scholarly journals Bacterial infection drives trained immunity through epigenetic remodeling of epithelial stem cells

2021 ◽  
Author(s):  
Scott Hultgren ◽  
Seongmi Russell ◽  
Hyung Joo Lee ◽  
Benjamin Olson ◽  
Jonathan Livny ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Death ◽  
Bacterial Infection ◽  
Bacterial Infections ◽  
Inflammatory Cell ◽  
Host Susceptibility ◽  
Epithelial Stem Cells ◽  
Caspase 1

Abstract Recurrent bacterial infections are a major health burden worldwide, yet the mechanisms dictating host susceptibility to recurrence are poorly understood. Here we demonstrate that an initial bacterial infection of the urinary bladder with uropathogenic E. coli (UPEC) can induce sustained epigenetic changes in the bladder epithelial (urothelial) stem cells that reprogram the differentiated urothelium. We established urothelial stem cell (USC) lines from isogenic mice with different urinary tract infection histories (naïve, chronic or self-resolving). Differentiation of the USC lines in Transwell culture resulted in polarized urothelial cultures that recapitulated distinct remodeling morphologies seen in vivo. In addition, we discovered differences in chromatin accessibility that segregated by disease history, resulting in differences in gene expression upon differentiation of the USC lines in vitro, based on ATAC-seq analysis of the USC lines. Differential basal expression of Caspase-1 led to divergent susceptibilities to inflammatory cell death upon UPEC infection. In mice with a history of chronic infection, enhanced caspase 1-mediated inflammatory cell death was found to be a protective response that enhanced bacterial clearance upon challenge infection. Thus, UPEC infection reshapes the epigenome leading to epithelial-intrinsic remodeling that trains the mucosal immune response to subsequent infection. These findings may have broad implications for the prevention of chronic/recurrent bacterial infections.

scholarly journals Contribution of Host Immune Responses Against Influenza D Virus Infection Toward Secondary Bacterial Infection in a Mouse Model

Viruses ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 994 ◽  
Author(s):  
Raegan M. Skelton ◽  
Kelly M. Shepardson ◽  
Alexis Hatton ◽  
Patrick T. Wilson ◽  
Chithra Sreenivasan ◽  
...  
Keyword(s):  
Immune Responses ◽  
Bacterial Infection ◽  
Bacterial Infections ◽  
Clinical Signs ◽  
A549 Cells ◽  
Host Susceptibility ◽  
Secondary Bacterial Infection ◽  
Aureus Infection

Influenza D viruses (IDV) are known to co-circulate with viral and bacterial pathogens in cattle and other ruminants. Currently, there is limited knowledge regarding host responses to IDV infection and whether IDV infection affects host susceptibility to secondary bacterial infections. To begin to address this gap in knowledge, the current study utilized a combination of in vivo and in vitro approaches to evaluate host cellular responses against primary IDV infection and secondary bacterial infection with Staphylococcus aureus (S. aureus). Primary IDV infection in mice did not result in clinical signs of disease and it did not enhance the susceptibility to secondary S. aureus infection. Rather, IDV infection appeared to protect mice from the usual clinical features of secondary bacterial infection, as demonstrated by improved weight loss, survival, and recovery when compared to S. aureus infection alone. We found a notable increase in IFN-β expression following IDV infection while utilizing human alveolar epithelial A549 cells to analyze early anti-viral responses to IDV infection. These results demonstrate for the first time that IDV infection does not increase the susceptibility to secondary bacterial infection with S. aureus, with evidence that anti-viral immune responses during IDV infection might protect the host against these potentially deadly outcomes.

scholarly journals Adipose-Derived Mesenchymal Stem Cells Migrate and Rescue RPE in the Setting of Oxidative Stress

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Aya Barzelay ◽  
Shira Weisthal Algor ◽  
Anat Niztan ◽  
Sebastian Katz ◽  
Moshe Benhamou ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stem Cells ◽  
Cell Death ◽  
Mesenchymal Stem Cells ◽  
Conditioned Medium ◽  
Early Passage ◽  
Systemic Injection ◽  
Rpe Cells

