scholarly journals Clostridioides difficileinfection damages colonic stem cells via TcdB, impairing epithelial repair and recovery from disease

2020 ◽  
Vol 117 (14) ◽  
pp. 8064-8073 ◽  
Author(s):  
Steven J. Mileto ◽  
Thierry Jardé ◽  
Kevin O. Childress ◽  
Jaime L. Jensen ◽  
Ashleigh P. Rogers ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Disease Recurrence ◽  
Gastrointestinal Infections ◽  
Cell Compartment ◽  
Epithelial Repair ◽  
Epithelial Regeneration ◽  
Clostridioides Difficile ◽  
Stem Cell Compartment ◽  
Colonic Stem Cells

Gastrointestinal infections often induce epithelial damage that must be repaired for optimal gut function. While intestinal stem cells are critical for this regeneration process [R. C. van der Wath, B. S. Gardiner, A. W. Burgess, D. W. Smith,PLoS One8, e73204 (2013); S. Kozaret al.,Cell Stem Cell13, 626–633 (2013)], how they are impacted by enteric infections remains poorly defined. Here, we investigate infection-mediated damage to the colonic stem cell compartment and how this affects epithelial repair and recovery from infection. Using the pathogenClostridioides difficile,we show that infection disrupts murine intestinal cellular organization and integrity deep into the epithelium, to expose the otherwise protected stem cell compartment, in a TcdB-mediated process. Exposure and susceptibility of colonic stem cells to intoxication compromises their function during infection, which diminishes their ability to repair the injured epithelium, shown by altered stem cell signaling and a reduction in the growth of colonic organoids from stem cells isolated from infected mice. We also show, using both mouse and human colonic organoids, that TcdB from epidemic ribotype 027 strains does not require Frizzled 1/2/7 binding to elicit this dysfunctional stem cell state. This stem cell dysfunction induces a significant delay in recovery and repair of the intestinal epithelium of up to 2 wk post the infection peak. Our results uncover a mechanism by which an enteric pathogen subverts repair processes by targeting stem cells during infection and preventing epithelial regeneration, which prolongs epithelial barrier impairment and creates an environment in which disease recurrence is likely.

scholarly journals The Epidermal Stem Cell Compartment: Variation in Expression Levels of E–Cadherin and Catenins Within the Basal Layer of Human Epidermis

1997 ◽  
Vol 45 (6) ◽  
pp. 867-874 ◽  
Author(s):  
Jean-Pierre Molès ◽  
Fiona M. Watt
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Basal Layer ◽  
Human Epidermis ◽  
Proliferative Potential ◽  
Stem Cell Markers ◽  
Cell Compartment ◽  
Stem Cell Compartment ◽  
E Cadherin ◽  
Cell Cell

The basal layer of the epidermis contains two types of proliferating keratinocyte: stem cells, with high proliferative potential, and transit amplifying cells, which are destined to undergo terminal differentiation after a few rounds of division. It has been shown previously that two- to three-fold differences in the average staining intensity of fluorescein-conjugated antibodies to β1 integrin subunits reflect profound differences in the proliferative potential of keratinocytes, with integrin-bright populations being enriched for stem cells. In the search for additional stem cell markers, we have stained sections of normal human epidermis with antibodies to proteins involved in intercellular adhesion and quantitated the fluorescence of individual cell-cell borders. In the basal layer, patches of brightly labeled cells were detected with antibodies to E-cadherin, β-catenin, and γ-catenin, but not with antibodies to P-cadherin, α-catenin, or with pan-desmocollin and pan-desmoglein antibodies. In the body sites examined, palm and foreskin, integrinbright regions were strongly labeled for γ-catenin and weakly labeled for E-cadherin and β-catenin. Our data suggest that there are gradients of both cell-cell and cell-extracellular matrix adhesiveness within the epidermal basal layer and that the levels of E-cadherin and of β-and γ-catenin may provide markers for the stem cell compartment, stem cells expressing relatively higher levels of γ-catenin and lower levels of E-cadherin and β-catenin than other basal keratinocytes.

Very small embryonic-like stem cells as a novel developmental concept and the hierarchy of the stem cell compartment

2014 ◽  
Vol 59 (2) ◽  
pp. 273-280 ◽  
Author(s):  
Mariusz Z. Ratajczak ◽  
Krzysztof Marycz ◽  
Agata Poniewierska-Baran ◽  
Katarzyna Fiedorowicz ◽  
Monika Zbucka-Kretowska ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Compartment ◽  
Stem Cell Compartment

scholarly journals Pluripotential stem cell differentiation in hemopoietic colonies

Blood ◽  
1976 ◽  
Vol 47 (2) ◽  
pp. 315-323 ◽  
Author(s):  
RL DeGowin ◽  
DP Gibson
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Mononuclear Cells ◽  
Tritiated Thymidine ◽  
Myeloid Cells ◽  
Stem Cell Differentiation ◽  
Lymphoid Cells ◽  
Cell Compartment ◽  
Split Dose ◽  
Stem Cell Compartment

