged allowing visualization of single GCs in intact colonic crypts, we show that murine colonic GCs have functional LRRC26-associated BK channels. In the absence of LRRC26, BK channels are present in GCs, but are not activated at physiological conditions. In contrast, all tested MUC2-negative cells completely lacked BK channels. Moreover, LRRC26-associated BK channels underlie the BK channel contribution to the resting transepithelial current across mouse distal colonic mucosa. Genetic ablation of either LRRC26 or BK-pore forming α-subunit in mice results in a dramatically enhanced susceptibility to colitis induced by dextran sodium sulfate (DSS). These results demonstrate that normal potassium flux through LRRC26-associated BK channels in GCs has protective effects against colitis in mice.SignificanceA primary function of goblet cells (GCs) of the intestinal epithelium is to generate a protective mucus layer lining the intestinal lumen. GC dysfunction is linked to Inflammatory Bowel Disease (IBD). GC mucus secretion is thought to be dependent on contributions of an ensemble of anion and cation fluxes, although understanding remains limited. Here, it is shown in mouse colon that the Ca2+- and voltage-dependent BK-type K+ channel, specifically in association with the LRRC26 regulatory subunit, plays a critical role in normal GC function, protecting mice against chemically-induced colitis. The results demonstrate that normal K+ fluxes mediated by LRRC26-containing BK channels are required for normal GC function, potentially providing insights into the potential role of BK channels in IBD.

scholarly journals Re-entry into mitosis and regeneration of intestinal stem cells through enteroblast dedifferentiation in Drosophila midguts

2021 ◽  
Author(s):  
Aiguo Tian ◽  
Virginia Morejon ◽  
Sarah Kohoutek ◽  
Yi-Chun Huang ◽  
Wu-Min Deng ◽  
...  
Keyword(s):  
Stem Cells ◽  
Pathogenic Bacteria ◽  
Growth Factor Receptor ◽  
Lineage Tracing ◽  
Intestinal Stem Cells ◽  
Stem Cell Marker ◽  
Secretory Cells ◽  
Ras Signaling ◽  
Epithelial Regeneration ◽  
Resident Stem Cells

Many adult tissues and organs including the intestine rely on resident stem cells to maintain homeostasis. In mammalian intestines, upon ablation of resident stem cells, the progenies of intestinal stem cells (ISCs) such as secretory cells and tuft cells can dedifferentiate to generate ISCs to drive epithelial regeneration, but whether and how the ISC progenies dedifferentiate to generate ISCs under physiological conditions remains unknown. Here we show that infection of pathogenic bacteria induces enteroblasts (EBs) as one type of ISC progenies to re-enter the mitotic cycle in the Drosophila intestine. The re-entry into mitosis is dependent on epithermal growth factor receptor (EGFR)-Ras signaling and ectopic activation of EGFR-Ras signaling in EBs is sufficient to drive EBs cell-autonomously to re-enter into mitosis. In addition, we examined whether EBs gain ISC identity as a prerequisite to divide, but the immunostaining with stem cell marker Delta shows that these dividing EBs do not gain ISC identity. After employing lineage tracing experiments, we further demonstrate that EBs dedifferentiate to generate functional ISCs after symmetric divisions of EBs. Together, our study in Drosophila intestines uncovers a new role of EGFR-Ras signaling in regulating re-entry into mitosis and dedifferentiation during regeneration and reveals a novel mechanism by which ISC progenies undergo dedifferentiation through a mitotic division, which has important implication to mammalian tissue homeostasis and tumorigenesis.

scholarly journals Intestinal cyto differentiation in vitro of chick stomach endoderm induced by the duodenal mesenchyme

Development ◽  
1984 ◽  
Vol 82 (1) ◽  
pp. 163-176
Author(s):  
Atsuko Ishizuya-Oka ◽  
Takeo Mizuno
Keyword(s):  
Electron Microscopy ◽  
Epithelial Cells ◽  
Intestinal Epithelium ◽  
Intestinal Epithelial Cells ◽  
Goblet Cells ◽  
Secretory Cells ◽  
Chick Embryos ◽  
Intestinal Epithelial ◽  
Self Differentiation