Oxidative stress leads to the degeneration of retinal pigment epithelial (RPE) and photoreceptor cells. We evaluated the potential of adipose-derived mesenchymal stem cells (ASCs) as a therapeutic tool by studying the migration capacity of ASCs in vitro and their protective effect against RPE cell death under oxidative stress in vitro and in vivo. ASCs exhibited enhanced migration when exposed to conditioned medium of oxidative stressed RPE cells obtained by hydrogen peroxide. Migration-related axis SDF-1/CXCR4 was studied, and upregulation of SDF-1 in stressed RPE and of CXCR4 in ASCs was detected. Moreover, ASCs’ conditioned medium prevented H2O2-induced cell death of RPE cells. Early passage ASCs had high expression level of HGF, low VEGF levels, and unmodulated IL-1β levels, compared to late passage ASCs. Thus, early passage ASCs show the potential to migrate towards damaged RPE cells and protect them in a paracrine manner from cell death induced by oxidative stress. In vivo, mice received systemic injection of NaIO3, and 72 h later, ASCs were transplanted in the subretinal space. Seven days after ASC transplantation, the eyes were enucleated fixed and frozen for immunohistochemical analysis. Under such conditions, ASC-treated mice showed preservation of nuclear layers in the outer nuclear layer and stronger staining of RPE and photoreceptor layer, compared to PBS-treated mice. Taken together, our results indicate that ASCs are able to home in on damaged RPE cells and protect against damage to the RPE and PR layers caused by oxidative stress. These data imply the potential that ASCs have in regenerating RPE under oxidative stress, providing the basis for a therapeutic approach to retinal degeneration diseases related to oxidative stress that could help save the eyesight of millions of people worldwide.

In vitro and in vivo differentiation of amniotic epithelial stem cells into hepatocyte-like cells

Placenta ◽  
2011 ◽  
Vol 32 ◽  
pp. S336
Author(s):  
F. Marongiu ◽  
R. Gramignoli ◽  
S. Doratiotto ◽  
M. Serra ◽  
M. Sini ◽  
...  
Keyword(s):  
Stem Cells ◽  
Epithelial Stem Cells ◽  
In Vivo Differentiation

scholarly journals Lactobacillus rhamnosus GG protects the intestinal epithelium from radiation injury through release of lipoteichoic acid, macrophage activation and the migration of mesenchymal stem cells

Gut ◽  
2018 ◽  
Vol 68 (6) ◽  
pp. 1003-1013 ◽  
Author(s):  
Terrence E Riehl ◽  
David Alvarado ◽  
Xueping Ee ◽  
Aaron Zuckerman ◽  
Lynn Foster ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Lamina Propria ◽  
Lactobacillus Rhamnosus ◽  
Lipoteichoic Acid ◽  
Epithelial Stem Cells ◽  
Tlr2 Agonist ◽  
Cox 2

ObjectiveLactobacillus rhamnosus GG (LGG), a probiotic, given by gavage is radioprotective of the mouse intestine. LGG-induced radioprotection is toll-like receptor 2 (TLR2) and cyclooxygenase-2 (COX-2)-dependent and is associated with the migration of COX-2+mesenchymal stem cells (MSCs) from the lamina propria of the villus to the lamina propria near the crypt epithelial stem cells. Our goals were to define the mechanism of LGG radioprotection including identification of the TLR2 agonist, and the mechanism of the MSC migration and to determine the safety and efficacy of this approach in models relevant to clinical radiation therapy.DesignIntestinal radioprotection was modelled in vitro with cell lines and enteroids as well as in vivo by assaying clinical outcomes and crypt survival. Fractionated abdominal and single dose radiation were used along with syngeneic CT26 colon tumour grafts to assess tumour radioprotection.ResultsLGG with a mutation in the processing of lipoteichoic acid (LTA), a TLR2 agonist, was not radioprotective, while LTA agonist and native LGG were. An agonist of CXCR4 blocked LGG-induced MSC migration and LGG-induced radioprotection. LGG given by gavage induced expression of CXCL12, a CXCR4 agonist, in pericryptal macrophages and depletion of macrophages by clodronate liposomes blocked LGG-induced MSC migration and radioprotection. LTA effectively protected the normal intestinal crypt, but not tumours in fractionated radiation regimens.ConclusionsLGG acts as a ‘time-release capsule’ releasing radioprotective LTA. LTA then primes the epithelial stem cell niche to protect epithelial stem cells by triggering a multicellular, adaptive immune signalling cascade involving macrophages and PGE2 secreting MSCs.Trial registration numberNCT01790035; Pre-results.

scholarly journals Hairless is a nuclear receptor corepressor essential for skin function

2009 ◽  
Vol 7 (1) ◽  
pp. nrs.07010 ◽  
Author(s):  
Catherine C. Thompson
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Nuclear Receptors ◽  
Chromatin Remodeling ◽  
Transcriptional Repression ◽  
Critical Role ◽  
Epithelial Stem Cells ◽  
Skin Function