Abstract To determine if mononuclear cells proliferating in murine hemopoietic spleen colonies were pluripotential in addition to possessing kinetic features of stem cells, we performed sequential studies of mice during their recovery from a split-dose irradiation regimen of 850 roentgens leg shielded-3-hr interval-850 roentgens leg irradiated (850R L.S. 3- L.I.). Injecting tritiated thymidine during stem cell compartment repletion 3 and 4 days after 850R L.S. 3- L.I. resulted in heavily labeled mononuclear cells resembling medium to large leptochromatic lymphocytes in the portion of spleen removed an hour after injection. The splenic remnant obtained from the same mouse 24–48 hr later contained lightly labeled erythroblasts, myeloid cells, and lymphoid cells. Grain counts suggested that erythroblasts and their precursors had undergone about four divisions, myeloid cells and their precursors two to three divisions, and lymphoid cells and their precursors two to three divisions during the 48-hr period. Similar studies in plethoric mice demonstrated the labeling of mononuclear cells on day 4 and their differentiation to myeloid and lymphoid cells by day 6. This finding confirmed that the labeled mononuclear cells were not exclusively erythroblast progenitors. On the basis of these and previous studies of post-irradiation survival and erythropoietic recovery, we conclude that these endogenous monomuclear cells, which resemble medium to large leptochromatic lymphocytes and replicate during stem cell compartment repletion, are pluripotential hemopoietic stem cells.

Unexpected Evidence That Chronic IGF-1 Deficiency In Laron Dwarf Mice Maintains High Levels of Hematopoietic Stem Cells (HSCs) In BM - Are HSCs Gradually Depleted From BM with Age In An IGF-1–dependent Manner? Implications for the Novel Effect of Caloric Restriction on the Hematopoietic Stem Cell Compartment and Longevity.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1551-1551
Author(s):  
Janina Ratajczak ◽  
Wu Wan ◽  
Rui Liu ◽  
Dong-Myung Shin ◽  
Magdalena Kucia ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Caloric Restriction ◽  
Hematopoietic Stem Cell ◽  
Cell Compartment ◽  
Hematopoietic Stem ◽  
Stem Cell Compartment ◽  
Low Levels ◽  
Dwarf Mice ◽  
High Calorie

Abstract Abstract 1551 Insulin-like growth factor-1 (Igf-1) or somatomedin is an important factor affecting proliferation of several types of cells, but its role in hematopoiesis remains controversial. Secretion of Igf-1 in the liver is stimulated directly by the growth hormone (GH)–GH receptor (GH-R) axis and indirectly by a high calorie diet. We have previously reported that Igf-1 does not directly stimulate proliferation of hematopoietic progenitors (J Clin Invest. 1994;94:320). However, our recent data indicate that Igf-1 stimulates proliferation of so-called very small embryonic-like stem cells (VSELs), that as we demonstrated, are the most developmentally primitive stem cells in adult bone marrow (BM) (Leukemia 2006;20:857) and may give rise to long-term repopulating hematopoietic stem cells (LT-HSCs) (Leukemia 2010; in press doi:10.1038/leu.2010.121). We envision that VSELs play a role in rejuvenation of the pool of tissue-committed stem cells in some tissues (e.g., HSCs and MSCs in BM) and we observed that the number of these cells in murine BM decreases with age. We also observed that erasure of the somatic imprint on some paternally imprinted genes (e.g., Igf2-H19 and RasGRF1) results in attenuation of insulin/insulin-like factors (e.g., Ins/Igf-1 signaling), keeps VSELs quiescent in BM, and protects them from uncontrolled proliferation. In the current work, to shed more light on the role of Igf-1 on hematopoiesis and stem cell compartment, we analyzed BM isolated from murine Laron dwarfs, which due to a genetic mutation in the GH-R, maintain very low levels of Igf-1 in peripheral blood (PB) and interestingly are long-living animals (Nature 2010;464:504). Analysis of PB cell counts, however, did not reveal any differences in the number of erythrocytes, platelets, and leucocytes between Laron dwarf mice and wild type controls. In striking contrast, however, we observed that Laron dwarf mice have in BM i) a ∼4–5-fold increase in the number of Sca-1+c-kit+lineage- (SKL) cells and ii) a >4-fold higher number of clonogenic CFU-Mix, CFU-GM, BFU-E, and CFU-Meg cells. Interestingly, Laron dwarfs also maintained ∼3-fold higher number of VSELs in BM tissue. Since the Igf-1 level is regulated by calorie uptake, these data shed new light on caloric restriction, senescence, and the hematopoietic stem cell compartment. Accordingly, we propose a new paradigm in which chronic Igf-1 deficiency somehow protects VSELs from age-related elimination from BM. This mimics a situation seen in chronic caloric restriction where the Igf-1 level is low and this results in longevity. Since the long-living Laron dwarf mice that maintain low levels of Igf-1 have higher numbers of VSELs and HSCs in BM, we postulate that chronically elevated levels of Igf-1, resulting e.g., from high calorie uptake, may lead to premature depletion of the stem cell pool, including VSELs and HSCs, and thus be responsible for premature aging. This hypothesis is currently being tested in animals that overexpress Igf-1, and interestingly, in contrast to IGF-1–deficient Laron dwarf mice, appear to have much shorter lifespans. Further studies are needed that will link the effect of chronic high Igf-1 signaling with the development of hematological malignancies. Of note, murine Laron dwarfs are significantly protected from developing cancer and human Laron dwarfs with chronic low Igf-1 level do not develop malignancies at all. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Stem cells in liver repair