The inductive action of duodenal mesenchyme on the cytodifferentiation of stomach endoderm in chick embryos was investigated in vitro with electron microscopy and immunofluorescence. Morphologically undifferentiated endoderm of the stomach of a 4-day embryo could differentiate only into a mucous secretory epithelium when cultured in the absence of mesenchyme. However, when cultivated in recombination with 6-day duodenal mesenchyme, most cells of 4-day stomach endoderm differentiated into intestinal absorptive cells possessing striated border and sucrase, and goblet cells, but not into stomach-type mucous secretory cells. In contrast, when 4-day stomach endoderm was cultured recombined with mesenchyme of embryonic digestive organs other than intestine, none of the stomach endoderm cells differentiated into intestinal epithelial cells. The competence of stomach endoderm for intestinal cytodifferentiation decreased rapidly with development, but remained until relatively later stages in the gizzard region. The present investigation demonstrates that duodenal mesenchyme can induce stomach endoderm, which has acquired the potency for self-differentiation into stomach-type epithelium, to cytodifferentiate into intestinal epithelium.

Generation of Clara cells from murine pluripotent stem cells – a new tool to explore airway epithelial regeneration

Pneumologie ◽  
2014 ◽  
Vol 68 (06) ◽  
Author(s):  
K Katsirntaki ◽  
C Mauritz ◽  
S Schmeckebier ◽  
M Sgodda ◽  
V Puppe ◽  
...  
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Airway Epithelial ◽  
Clara Cells ◽  
Epithelial Regeneration

Epithelial Regeneration after Doxorubicin Arises Primarily from Early Progeny of Active Intestinal Stem Cells

2020 ◽  
Author(s):  
Breanna Sheahan ◽  
Ally N. Freeman ◽  
Theresa M. Keeley ◽  
Linda C. Samuelson ◽  
Jatin Roper ◽  
...  
Keyword(s):  
Stem Cells ◽  
Intestinal Stem Cells ◽  
Epithelial Regeneration

Targeting Nodal and Cripto-1: Perspectives Inside Dual Potential Theranostic Cancer Biomarkers

2019 ◽  
Vol 26 (11) ◽  
pp. 1994-2050 ◽  
Author(s):  
Annamaria Sandomenico ◽  
Menotti Ruvo
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Normal Development ◽  
Cancer Biomarkers ◽  
Normal Tissues ◽  
Tumor Relapse ◽  
Developmental Factors ◽  
Theranostic Agents ◽  
Tumor Types ◽  
Embryonic Signaling

Background:Elucidating the mechanisms of recurrence of embryonic signaling pathways in tumorigenesis has led to the discovery of onco-fetal players which have physiological roles during normal development but result aberrantly re-activated in tumors. In this context, Nodal and Cripto-1 are recognized as onco-developmental factors, which are absent in normal tissues but are overexpressed in several solid tumors where they can serve as theranostic agents.Objective:To collect, review and discuss the most relevant papers related to the involvement of Nodal and Cripto-1 in the development, progression, recurrence and metastasis of several tumors where they are over-expressed, with a particular attention to their occurrence on the surface of the corresponding sub-populations of cancer stem cells (CSC).Results:We have gathered, rationalized and discussed the most interesting findings extracted from some 370 papers related to the involvement of Cripto-1 and Nodal in all tumor types where they have been detected. Data demonstrate the clear connection between Nodal and Cripto-1 presence and their multiple oncogenic activities across different tumors. We have also reviewed and highlighted the potential of targeting Nodal, Cripto-1 and the complexes that they form on the surface of tumor cells, especially of CSC, as an innovative approach to detect and suppress tumors with molecules that block one or more mechanisms that they regulate.Conclusion:Overall, Nodal and Cripto-1 represent two innovative and effective biomarkers for developing potential theranostic anti-tumor agents that target normal as well as CSC subpopulations and overcome both pharmacological resistance and tumor relapse.

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