The activity of nuclear receptors is modulated by numerous coregulatory factors. Corepressors can either mediate the ability of nuclear receptors to repress transcription, or can inhibit transactivation by nuclear receptors. As we learn more about the mechanisms of transcriptional repression, the importance of repression by nuclear receptors in development and disease has become clear. The protein encoded by the mammalian Hairless (Hr) gene was shown to be a corepressor by virtue of its functional similarity to the well-established corepressors N-CoR and SMRT. Mutation of the Hr gene results in congenital hair loss in both mice and men. Investigation of Hairless function both in vitro and in mouse models in vivo has revealed a critical role in maintaining skin and hair by regulating the differentiation of epithelial stem cells, as well as a putative role in regulating gene expression via chromatin remodeling.

Elucidating the role of P63 during development of the mammalian nervous systems

2007 ◽  
Vol 30 (4) ◽  
pp. 79
Author(s):  
Sagar Dugani ◽  
Annie Paquin ◽  
David R. Kaplan ◽  
Freda D. Miller
Keyword(s):  
Stem Cells ◽  
Cell Death ◽  
Cortical Neurons ◽  
Sympathetic Neurons ◽  
Fold Increase ◽  
P53 Family ◽  
Ongoing Work ◽  
Cortical Precursors

Background: The protein p63, a recently discovered member of the p53 family of proteins, is implicated in the maintenance and differentiation of stem cells in the epidermis and is involved in the regulation of naturally-occurring cell death in sympathetic neurons of the peripheral nervous system. Since initial data from our laboratory indicated that p63 is also widely expressed in stem cells and neurons within the developing brain, we assessed its involvement in regulating the genesis and survival of developing cortical neurons. As neurogenesis is initiated at embryonic day 12 (E12), we isolated cortical precursors from p63-/- embryos at E14 and cultured them for 2 days in vitro (DIV). Methods: Based on immunocytochemistry to known markers of apoptosis and neurons, we assessed the level of cell death and neurogenesis. Results: Compared to p63+/+ cortical precursors, p63-/- precursors from littermates showed a 50 % reduction in neuronal death, as assessed by the apoptosis marker, cleaved caspase 3. Interestingly, the proportion of neurons and astrocyte precursors, the latter identified by S100b was also reduced in p63-/- embryos, as compared to p63+/+ littermates. Conclusions: These results suggest that p63 may be involved in the regulation of cell survival and in the differentiation of precursors into neurons and astrocytes. To assess the former, we overexpressed TAp63a, a full-length isoform of p63, in E12/13 cortical precursors and assessed the level of cell death after 2 DIV. Compared to control cells, cells transfected with TAp63a demonstrated a 2-fold increase in cell death. Ongoing work will characterize p63 involvement in differentiation of precursor cells into neurons and astrocytes. To assess if these findings are relevant in vivo, we will use p63flox,flox X Nextin-Cre mice, which have p63 specifically ablated in neural precursors. We will analyze the survival, proliferation, and fate of these p63-/- cells. Together, these studies will help to determine a role for p63 in neural proliferation and apoptosis, processes central to development and response to injury.

Abstract TP270: Adipose Derived Mesenchymal Stem Cells Reduce Autophagic Flux After Ischemic Stroke in Mice via Extracellular Vesicle Transfer of MiR-25-3p

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Yaoyun Kuang ◽  
Xuan Zheng ◽  
Lin Zhang ◽  
Irina Graf ◽  
Mathias Bähr ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Death ◽  
Mesenchymal Stem Cells ◽  
Glucose Deprivation ◽  
Neurological Recovery ◽  
Signaling Cascades ◽  
Autophagic Flux ◽  
Primary Neurons