2006 ◽  
Vol 28 (1) ◽  
pp. 11-14
Author(s):  
Yiannis N. Kallis ◽  
Stuart J. Forbes
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Liver Regeneration ◽  
Liver Tissue ◽  
Metabolic Diseases ◽  
Viral Infections ◽  
Biliary Tree ◽  
Cell Compartment ◽  
Stem Cell Compartment

The liver can be subjected to many damaging insults, usually from toxins, viral infections, immune or metabolic diseases, during its lifetime. Normal restoration of liver tissue occurs via division of mature functional hepatocytes. In addition, a liver-stem-cell compartment, lying deep within the intrahepatic biliary tree, can be activated during severe or iterative stress. Recent studies have suggested that the bone marrow (BM) may also contribute to liver regeneration, although these observations remain controversial.

scholarly journals p53 activity is selectively licensed in the Drosophila stem cell compartment

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Annika Wylie ◽  
Wan-Jin Lu ◽  
Alejandro D’Brot ◽  
Michael Buszczak ◽  
John M Abrams
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Stem Cell ◽  
Tumor Suppression ◽  
Regulatory Network ◽  
Dna Breaks ◽  
Cell Compartment ◽  
Stem Cell Compartment ◽  
Oncogenic Stress

Oncogenic stress provokes tumor suppression by p53 but the extent to which this regulatory axis is conserved remains unknown. Using a biosensor to visualize p53 action, we find that Drosophila p53 is selectively active in gonadal stem cells after exposure to stressors that destabilize the genome. Similar p53 activity occurred in hyperplastic growths that were triggered either by the RasV12 oncoprotein or by failed differentiation programs. In a model of transient sterility, p53 was required for the recovery of fertility after stress, and entry into the cell cycle was delayed in p53- stem cells. Together, these observations establish that the stem cell compartment of the Drosophila germline is selectively licensed for stress-induced activation of the p53 regulatory network. Furthermore, the findings uncover ancestral links between p53 and aberrant proliferation that are independent of DNA breaks and predate evolution of the ARF/Mdm2 axis.

scholarly journals The kinetics of murine hematopoietic stem cells in vivo in response to prolonged increased mature blood cell production induced by granulocyte colony-stimulating factor

Blood ◽  
1995 ◽  
Vol 86 (8) ◽  
pp. 2986-2992 ◽  
Author(s):  
G de Haan ◽  
B Dontje ◽  
C Engel ◽  
M Loeffler ◽  
W Nijhof
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Blood Cells ◽  
Granulocyte Colony Stimulating Factor ◽  
Cell Compartment ◽  
Hematopoietic Stem ◽  
Cell Numbers ◽  
Stem Cell Compartment ◽  
Stimulating Factor

Abstract Because of the complexity of appropriate stem cell assays, little information on the in vivo regulation of murine stem cell biology or stemmatopoiesis is available. It is unknown whether and how in vivo the primitive hematopoietic stem cell compartment is affected during a continued increased production of mature blood cells. In this study, we present data showing that prolonged (3 weeks) administration of granulocyte colony-stimulating factor (G-CSF), which is a major regulator of mature granulocyte production, has a substantial impact on both the size and the location of various stem cell subset pools in mice. We have used the novel cobblestone area forming cell (CAFC) assay to assess the effects of G-CSF on the stem cell compartment (CAFC days 7, 14, 21, and 28). In marrow, in which normally 99% of the total number of stem cells can be found, G-CSF induced a severe depletion of particularly the most primitive stem cells to 5% to 10% of normal values. The response after 7 days of G-CSF treatment was an increased amplification between CAFC day 14 and 7. However, this response occurred at the expense of the number of CAFC day 14. It is likely that the resulting gap of CAFC day 14 cell numbers was subsequently replenished from the more primitive CAFC day 21 and 28 compartments, because these cell numbers remained low during the entire treatment period. In the spleen, the number of stem cells increased, likely caused by a migration from the marrow via the blood, leading to an accumulation in the spleen. The increased number of stem cells in the spleen overcompensated for the loss in the marrow. When total body (marrow and spleen) stem cell numbers were calculated, it appeared that a continued increased production of mature granulocytes resulted in the establishment of a higher, new steady state of the stem cell compartment; most committed stem cells (CAFC day 7) were increased threefold, CAFC day 14 were increased 2.3-fold, CAFC-day 21 were increased 1.8-fold, and the most primitive stem cells evaluated, CAFC day 28, were not different from normal, although now 95% of these cells were located in the spleen. Four weeks after discontinuation of the G-CSF treatment, the stem cell reserve in the spleen had returned to a normal level, whereas stem cell numbers in marrow had recovered to values above normal. This study shows that the primitive stem cell compartment is seriously perturbed during an increased stimulation of the production of mature blood cells.(ABSTRACT TRUNCATED AT 400 WORDS)

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