Transplantation of mesenchymal stem cells (MSCs) yields neuroprotection and enhanced neurological recovery in pre-clinical stroke models, which is mediated by the secretion of extracellular vesicles (EVs). The latter are a heterogenous group of vesicles containing microvesicles, exosomes, and apoptotic bodies. The neuroprotective cargo of EVs, however, has not yet been identified. To investigate such a cargo and its underlying mechanism, we designed a series of in vitro and in vivo experiments. Primary neurons were exposed to oxygen-glucose-deprivation (OGD) and co-cultured with either adipose-derived MSCs (ADMSCs) or treated with ADMSC-secreted EVs. As expected, both ADMSCs and ADMSC-secreted EVs significantly reduced neuronal death after 12 h of OGD and 24 h of reoxygenation, showing no difference between the two treatment groups. Screening for various signaling cascades being involved in the interaction between ADMSCs and neurons revealed a decreased autophagic flux as well as a declined p53-Bnip3 activity. However, these signaling cascades were significantly blocked when ADMSCs were pretreated with the inhibitor of exosomal secretion GW4869. In light of miR-25-3p being the most highly expressed miRNA in ADMSC-EVs interacting with the p53 pathway, further in vitro work focused on this pathway. Treatment with a miR-25-3p oligonucleotide mimic reduced cell death, whereas the anti-oligonucleotide increased autophagic flux and cell death by modulating p53-Bnip3 signaling in primary neurons exposed to OGD. Likewise, native ADMSC-EVs but not EVs obtained from ADMSCs pretreated with the anti-miR-25-3p oligonucleotide (ADMSC-EVs anti-miR-25-3p ) confirmed the aforementioned in vitro observations in C57BL6 mice exposed to cerebral ischemia. Infarct size was reduced and neurological recovery was increased in mice treated with native ADMSC-EVs when compared to ADMSC-EVs anti-miR-25-3p . As such, ADMSCs induce neuroprotection - at least in part - by improved autophagic flux through secreted EVs containing miR-25-3p. Hence, our work for the first time uncovers a key factor in naturally secreted ADMSC-EVs for the regulation of autophagy and induction of neuroprotection in a pre-clinical stroke model.

Abstract 130: Ox-LDL Impairs The Survival Of Bone Marrow Stem Cells Partially Through Membrane Damage Independent Of ROS Production In Vitro

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Xin Li ◽  
Yuan Xiao ◽  
Yuqi Cui ◽  
Hua Zhu ◽  
Chandrakala A Narasimhulu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Cell Death ◽  
Membrane Damage ◽  
Final Concentration ◽  
Bone Marrow Stem Cells ◽  
Cell Membrane Damage ◽  
Cell Based Therapy

Aims: cell-based therapy with bone marrow stem cells (MSCs) remains a viable option for tissue repair and regeneration. One of the major challenges for cell-based therapy is the limited survival of the cells after in vivo administration. The exact mechanism(s) for impaired in vivo survival of the implanted MSCs remains to be defined. Oxidized low-density lipid protein (ox-LDL) is a natural product in human blood, and the major contributor to the development of atherosclerosis. The present study was to investigate the effect of ox-LDL on the survival of bone marrow stem cells and the mechanisms in vitro. Methods and Results: Rat bone marrow multipotent adult progenitor cells (MAPCs) were treated with ox-LDL (with the final concentration of 10 and 20 ug/ml) for up to 48 hours. Exposure to ox-LDL resulted in significant cell death and apoptosis of MAPCs in association with a significant increase in LDH release in the conditioned media in a dose- and time-dependent manner, indicating significant cell membrane damage. The membrane damage was further confirmed with the rapid entry of the small fluorescent dye FM1-43 as detected using confocal microscope. Ox-LDL generated a significant amount of reactive oxygen species (ROS) in the culture system as measured with electron paramagnetic resonance spectroscopy. The antioxidant N-acetylcysteine (NAC, 0.1 mM) completely inhibited the production of ROS from ox-LDL. However, it didn’t prevent ox-LDL-induced cell death or apoptosis. However, pre-treatment of the cells with the specific membrane protective recombinant human MG53 protein (rhMG53)(66 ug/ml, final concentration) significantly, reduced LDH release and the entry of FM1-43 dye into the cells exposed to ox-LDL. Conclusion: Ox-LDL enhanced cell death and apoptosis of MAPCs with a mechanism independent of ROS generation in vitro. Ox-LDL impaired the survival of MAPCs partially through cell membrane damage in vitro.

Growth Factor Independence 1 (Gfi1) Is An Essential Factor for the Development of Lymphoma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 297-297
Author(s):  
Cyrus Khandanpour ◽  
Ehssan Sharif- Askari ◽  
Paul Jolicoeur ◽  
Ulrich Duehrsen ◽  
Tarik Moroy
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Cell Death ◽  
T Cell ◽  
Cell Lymphoma ◽  
Latency Period ◽  
T Cell Lymphoma ◽  
Hematopoietic Stem

Abstract Hematopoietic differentiation is controlled to a large extent by a network of transcription factors and chromatin modifiers and disruption of this system can lead to leukemia or lymphoma. One of the transcription factor genes, which is aberrantly expressed in human T-cell lymphoma is Growth Factor Independence 1 (Gfi1). Since over expression of Gfi1 can accelerate experimentally induced T-cell tumors in mice, it is likely that Gfi1 plays a crucial role in establishing or maintaining lymphoid neoplasms. To test this hypothesis we have used, N-ethyl-N-nitrosourea (ENU) to induce T-cell tumors in WT mice (Gfi1+/+), Gfi1-deficient mice (Gfi1−/−) or mice transgenically over expressing Gfi1 under the control of the pan-hematopoietic vav-promoter (vav-Gfi1). As expected, most of Gfi1+/+ mice (25/27) developed T-cell tumors and acute myeloid leukemia within 118 days. Similarly, vav-Gfi1 mice (10/10) developed T-cell lymphoma, but within a shorter latency period (88 days). In contrast, only 3/14 Gfi1−/− mice developed hematopoietic neoplasia with a prolonged median latency period of 126 days. Other approaches using infection of newborn mice with Moloney Murine leukemia virus (MoMuLV) to induce T-cell lymphoma or co expression of an Eμ-myc transgene to induce B-cell lymphoma showed a similar dependency of tumor formation on the presence and expression of Gfi1. Closer analysis of tumors forming in Gfi1−/− mice demonstrated that Gfi1 deficiency correlated with a smaller size of the tumors and a noticeably increased rate of cell death within the tumor samples. This pointed to a potential role of Gfi1 in the regulation of apoptosis. To explore this hypothesis, we exposed both thymocytes and hematopoietic stem cells (Lin-, Sca1+, c-kit+, LSK) to ENU or gamma-irradiation in vitro. We could observe that Gfi1−/− thymocytes and stem cells (LSK cells) have a higher rate of cell death following exposure to these DNA damage inducing agents in vitro than the WT controls. To validate these results, we recapitulated these experiments in vivo. Gfi1−/− mice exhibited severe bone marrow failure and a more pronounced loss of hematopoietic stem cells (LSK) than Gfi1+/+ mice after ENU treatment or gamma irradiation in vivo. To explore this mechanism on the molecular basis we evaluated expression of the different pro and antiapoptotic components in Gfi1+/+ and Gfi1−/− thymocytes after irradiation. Strikingly, Gfi1−/− thymocytes expressed higher levels of the pro-apoptotic proteins such as Bax and Noxa and lower levels of the CDK inhibitor p21WAF than WT thymocytes following induction of DNA damage. Our model would be that Gfi1 represents a new regulator in the cellular response to DNA damage in the hematopoietic system by inhibiting different proapoptotic factors. We propose that Gfi1 is essential for the development of lymphoid and potentially myeloid neoplasms by inhibiting apoptosis. We suggest that Gfi1 could represent a possible new target structure for therapeutic intervention.

scholarly journals Mesenchymal Stem Cells Attenuate Radiation-Induced Brain Injury by Inhibiting Microglia Pyroptosis

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Huan Liao ◽  
Hongxuan Wang ◽  
Xiaoming Rong ◽  
Enqin Li ◽  
Ren-He Xu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Brain Injury ◽  
Inflammasome Activation ◽  
Rt Pcr ◽  
Caspase 1 ◽  
Radiation Induced ◽  
The Impact

Radiation-induced brain injury (RI) commonly occurs in patients who received head and neck radiotherapy. However, the mechanism of RI remains unclear. We aimed to evaluate whether pyroptosis was involved in RI and the impact of mesenchymal stem cells (MSCs) on it. BALB/c male mice (6–8 weeks) were cranially irradiated (15 Gy), and MSCs were transplanted into the bilateral cortex 2 days later; then mice were sacrificed 1 month later. Meanwhile, irradiated BV-2 microglia cells (10 Gy) were cocultured with MSCs for 24 hours. We observed that irradiated mice brains presented NLRP3 and caspase-1 activation. RT-PCR then indicated that it mainly occurred in microglia cells but not in neurons. Further, irradiated BV-2 cells showed pyroptosis and increased production of IL-18 and IL-1β. RT-PCR also demonstrated an increased expression of several inflammasome genes in irradiated BV-2 cells, including NLRP3 and AIM2. Particularly, NLRP3 was activated. Knockdown of NLRP3 resulted in decreased LDH release. Noteworthily, in vivo, MSCs transplantation alleviated radiation-induced NLRP3 and caspase-1 activation. Moreover, in vitro, MSCs could decrease caspase-1 dependent pyroptosis, NLRP3 inflammasome activation, and ROS production induced by radiation. Thus, our findings proved that microglia pyroptosis occurred in RI. MSCs may act as a potent therapeutic tool in attenuating pyroptosis.

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